Preparation of Tetradentate Copper Chelators as Potential Anti-Alzheimer Agents

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

Preparation of new tetradentate copper chelators as potential

anti-Alzheimer agents.

[

a]‡

[a]‡

[a]

Weixin Zhang, Daya Huang, Meijie Huang, Ju Huang, Dean Wang, Xingguo Liu, Michel

[

b]

[b]

[c]

[b]

[a]

[a,b]

Nguyen, Laure Vendier, Serge Mazères, Anne Robert,* Yan Liu,* Bernard Meunier*

[

a]

Weixin Zhang, Daya Huang, Meijie Huang, Ju Huang, Dean Wang, Dr. Xingguo Liu, Prof. Yan Liu, Prof. Bernard Meunier

School of Chemical Engineering and Light Industry

Guangdong University of Technology (GDUT)

n° 100 Waihuan Xi road, Education Mega Center, Guangzhou, P. R. China.

E-mail: Yan Liu yanliu@gdut.edu.cn

[

b]

c]

Dr. Michel Nguyen, Dr. Laure Vendier, Dr. Anne Robert, Prof. Bernard Meunier

Laboratoire de Chimie de Coordination du CNRS

Centre National de la Recherche Scientifique

205 route de Narbonne, BP 44099, 31077 Toulouse cedex 4, France.

E-mail: Anne Robert anne.robert@lcc-toulouse.fr; Bernard Meunier bmeunier@lcc-toulouse.fr

Dr. Serge Mazères

[

Institut de Pharmacologie et Biologie Structurale

Centre National de la Recherche Scientifique

205 route de Narbonne, BP 64182, 31077 Toulouse cedex 4, France.

‡

These authors equally contributed to the present work.

Supporting information for this article is given via a link at the end of the document.

[

3]

Abstract: The non-controlled redox activity of metal ions, especially

copper, in the brain of patients with Alzheimer's disease (AD) should

be considered at the origin of the intense oxidative damage on

neurons in AD brain. In order to obtain low molecular weight copper

chelators acting as tetradentate ligands, we designed new

compounds based on an 8-aminoquinoline motif with a lateral chain

attached at the position 2 of the aromatic ring. Some of these new

ligands, named TDMQ for TetraDentate MonoQuinolines, are

specific for copper chelation. Full characterization of these ligands

are reported in the present article, as well as their affinities for Cu(II),

and their capacities to inhibit oxidative stress induced by copper-

amyloids activated by a reductant. Such metal ligands can be

considered as potential anti-AD agents, are able to regulate the

homeostasis of copper in brains.

down the neurodegenerative process. Originality of projects

should be favored to avoid to use the same tracks that produced

failures over the past 15 years.

AD is characterized by abnormal deposition of the amyloid

proteins (A) and hyperphosphorylated tau proteins, both

proteins have been considered as the main drug targets up to

now. A priority is to enlarge the panel of drug targets for this

aging disease induced by many different parameters. Moreover,

the general use of transgenic mouse models that do not

accurately reflect the human pathogenesis of that non-genetic

disease is probably one of the reasons of the failures of AD-drug

[

4]

candidates. AD is a multi-parameter disease outside of the

simple concept "one disease, one target-protein, one drug".

[

5]

There are extensive evidences linking AD to (i) tau pathology, (ii)

A-aggregation and (iii) metal dysregulation. These three targets

are probably interconnected. For instance, excessive A

production from -amyloid precursor protein (APP) has been

considered important, but amyloid aggregates alone is not a

Introduction

[

6]

sufficient cause of disease.

Currently, millions of patients are suffering from Alzheimer's

disease (AD), a neurodegenerative disease related to aging, and

Considering that the rupture of metal homeostasis in the

brain of AD patients is at the origin of the redox stress that

reduces the neuron population, we decided to focus our project

on the design of new tetradentate ligands able to chelate copper

ions trapped by amyloids. The post-mortem analysis of amyloid

plaques indicates an excessive accumulation of copper, iron and

zinc by 5.7, 2.9 and 2.8 times the levels observed in normal

Cu-amyloids, in the presence of

endogeneous reductants, should induce the reduction of

[

1]

this number is expected to reach 100 million in 2050. The

pathology duration (5 to 8 years) generates considerable painful

loads on patients, families, caregivers and on public health

costs. The search for efficient anti-AD therapies is currently one

of the main challenges in drug discovery. Current AD therapies

are based on few acetylcholine esterase (AChE) inhibitors and

memantine, a weak antagonist of the N-methyl-D-aspartate

[7]

brains, respectively.

(

NMDA) receptor. These drugs are not curative, and they have

dioxygen and produce reactive oxygen species (ROS) involved

The possibility of use metal chelators to

regenerate normal trafficking of metal ions has been presented

side effects and questionable efficiency/cost ratios. Since 2003,

no new AD drug has been approved by FDA. With the only

exception of memantine, approved in 2003, all AD clinical trials

undertaken from 2002 to 2012 with 244 new compounds failed

[8-10]

in neuron death.

[11-14]

in recent review articles.

To restore metal homeostasis in AD-brain, mild chelators

should be able to extract copper ions from sinks (amyloids being

the major one) and transfer them to copper-carrier proteins.

Bidentate ligands like clioquinol (CQ) and PBT2 form ternary

[

2]

at different stages. By comparison, the success rate is 20% for

[

2]

drugs for cardiovascular diseases. Therefore, there is an

urgent need for new disease-modifying therapies to stop or slow

1

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

complexes with Cu-amyloids, and for this reason, are not able to

concentrated nitric- and sulfuric acids. TDMQ5 and 14 were

prepared from the 3,5-dichloro- or 3,5-dimethylaniline,

respectively (Scheme 1, compound B). The 8-nitroquinoline

precursors were then reduced by metallic iron associated with

acetic acid, to provide the 8-amino-2-methylquinoline derivatives

(compound E).

[15-19]

extract copper from Cu-amyloids.

Tetradendate ligands of

the PA1637 series efficiently regulate copper homeostasis and,

[15-19]

consequently, inhibit ROS production induced by Cu-A.

However, in order to reduce the size and the molecular weight of

these bis-aminoquinoline ligands for facilitating their passage

through the blood-brain-barrier (BBB), we designed new

tetradentate copper ligands based on a monoquinoline motif.

These

ligands

named

“TDMQ”

for

“TetraDentate

[20]

MonoQuinolines” (Figure 1) are based on a 8-aminoquinoline

Table 1. Modulation of the structure of tetradentate mono-8-aminoquinoline

skeleton, substituted at C2 by a bis-chelating side chain (the

distal substituent R containing at least one coordinating atom).

1

Several 8-hydroxyquinoline analogues are also reported for

comparison.

The chelating capacities of these ligands have been

evaluated. The affinity constants for copper of a series of TDMQ

are in the range 14-17 (log units). TDMQ20 and 22 exhibited the

highest Cu/Zn selectivity, thus supporting their capacity to

extract the excess of copper ions linked to amyloids without

disturbing zinc homeostasis. So, in-depth studies were carried

out on TDMQ20 and 22. TDMQ5 and 19, having the same

quinoline moiety, but different side chains as TDMQ20, and

TDMQ16 (similarly related to TDMQ22), were used as

comparators in order to link structural features of these ligands

to their ability to regulate copper homeostasis, and to inhibit the

production of reactive oxygen species triggered by Cu-amyloids

when exposed to a reducting agent.

2

Figure 1. General structure of TDMQ ligands (8-amino-: X = NH , or 8-

hydroxy: X = OH).

Results and Discussion

Synthesis and characterization

Structural modulations of the 8-aminoquinoline series were

carried out by preparing compounds having (i) different

substituents on the quinoline nucleus (R, Figure 1), (ii) variable

length of the side chain [variable proximal (n) and distal (m)

methylene units] and (iii) different distal substituents R . A short

1

series of 8-hydroxyquinolines was also prepared for comparison.

The structures of all these new ligands are reported in Table 1.

Modulation of the quinoline ring substituents. The

masterpiece of the syntheses of TDMQ4-6, 8-16, and TDMQ18

(

Table 1a) was the corresponding 8-nitro-2-methylquinoline

Scheme 1, compound A). However, this derivative was

commercially available only for TDMQ4, i.e. without substituent.

The reaction of the suitably substituted 2-nitroaniline (Scheme 1,

compound D) with acetaldehyde in concentrated hydrochloric

acid allowed to prepare the 8-nitroquinoline precursors of

TDMQ6, 8-13, and 16. The ligand TDMQ18 was prepared by

nitration at C8 of the commercially available 4-chloro-2-

methylquinoline (Scheme 1, compound C) in a mixture of

Scheme 1. General scheme of the syntheses of TDMQ4-6, 8-16, and 18. (a)

o

[

21]

CH CHO/12 N HCl, 4 h; (b) NHO /H SO , rt, 2 h; (c) Fe, AcOH, EtOH, 80 C, 4

3

2

4

o

h; or SnCl

h; (d) AcCl, Pr

2

•2H

2

O, HCl, EtOH, 50 C, 1 h; or Na

2

S•9H

2

O, NH

4

Cl, MeOH, 65 C,

i

o

5

2

NEt, CH

2

Cl

2

, rt, 12 h; or Boc

2

O, 1,4-dioxane, 80 C, 12 h; (e)

2

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

o

SeO

h, then NaBH(OAc)

EtOAc.

2

,1,4-dioxane, 80 C, 12 h; (f) NH

2

(CH

2

)

n

N(CH

3

)

2

(n=0 or 1), CH

3

CHCl

2

, Ar,

O,

clioquinol and PBT2 chelators were based on

hydroxyquinoline skeleton.

3

a

8-

The 8-hydroxyquinolines TDMQ1-

(Table 1) were prepared from the corresponding 2-methyl-8-

1

3

, 12 h, then HCl, CH

2

Cl ; or TFA, CH

2

Cl ; (g) HCl/ Et

2

[11]

hydroxyquinoline or 2-aminophenol (compounds M, or L,

respectively, Scheme 3). Oxidation of the methyl at C2 and

introduction of the side chain by reductive amination, followed by

protonation, were carried out as described above for TDMQ4-6,

After protection of the aniline nitrogen by acetate or

butoxycarbonyl (compound F), the 2-methyl group was oxidized

to an aldehyde by selenium dioxide (compound G). The side

chain was introduced by reductive amination of the aldehyde

function by N,N-dimethyl-1,2-ethanediamine in the presence of

triacetoxyborohydride. In situ deprotection yielded the free base

ligands H. After purification, they were protonated in an etherate

solution of hydrochloric acid.

8-16, and 18.

Chemical stability

The thermal, air and light stabilities of TDMQ5, -20 and -22 were

evaluated. In solid state, these ligands were stable upon storage

at room temperature under air for 6 months, without any

1

detectable change in HPLC and H NMR analyses. They were

Modulation of the side chain. TDMQ19 (m = 3) was prepared

as follows. The reaction of 5,7-dichloro-2-methylquinolin-8-ol

with 2-bromo-2-methylpropionamide resulted in substitution of

the hydroxy function at C8 by a protected 8-amino function.

From this intermediate, the method used to synthesize TDMQ19

was an adaptation of that above reported for its analogue

TDMQ5 (details are provided in Scheme S1). The synthesis of

TDMQ20-27 is reported in Scheme 2. These compounds were

also prepared from the 2-methyl-8-nitroquinolines, which were

prepared as reported in Scheme 1, from the corresponding

anilines B (for TDMQ20-21) or 2-nitroanilines D (for TDMQ22-

2

also stable after 4 weeks in solution in D O at room temperature,

under air and light (checked by H NMR and HPLC).

1

27), respectively. Subsequent functionalization of substituted 2-

methyl-8-nitroquinolines with ferric chloride and potassium

persulfate in N,N-dimethylacetamide (DMA) afforded 8-nitro-2-

vinylquinolines (compound I). Reaction of 8-nitro-2-vinylquinoline

with amine side chain (compound J), followed by reduction of

the nitro group at C8, provided the tetradentate ligands K.

Protonation of these free base ligands with hydrogen chloride

afforded TDMQ20-27.

3

Scheme 3. General scheme of the syntheses of TDMQ1-3. (a) CH CHO/12 M

HCl,

4

h; (b) SeO

Cl

2

,1,4-dioxane, 80 °C, 12 h; (c) N,N-dimethyl-1,2-

, Ar, 1 h, then NaBH(OAc) , 12 h; (d) HCl, Et O.

ethanediamine, CH

2

3

2

pKa and logP values of the TDMQ ligands

The single experimental pK value of a 2-alkyl-8-aminoquinoline

derivatives bearing no R substituent was previously reported to

a

[

16]

be in the range 3.1-3.3. The withdrawing R substituents, like

the 5,7-dichloro- (TDMQ5, and TDMQ19-21) are expected to

significantly decrease the pK

The pK of the side chain nitrogen atoms of the present series

were calculated.

a

of the 8-aminoquinoline moiety.

a

[

22]

They were found to only dependent on the

length of the proximal (n = 1 or 2) or distal (m = 1, 2 or 3) parts

of the side chain, but not on the substituents of the quinoline

moiety, including 8-hydroxy vs. 8-amino. With a short proximal

chain (n = 1, TDMQ5 and -19), the pK

was 8.5-8.7, while it was in the range of 9.5-9.7 with a longer

distal chain (n = 2, TDMQ20 and -21). The pK of the distal

a

of the proximal nitrogen

Scheme 2. General scheme of the syntheses of TDMQ20-27. (a) FeCl

3

,

a

o

K

2

S

2

O

8

, N,N-dimethylacetamide (DMA), 110 C, 1.5 h; (b) NH

2

CH

2

R

1

, K

2

CO

3

nitrogen was 8.3 when m = 2 (TDMQ5 and -20), and 9.4 when m

= 3 (TDMQ19 and -21). In these conditions, the specificity of the

coordination of metal ions by these ligands at physiological pH

was expected to be dependent mainly of steric factors. In

addition, the calculated logP values of TDMQ5, and 19-23 were

in the range 2.2-2.6, a conducive condition for blood-brain

o

1,4-dioxane, 1 h; (c) Fe, AcOH, EtOH, 80 C, 4 h; or SnCl

2

•2H O, HCl, EtOH,

Cl, MeOH, 65 C, 5 h; (d) HCl/Et O, EtOAc.

2

o

50 C, 1 h; or Na

2

S•9H

2

O, NH

4

2

8

-Hydroxyquinoline series. Three 8-hydroxyquinoline were

also synthesized in order to compare their properties to those of

-aminoquinoline. Please take note that the previously used

[

23]

barrier penetration. Consequently, we carried out an in-depth

study specially with TDMQ5 and TDMQ19-22.

8

3

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

(

EDA) or nitriloacetic acid (NTA) as competitive chelator (C), as

[

16]

Solubility

previously reported.

amounts of TDMQ, Cu

saline pH 7.4/methanol, 1/1, v/v, log Kapp [Cu -TDMQ] was

In

a

solution containing equimolar

2

+

The solubilities of TDMQ5, -20, and -22 in water at room

temperature were 19 mg/mL, 15.8 mg/mL and 46.7 mg/mL,

respectively. As expected for hydrochloric salts, their solubility in

ethanol was lower than in water: 0.1, 0.4, and 0.7 mg/mL for

TDMQ5, -20, and -22, respectively.

II

0

.7

.6

.5

0

.08

.06

350 nm

TDMQ19

Metal chelation by TDMQ ligands

II

Cu -TDMQ19 / NTA, 1/1

Complexation of TDMQ ligands by Cu(II) or Zn(II) in solution.

0.04

II

Cu -TDMQ19

II

The ability of TDMQ ligands to chelate metals Cu and Zn was

monitored by using UV-visible titration of the aminoquinoline ring

0.4

0.3

0

.02

0

[

16,24,25]

(

230-400 nm),

as previously reported.

Spectral

3

20

340

360

380

400

modifications upon addition of aliquots of concentrated aqueous

0

.2

.1

0

Wavelength / nm

2

+

2+

solutions of Cu , or Zn salts were recorded and considered

significant for the metal complexation by the TDMQ ligand.

Stoichiometry of the Cu(II) complexes. In all cases, upon

0

2

+

addition of Cu

Tris·HCl buffer, pH 7.4), spectral changes were immediately

200

250

300

350

400

450

Wavelength / nm

2

+

observed from 0.25 to 1 mole equivalent of Cu , as the result of

a fast and complete complexation. No further changes were

II

Figure 3. Determination of log Kapp of Cu -TDMQ19 by using UV-visible

spectrometry in Tris-buffered saline pH 7.4. Dashed line: TDMQ19, grey line:

Cu /TDMQ19 = 1/1, black line: Cu /TDMQ19/NTA = 1/1/1.

2

+

observed when an excess of Cu was added (up to 2-4 mole

equivalents with respect to the ligand). Observation of isosbestic

points is in agreement with the formation of a single Cu(II)

complex with a stoichiometry metal/ligand = 1/1. As a matter of

2+

2

+

Table 2.

Affinity constants of TDMQ ligands for Cu(II) and Zn(II).

Selectivity for Cu(II) with respect to Zn(II).

example, the titration of TDMQ19 by Cu is reported in Figure 2.

The absorbance at 257 and 340 nm of the free ligand (Figure 2,

dashed line) disappeared in favor of a band at 240 nm assigned

II

to the Cu –TDMQ19 complex. Isosbestic points are well defined

_

_________________________________________

at 250, 271, and 333 nm. The plot of absorbance at 320 nm

a

b

2

+

TDMQn

n =

log Kapp [M-L]

M = Cu

Selectivity

Cu /Zn

versus the number of Cu mole equivalents confirms that the

stoichiometry of the complex is metal/ligand 1/1, as previously

reported for bis(8-aminoquinolines).

II

M = Zn

_

_________________________________________

1

4

14.0

14.4

16.5

15.1

16.0

15.9

8.5

9.4

4.2

4.1

6.0

5.7

5.5

5.0

12.3

11.0

10.0

10.2

1

5

0

.8

.7

.6

.5

.4

.3

.2

.1

0

2

40

0

.11

20

22

0.09

0.07

0.05

0.03

2

4

27

2

57

4

11.7

9.8

10.6

10.2

9.7

10.8

10.2

10.4

10.0

10.5

10.2

8.1

5.3

4.2

5.9

4.7

4.5

5.6

4.7

4.6

4.5

5.1

< 3

6.4

5.6

4.7

5.5

5.2

5.5

5.8

5.5

0

1

2

3

4

5

8

9

2+

Cu /TDMQ19 molar ratio

333

1

0

340

250

11

12

2

71

1

3

2

00

250

300

Wavelength / nm

350

400

1

6

1

8

5.4

1

9

> 7.2

> 5.1

> 6.3

> 5.7

2

1

Figure 2. Titration of TDMQ19 (15 μM) from 0 (dashed line) to 4 mole

equivalent of Cu in Tris-buffered saline pH 7.4. Insert: Absorbance at 320 nm

against the Cu / TDMQ19 mole ratio. Arrows indicate the decrease of free

TDMQ19 (257 nm) and increase of Cu(II)-TDMQ19 (240 nm).

23

26

9.3

8.7

2

+

2+

--------------------------------------------------------------

For comparison: 8-hydroxyquinolines TDMQn

n =

1

2

3

15.8

15.0

15.9

13.6

10.0

9.6

2.2

5.0

6.3

Affinity of TDMQ ligands for Cu(II). The affinity constants of Cu(II)

for TDMQ ligands were measured by UV-visible spectrometry,

using ethylene diamine tetracetic acid (EDTA), ethylenediamine

_

_________________________________________

a

Evaluated by UV-visible spectrometry in the presence

of a competitor, except otherwise stated.

Measured as log K [Cu -TDMQ]–log K [Zn -TDMQ].

N,N'-diacetic

acid

(EDDA),

ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA), 1,2-

cyclohexylenedinitrilotetraacetic acid (CDTA), ethylene diamine

b

II

4

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

II

calculated from log Kapp [Cu -C] in these conditions (17.1 where

C = CDTA, 15.9 where C = EDTA, 14.5 where C = EGTA, 13.9

where C = EDDA, 10.3 where C = NTA, and 7.8 where C =

2

+

Tris·HCl buffer, pH 7.4), 20-40 mole equivalent of Zn were

required to saturate the ligand, indicating that free- and chelated

Zn were in equilibrium in the UV-visible concentration, as the

result of a low affinity of Zn(II) for these ligands. In these cases,

the affinity constant of Zn(II) was calculated from the mole ratio

[

26]

II

EDA)

and the proportion of Cu -TDMQ evaluated at

equilibrium. The evaluation of the affinity of Cu(II) for TDMQ19 in

the presence of NTA is depicted in Figure 3. In the presence of

TDMQ19/Cu/NTA = 1/1/1, the proportion of Cu(II) ligated by

2

+

[28]

Zn /L required to achieve half metallation.

For instance, the

II

2+

TDMQ19 was 47 % (Figure 3). So, calculated log Kapp [Cu -

titration of TDMQ5 by Zn is reported in Figure 4.

II

TDMQ19] was 10.2. The log Kapp [Cu -L] values, for TDMQ

243

ligands are reported in Table 2. TDMQ4, bearing no substituent

on the quinoline ring, having a side chain with n=1, m=2, and a

distal N,N-dimethylamine, exhibited an affinity value for Cu(II) =

0

.6

0.07

Equiv

_Z_n2+/TDMQ5

0.5

0.4

0.3

257

0.06

0.05

0.04

0

1

1.7, slightly above the reported affinities the reported affinities

[

27]

½ metallation

-

amyloids for copper (log Kapp =10–11). Ligands bearing

methyl substituent(s) on the quinoline ring exhibited

significantly higher affinity for Cu(II) (log Kapp [Cu -L] = 14.0 and

a

II

5

14.4 for (TDMQ14, and -15, respectively).

0

10

20

30

40

50

0

.2

10

Zn²⁺/ TDMQ5 molar ratio

Substitution of the quinoline ring by one or several electron

309

withdrawing substituent(s) resulted in a lower affinity for Cu(II):

330

340

276

II

0.1

0

250

log Kapp [Cu -L] = 9.7 to 10.8 for TDMQ5, 8, 9, 10, 11, 12, 13, 16,

and -18, whose quinoline was substituted by 5,7-Cl

2

, 5-F, 6-F,

5

,6-Cl , 5-Cl, 6-Cl, 7-Cl, 6-CF , and 4-Cl, respectively. More

2

3

2

00

250

300

350

400

450

importantly, the affinity for Cu(II) was drastically modulated by

the side chain. The values of log Kapp were 9.8, 10.2, and 16.5

for TDMQ5 (n=1, m=2), TDMQ19 (n=1, m=3), and TDMQ20

Wavelength / nm

Figure 4. Titration of TDMQ5 from 0 (dashed trace) to 100 mole equivalent of

Zn , in Tris-buffered saline pH 7.4/methanol, 1/1, v/v. Insert Absorbance at

320 nm against the Zn /TDMQ5 mole ratio. Arrows indicate the decrease of

free TDMQ5 (257 nm) and increase of Zn(II)-TDMQ5 (243 nm).

(

n=2, m=2), respectively. This indicates that increasing the

2+

length of the proximal part of the side chain (TDMQ20 compared

to -19), but not the distal part (TDMQ19 compared to TDMQ5),

resulted in increasing the affinity for Cu(II) by ca. 6 orders of

magnitude. In addition, TDMQ20 having such an aliphatic

diamine side chain (equal distal and proximal chains with two

methylene residues each) seems to be an optimal feature: a

further increase of the distal chain resulting in a drastically lower

The absorbances of the free TDMQ5 at 257 and 340

disappeared upon addition of Zn, and the Zn(II) complex of

TDMQ5 was detected at 243 and 309 nm. Isosbestic points

were well defined at 250, 276, and 330 nm. Half-metallation was

achieved upon addition of 4 mole equivalents of Zn (Figure 4,

Insert), and the calculated value of log Kapp [Zn -TDMQ5] was

.2. All ligands TDMQ4, 5, 8, 9, 10, 11, 12, 13, 16, 20 and -22

had log Kapp [Zn -L] in the range 4-6. With ligands TDMQ19, 21,

3, and -26, addition of up to 1000 mole equivalents of Zn did

not allow to saturate the ligand. In these cases, log Kapp [Zn -L]

values were below 3. On the contrary, with TDMQ14, and -15,

spectral changes were immediately observed from 0.25 to 1

mole equivalent of Zn , as the result of a fast and complete

complexation. In these cases, log Kapp [Zn -L] values were

evaluated in the presence of a competitive chelator, as reported

above for copper, and found in the range 8.5-9.4 (Table 2).

In conclusion, except when the quinoline ring was

substituted by methyl groups (TDMQ14 and -15), the affinity of

II

log Kapp (Cu -TDMQ21 = 8.1, n=2, m=3). A similar trend was

2

+

observed for ligands TDMQ16, TDMQ22, and TDMQ23, bearing

II

a 6-CF

and (n=2, m=3), respectively. The log Kapp [Cu -L] values were

0.0, 15.1, and 9.3, respectively, thus confirming that a “(2 + 2)

3

-quinoline, but side chains with (n=1, m=2), (n=2, m=2),

II

4

II

1

2

+

2

diamine side chain” should be a preferred configuration. Finally,

ligands bearing an aromatic amine as distal substituent (2-

pyridyl or 2-pyrimidyl in TDMQ24 or TDMQ27, respectively)

exhibited a Cu(II) affinity close to 16, in the same range than that

of ligands with an aliphatic side chain. Contrary to aromatic

II

2

+

II

amines, a distal 2-furanyl resulted in a lower affinity for copper

II

(

log Kapp [Cu - TDMQ26 = 8.7]).

These results indicate that the modulation of the structure,

especially the side chain, allows to modulate the affinity of these

ligands for Cu(II). In several cases, the affinity values are 5–6

the ligands for Zn(II) was below 6. For example, the log Kapp

-

amyloids

II

[

27]

[

Zn -L] values were found in the range 4.2 to 4.7 for TDMQ5, 9,

for copper (log Kapp =10–11). Consequently, these TDMQ are

expected to extract any adventitious copper ions chelated by β-

amyloids in AD brains.

1

0, 12, 13, and -16, with quinoline skeleton substituted by 5,7-

Cl , 6-F, 5,6-Cl , 6-Cl, 7-Cl, and 6-CF , respectively. In addition,

with 6-CF or 5,7-dichloroquinoline, the zinc affinity

2

3

a

3

-

a

remained below 4.2, whatever the length of the alkyl diamine

side chain, (Table 2, TDMQ16, TDMQ5, and TDMQ19-23).

These values are below the affinity of many proteins for Zn(II)

Titration of TDMQ ligands by ZnCl

2

and affinity constants of

Zn(II) for TDMQ ligands. Titration of each ligand was achieved

2

+

by addition of Zn and monitored by UV-visible spectrometry in

[

29]

2

+

II

(

log Kapp [Zn-HSA] = 6-8), suggesting that these TDMQ should

a similar way as reported above for Cu , and log Kapp [Zn -L]

values were evaluated. Results are reported in Table 2. In all

cases, absorbances of the free ligands at ca. 257 and 340 nm

decreased, and a new band assigned to the Zn(II) complex

increased at ca. 240 nm, with well defined isosbestic points. For

not interact with zinc proteins. This point is particularly important

to avoid the depletion of zinc-proteins by an exogeneous ligand

as potential drug-candidate.

5

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10.1002/cmdc.201700734

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In addition, the 8-aminoquinoline ligands have an affinity for

Zn(II) which is several orders of magnitude below that of their 8-

hydroxyquinoline analogues. For instance, log Kapp [Zn -L] =

values for the 8-aminoquinoline TDMQ5 and its 8-

hydroxyquinoline analogue TDMQ2 were 4.2 and 10.0,

respectively (Table 2).

In all cases, complexes with a stoichiometry metal/ligand = 1/1

were isolated, even where the metal/ligand molar ratio in the

crystallization mixtures was 1/2. This indicates that complexes

with stoichiometry metal/ligand = 1/2, previously reported in the

II

[

28]

case ligands based on a 8-hydroxyquinoline scaffold,

unlikely with the TDMQ series.

are

The ORTEP views of the copper complexes are depicted in

Figure 5. In the complexes Cu-TQMQ5 (Figure 5a) and Cu-

TQMQ19 (Figure 5b), the copper ion was pentacoordinated in a

distorted square based pyramid. The 2 nitrogen atoms of the

quinoline, the proximal nitrogen from the side chain (secondary

amine), and a chloride, in position trans with respect to the

pyridyl nitrogen, were involved in the basis of the pyramid. The

apical ligand is a water molecule or a chloride in Cu-TDMQ5 and

Cu-TDMQ19, respectively, and the distal tertiary amine was

protonated, resulting in cationic complexes. The dihedral angle

between the planes Npyridine-Cu-Naniline and Nproximal-Cu-Cl1 were

17.3° and 25.4° for Cu-TDMQ5 and Cu-TDMQ19, respectively,

indicating a significant distortion of the Cu(II) environment. The

most striking feature was the fact that the distal nitrogen did not

take part in the chelation. So, in the ligands having a single

methylene group as the proximal part of the side chain (TDMQ5

and -19, n=1), the coordination of the proximal nitrogen atom

was possible. However, the steric constraint did not allow

coordination of the distal nitrogen, even where m=3 (TDMQ19).

On the contrary, TDMQ22, having a side chain with n=m=2,

yielded a neutral copper complex with all four nitrogen atoms of

Selectivity of TDMQ for Cu(II) with respect to Zn(II). In the series

of ligands bearing an alkyl diamine side chain at C2 (Table 2,

TDMQ4-23), TDMQ20 and-22 exhibited the highest selectivity

II

for Cu(II), with log Kapp [Cu -L] – log Kapp [Zn -L] as high as 12.3

and 11.0, for TDMQ20 and TDMQ22, respectively.

Consequently, these ligands can be considered as leads, in

order to extract Cu(II) from the copper loaded amyloids, without

disturbing the structure and function of zinc-dependent proteins.

It should be noted that ligands TDMQ24 and TDMQ27, bearing

a 2-pyridyl- or 2-pyrimidyl as distal substituent also exhibited

high affinities for Cu(II), and high selectivity for copper with

respect to zinc.

Structures of the Cu(II) and Zn(II) complexes in the solid

state. Single crystals suitable for structure determination by X-

ray diffraction were obtained for the copper complexes of

TDMQ5, 19, and -22, and for the zinc complexes of TDMQ5, 19,

and 20, that were found representative of the copper- and zinc

complexes of TDMQ ligands.

II

the ligand involved in a nearly perfect

square planar environment of the copper

ion (Figure 5c). The two chloride atoms

completed the octahedral environment of

this neutral complex. The lengths of the

(

a) Cu -TDMQ5

(b) Cu -TDMQ19

(c) Cu -TDMQ22

bonds between Cu and Naniline, Npyridine

,

and Nproximal were quite similar, measured

at 2.014, 2.018, and 1.995 Å, respectively.

The Cu–Ndistal was slightly longer, at 2.088

Cl

N

Å. The basis Cu–N

with

distal angles at 84.26° and 84.81°,

respectively, slightly lower than Naniline-Cu-

4

was slightly stretched,

2+

Cl

OH2

+

Cl

H

N

F3C

Npyridine-Cu-Naniline and

Nproximal-Cu-

Cu^I^I

N

NH

N

Cu^I^I

Cl

2 Cl^–• H2O

H

CuII

Cl

• Cl^–• 2 H2O

H

N

H

HN

H

HN

H

Cl

•

H2O

•

Ndistal and Npyridine-Cu-Nproximal measured at

97.55° and 98.45°, respectively. The

Figure 5. X-Ray diffraction structures of the Cu(II) complexes of TDMQ5, -19,

and -22.

dihedral angle between N_p_y_r_i_d_i_n_e-Cu-N_a_n_i_l_i_n_eand N_p_r_o_x_i_m_a_l-Cu-N_d_i_s_t_a_l

was below 2.3°, assessing the planarity of the basis. The lack of

distortion of the Cu–TDMQ22 complex is consistent with the

higher affinity of TDMQ22 (n=m=2) for copper, compared with its

II

analogue TDMQ16 having a shorter side

chain (n=1, m=2).

(

a) Zn -TDMQ5

(b) Zn -TDMQ19

(c) Zn -TDMQ20

X-Ray diffraction structures were also

obtained for the Zn(II) complexes of TDMQ5,

1

5

9, and -20, three ligands based on the same

,7-dichloroquinoline nucleus, but with

Cl

different side chain lengths. ORTEP drawings

of these complexes are reported in Figure 6,

along with the chemical structures. The

structures of these neutral complexes were

very similar. The Zn(II) ion was ligated only by

N

Zn^I^I

N

Zn^I^I

N

Cl

H2N

ZnII

H2N

Cl

H N

2

Cl

the two nitrogen atoms of the side chain, but the aminoquinoline

moiety did not take part in the complexation. The environment of

Zn(II) was tetrahedral, with two chloride involved in the

Figure 6. X-Ray diffraction structures of the Zn(II) complexes of TDMQ5, -19,

and -20.

II

coordination sphere. In Zn -TDMQ19 (Figure 6b), the distances

6

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

of Zn to Nproximal and Ndistal were 2.060 and 2.066 Å, respectively.

copper complexes of TDMQ should be able to release their

copper in favor of natural copper transporters or copper proteins.

The release of copper from Cu -TDMQ22 in the presence of

The dihedral angle between the planes Cl-Zn-Cl and Nproximal-Zn-

II

N

distal was 88.97°. In Zn -TDMQ20 (Figure 6c), the distances of

Zn to Nproximal and Ndistal were 2.085 and 2.084 Å, respectively,

and the dihedral angle between the planes Cl-Zn-Cl and Nproximal

glutathione, which is a physiological provider of copper to

proteins, has been monitored by UV-visible spectrometry in

Hepes buffer, pH 7.4. In fact, as already reported in the case of

bis-8-aminoquinoline ligands, GSH can act both as a reducing

agent for copper ion, and as a competitive ligand for the

-

Zn-Ndistal was 89.97°, indicating a nearly perfect tetrahedron

II

around zinc in these complexes. In the complex Zn -TDMQ5

(

Figure 6a), the distances of Zn to Nproximal and Ndistal were 2.064

[

18]

and 2.113 Å, respectively, and the dihedral angle between the

planes Cl-Zn-Cl and Nproximal-Zn-Ndistal was 85.48°.

generated Cu(I)-glutathione complex.

Results are reported in

II

Figure 8. Starting from Cu -TDMQ22 (20 M), addition of

aliquots of glutathione resulted in decrease of the absorbance at

285-290 nm, and increase of the absorbance of the

demetalation ligand TDMQ22 at 332 nm, with well defined

isosbestic points at 272 and 318 nm. After addition of 200 mole

It should be mentioned that the lack of coordination of the 8-

aminoquinoline probably account for the low affinity of this series

for zinc. In contrast, with chelators derived from 8-

hydroxyquinoline scaffold like PBT2, the 8-hydroxyquinoline

[

30]

II

moiety is involved in the coordination sphere of Zn(II).

This

equivalents of GSH with respect to Cu -TDMQ22, the spectrum

feature results in much higher affinities for Zn(II), and much

lower Cu/Zn selectivities, of 8-hydroxyquinolines with respect to

of the product was superimposable to the addition of those of

free TDMQ22 and Cu -SG (black, full trace). So, 200 mole

I

8

-aminoquinoline analogues. In fact, in the present series, log

equivalents of GSH were required for the complete release of

the copper from Cu -TDMQ22. Simultaneously, the release of

II

K

app [Zn -L] values were 10.0 and 4.2, for the 8-hydroxyquinoline

TDMQ2 and its 8-aminoquinoline analogue TDMQ5, respectively

Table 2) .

TDMQ22 allows this ligand to act as a catalyst for the extraction

II

(

of Cu from the amyloid peptide.

Ability to regulate copper homeostasis

Transfer of copper from Cu -A to TDMQ22. Demetalation of

Cu-A1-16 in the presence of TDMQ22 was monitored by UV-

visible spectrometry. Starting from Cu-A1-16 [trace (a), Figure 7],

addition of 1 mole equivalent of TDMQ22 resulted in trace (b)

Equiv GSH/

Cu-TDMQ22

II

0

.2

0.175

.15

272 nm

0

30

50

0

II

100

50

200

that was superimposable to the spectrum of Cu -TDMQ22 [trace

1

0

.125

0.1

(



d), max = 301, 316 nm], while the free TDMQ ligand [trace (c),

max = 253 nm (not shown) and 332 nm] was not detected. This

3

18 nm

result indicates that 1 mole equivalent of TDMQ22 was able to

fully abstract copper from Cu-A1-16 to yield Cu -TDMQ22. This

II

0.075

0.05

is consistent with the high affinity of TDMQ22 for Cu(II), which is

II

4

-5 orders of magnitude above that of A [log Kapp (Cu -A) =

0

.025

0

TDMQ22

GSH

I

[

27]

Cu -SG

10-11],

associated with the tetradentate coordination of

TDMQ22 that disfavors the formation of ternary A1-16-Cu-TDMQ

2

50

300

350

400

complexes.

Wavelength / nm

II

0

.25

.2

.15

.1

Figure 8. Titration of Cu -TDMQ22 from 0 to 20 mole equivalent of glutathione,

in Hepes buffer pH 7.4. The spectra of metal-free TDMQ22 (dashed trace),

I

GSH, Cu -SG, are given for comparison. The calculated trace of TDMQ22 +

Cu -SG is also given (black full line).

0

(b)

I

(

d)

3

01

316

Redox studies of Cu(II) complexes of TDMQ5, 19, 20, and -

22.

In order to evaluate these copper chelators as drug candidates,

a major issue is the potential ability of these ligands to inhibit the

production of ROS induced by Cu -A in the presence of a

biological reducing agent. Therefore, we measured ascorbate

oxidation by Cu or Cu -

equivalents of ligands L as an indirect evaluation of the ability to

reduce dioxygen and consequently to induce an oxidative stress,

(

c)

0

332

(

a)

.05

0

II

2+

II

2

50

300

350

400

Wavelength / nm

[

31]

(

2 2

L = TDMQ5, 19, 20, and -22), and production of H O .

II

Figure 7. UV-vible spectra in Hepes buffer, pH 7.4 of (a) Cu -A1-16 (20 M),

b) Cu -A1-16 + 1 mole equiv of TDMQ22. Spectra of ligand TDMQ22 [(c),

dashed trace] and Cu -TDMQ22 (d), 20 M in Hepes buffer, pH 7.4 are given

for comparison.

II

(

II

Oxidation of ascorbic acid. The assay was carried out in

saline Hepes buffer containing 0.5 vol% of DMSO, and

ascorbate oxidation was measured by UV-visible absorbance at

Results are depicted in Figure 9.1. for ligand

TDMQ20, having a distal dimethylamine side chain with n = m =

2, and a 5,7-dichloroquinoline nucleus. Residual autoxidation of

[

32]

265 nm.

II

Demetalation of Cu -TDMQ22 in the presence of glutathione

GSH). In order to efficiently regulate copper homeostasis, the

(

7

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

ascorbate was below 5% at 10 min [trace (a), dotted line). As

expected, the ascorbate was extensively oxidized in the

presence of CuCl or Cu-

2

fully inhibit ROS production (Figure S1.2.). This observation is

consistent with the fact that the X-ray diffraction geometry of Cu-

TDMQ5 and Cu-TDMQ19 is compatible in some extent with

chelation of Cu(I) as well as Cu(II). On the contrary, the perfect

square planar N4 coordination of Cu-TDMQ19 is obviously

unfavorable to the reduction of Cu(II) to Cu(I).

respectively, in 10 min]. The oxidation of ascorbate in the

II

presence of Cu -TDMQ20 was negligible [< 5% in 10 min, trace

II

(

d)], confirming that Cu -TDMQ20 was able neither to reduce

dioxygen nor to release catalytically active copper ions under

these reductive conditions. Moreover, addition of

stoichiometric amount of TDMQ20 to a Cu-A solution was able

to fully inhibit the oxidation of ascorbate by Cu-A. Similarly,

ligand TDMQ22, bearing the same side chain than TDMQ20, but

a

2 2

Production of hydrogen peroxide. The production of H O in

2

+

reaction mixtures containing Cu , A1-16, TDMQ 5, 19, 20, or -22,

and ascorbate, was measured using the fluorescence of a

peroxidase substrate (« Red hydrogen peroxide assay kit »,

from Enzo Life Sciences, ex = 540 nm, em = 584 nm). In a

3

a 6-CF -quinoline moiety, was able to fully inhibit the oxidation

2

+

the oxidation of ascorbate by Cu-A (Figure S1.1.).

typical reaction, CuCl

2

([Cu

M) was first introduced in the

II

reaction buffer, followed by 1 mol equiv of A1-16 to yield the Cu -

A1-16 complex. The studied TDMQ metal chelator, was then

added, and possibly resulted in transfer of copper ion from A1-18

to ligand (see paragraph above). Ascorbate (10 mol equiv with

(

9.1.)

Ascorbate oxidation =

5%

<

1

,4

,2

1

(

a) Ascorbate

e) Cu-Ab + TDMQ20, 1/1.1

d) Cu–TDMQ20, 1/1.1

2+

respect to Cu ) was then added to activate the production of

(

2 2

H O .

(

2 2 2

The concentration of H O produced by CuCl /ascorbate in

0

,8

,6

,4

,2

0

not shown), close

M), suggesting

57%

(c) Cu-Ab

that the concentration of ascorbate was the limiting factor of the

catalytic production of H by Cu-A1-16. This concentration

was considered as 100%, and the production of H after

normalization is reported in Figure 10. In all control experiments

2

O

2

(

b)

2

O

2

CuCl₂

>

98%

2

+

(

without Cu or without ascorbate), the production of H

below detectable level (data not shown).

In the absence of any metal chelator, the copper complex of

A1-16 in the presence of ascorbate was able to produce H at

a rate close to that observed with CuCl alone, the final

production of H being 89% (Figure 10, lane 2). This result is

consistent with previously reported.

production of by the Cu-TDMQ20 or Cu-TDMQ22

2 2

O was

0

5

10

15

20

25

30

Time / min

(9.2.)

2

O

2

Ascorbate oxidation =

1

,4

,2

1

5%

2

O

2

(a) Ascorbate

1

8%

22%

6%

[16]

In similar conditions, the

(

e) Cu–TDMQ19, 1/2.2

(

f) Cu-Ab + TDMQ19,

2 2

H O

3

1/2.2

complexes, having a side chain that allow chelation of copper in

a N4 square planar environment, was very low. In fact, the final

production of H O was 7% in the absence of A1-16 (lanes 11

2 2

and 13, respectively), and 6% in the presence of A1-16 (lanes 12

and 14, respectively), below the stoichiometric amount of the

copper ion concentration. This result indicates that the chelators

0

,8

,6

,4

,2

0

57%

(d) Cu–TDMQ19,

1

/1.1

(

b)

(c)

Cu-Ab

CuCl₂

> 98%

2 2

TDMQ20 and -22 efficiently inhibit the production of H O by Cu-

0

5

10

15

Time / min

20

25

30

A1-16, suggesting that these chelators should be able to protect

biomolecules located in the vicinity of amyloids from oxidative

damages induced by Cu-A.

TDMQ5 and -19 do also inhibit the production of H

some extent. The final production of H O

2 2

2

O

2

in

by Cu -A1-16 was 20-

21% in the presence of 1 or 2 mole equivalents of TDMQ5

lanes 5 and 6, respectively), and 32-24% with TDMQ19 (lanes

Figure 9. (9.1.) UV-visible (265 nm) kinetic spectra of ascorbate oxidation

II

2

under air in the presence of (a) no additive (dotted line), (b) CuCl , (c) Cu –

II

Aβ1-16, 1/1, (d) Cu –TDMQ20, 1/1.1, (e) Cu –Aβ1-16, 1/1, + TDMQ20 (1.1 mole

equiv). (9.2.) UV-visible (265 nm) kinetic spectra of ascorbate oxidation under

(

II

air in the presence of (a) no additive (dotted line), (b) CuCl

(

2

, (c) Cu –Aβ1-16, 1/1,

II

9 and 10, respectively). However, these chelators having a side

chain that do not allow chelation of copper in a N4 square planar

environment, were less efficient than TDMQ20 and -22.

These results fully indicate a clear correlation between (i) a

square planar N4 coordination of the Cu(II), as observed in Cu-

TDMQ22, but not in Cu-TDMQ5 or Cu-TDMQ19, and (ii) efficient

inhibition of dioxygen reduction, thus confirming the crucial role

of the side chain design.

d) Cu –TDMQ19, 1/1.1, (e) Cu –TDMQ19, 1/2.2, (f) Cu –Aβ1-16

, 1/1, +

TDMQ19 (2.2 mole equiv). In both cases, [ascorbate] = 100 μM, [Cu] = 10 μM,

[

Aβ1-16] = 11 μM.

By contrast, the ascorbate oxidation by Cu(II) was 36% and

18% in the presence of 1 or 2 mole equivalents, respectively, of

TDMQ19 (n = 1, m = 3) [Figure 9.2., traces (d) and (e),

respectively]. Consequently, the addition of 2 mole equivalents

of TDMQ19 with respect to Cu-A1-16 resulted in partial inhibition

[

18-22%, trace (f), Figure 9.2.] of the oxidation of ascorbate by

Cu-A1-16 alone [57%, trace (c), Figure 9.2.]. TDMQ5, with a

shorter side chain (n = 1, m = 2) was also found inefficient to

8

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

performed on silica gel column (Fluka 60-200 µm)

or using a CombiFlash Companion (Teledyne

Isco) with RediSep silica flash columns (35-70

µm). The production of H O was quantified using

2 2

the Red Hydrogen Peroxide Assay kit (Enzo Life

Sciences).

1

00

8

4

1

00

89

9

8

7

6

5

4

3

2

1

0

51

6

4

Fluorescence spectra were recorded on a

FLSP920 spectrometer (Edinburgh Instruments),

with band width for excitation and emission = 2

nm, λexc. = 540 nm, λem. = 584 nm, acquisition

range = 550-700 nm), repeats: 3 scans for each

acquisition. UV-visible spectra were recorded on

Agilent 8453 or Specord 205 (Analytik Jena)

2

7

32

2

1

24

22

7

6

1

13

spectrophotometers. H- and C-NMR spectra

were recorded on Brucker Avance 400

a

lane

1

+

–

2

+

–

3

4

+

–

2

5

6

7

8

+

–

2

9

+

1

10 11

12 13 14

2

+

spectrometer using tetramethylsilane (TMS) as

the external standard. Mass spectra were

obtained on ThermoFisher (DCI) or GCT Premier

Cu

Ab₁_-₁₆

+

–

1

+

1

+

2

+

–

1

+

2

+

–

1

+

1

+

–

1

+

1

L (mol equiv)

4

spectrometer (DCI, CH , HRMS), or Xevo G2

+

QTOF

(Waters,

ESI ,

HRMS).

X-Ray

L

none

TDMQ5

TDMQ19

TDMQ20 TDMQ22

crystallographic data were collected at low

temperature (180 K) on an Oxford Diffraction XCalibur diffractometer

using graphite-monochromated Mo-K radiation ( = 0.71073Å) and

equipped with an Oxford Cryosystems Cryostream Cooler Device. The

final unit cell parameters were obtained by means of least-squares

refinement performed on a set of 2863 well-measured reflections. The

2 2

Figure 10. Production of H O by copper complexes of TDMQ5, 19, 20 or 22,

associated to ascorbate, in the presence (hatched bars) or absence (grey

bars) of Aβ1-16. Standard deviation from three independent assays is indicated.

[

33]

structures were solved by direct methods using SHELXS86,

and

Conclusion

refined by means of least-squares procedures on an F with the aid of the

[

34]

program CRYSTALS.

The atomic scattering factors were taken from

[

35]

In this reported series of 8-amino-TDMQ ligands, several

ones exhibit a high affinity for Cu(II) (log Kapp > 14) associated

to a very high selectivity for Cu(II) with respect to Zn(II) and a

strong ability to fully inhibit in vitro the oxidative stress induced

International Tables for X-Ray Crystallography.

All non hydrogen

atoms were refined anisotropically. Hydrogen atoms were refined by

using a riding model. Absorption corrections were introduced by using

[

36]

the program MULTISCAN.

ORTEP32

Molecules were drawn with the program

with 30% probability displacement ellipsoids for non-

hydrogen atoms.

[

37]

II/I

by Cu -A1-16 in the presence of a reductant. These features are

clearly related to the association of a 8-aminoquinoline scaffold

bearing a side chain suitable to chelate Cu(II) in a 1/1 square

planar complex. In this TDMQ series, the best side chain to

obtain these properties was that one with 2 + 2 methylene

groups. These results support the development of such copper

chelators, which are very different from the former 8-

hydroxyquinoline derivatives clioquinol and PBT2, in terms of

Crystallographic data (without structure factors) for the structures of

copper- and zinc complexes were deposited with the Cambridge

Crystallographic Data Centre (CCDC) as supplementary publication no.

CCDC 1560885-1560890. Copies of the data can be obtained free of

charge from the CCDC (12 Union Road, Cambridge CB2 1EZ, UK; e-

mail: deposit@ccdc.cam.ac.uk; Web site: http://www.ccdc.cam.ac.uk .

[

18]

coordination chemistry behavior.

Synthesis and characterization of TDMQ ligands

The excess of copper ions trapped by reticulated amyloids in

AD brains is probably not accessible for copper carrier (or

chaperone) proteins, whereas a low molecular weight chelator

like TDMQ one should be able to extract the excess of copper

ions and then deliver these copper ions to chaperone proteins

involved in extra- and intracellular copper trafficking systems.

The pharmacology of these TDMQ ligands is under investigation.

The TDMQ ligands and their synthetic intermediates have been prepared

according to general protocols depicted in Schemes 1-3. Each compound

was numbered as “X-TDMQn”, where X stands for the letter of the given

intermediate in Schemes 1-3, followed by the target TDMQ, with n = 1-27.

Synthesis of TDMQ-1

8-Hydroxyquinoline-2-carbaldehyde (N-TDMQ1, Scheme 3, R = H). To

Experimental section

a solution of 2-methylquinolin-8-ol (M-TDMQ1, 1.59 g, 10 mmol) in 1,4-

dioxane (20 mL) was added selenium dioxide (1.66 g, 15 mmol). The

o

Chemicals and methods

reaction mixture was heated, and the temperature was raised to 80

C

and stirred for 12 h. The reaction mixture was filtered through a celite pad

and the product was eluted with dichloromethane. The combined filtrates

were evaporated under reduced pressure to dryness. The residue was

purified by silica gel flash column chromatography (ethyl acetate/

petroleum ether, 1:20, v/v). After evaporation of the eluent, compound 1

was obtained as a yellow solid (1.21 g, 70 %). H NMR (300 MHz,

6

DMSO-d ): δ = 10.29 (brs, 1 H), 10.11 (s, 1 H), 8.45 (d, J = 8.4 Hz, 1 H),

7.92 (d, J = 8.4 Hz, 1 H), 7.58 (t, J = 8.1 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1

H), 7.20 (d, J = 8.1 Hz, 1 H).

All solvents and commercially available reagents were purchased from

Sigma-Aldrich, Fluka, Acros, or TCI, except A1-16, purchased from

Bachem. They were used without further purification. Cu(II)- and Zn(II)

cloride or sulfate were used as source of metal ions. A1-16 stock solution

was prepared by dissolving the peptide in DMSO or water, and the

concentration was determined by UV-visible spectroscopy [276(Tyr10) =

1

-

1

-1 [22b]

1410

M

cm ].

Reactions were monitored by thin layer

chromatography (TLC), using silica gel-coated aluminium plates with

fluorescent indicator 254 nm. Preparative chromatography was

9

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

2-(((2-(Dimethylamino)ethyl)amino)methyl)quinolin-8-ol (O-TDMQ1,

for 4 h. The resulting mixture was poured into ice-cold water and

Scheme 3, R = H). To a solution of N-TDMQ1 (346 mg, 2 mmol) in 1,2-

dichloroethane (15 mL) was added N,N-dimethyl-1,2-ethanediamine (352

mg, 4 mmol) under argon. The reaction mixture was stirred at room

temperature for 1 h, and sodium triacetoxyborohydride (848 mg, 4 mmol)

was added. The resulting mixture was stirred for additional 12 h and

neutralized with aqueous ammonium. After extraction with CH

2 2

Cl , the

organic phase was dried over Na SO , filtered, and concentrated under

2

4

reduced pressure. The crude mixture was purified by silica gel flash

column chromatography (ethyl acetate/ petroleum ether, 1/20, v/v). After

evaporation of the eluent, M-TDMQ3 was obtained as a yellow solid

1

diluted with 50 mL CH

2

Cl

2

, followed by the addition of saturated aqueous

(2.93 g, 69%). H NMR (400 MHz, CDCl

3

): δ = 8.22 (d, J = 8.4 Hz, 1 H),

13

sodium bicarbonate solution (20 mL). The organic phase was separated.

The aqueous phase was added 2 mL ammonium hydroxide, extracted

7.32 (d, J = 8.8 Hz, 1 H), 7.04 (t, J = 10.4 Hz, 1 H), 2.74 (s, 3 H);

C

NMR (100 MHz, CDCl ): δ = 159.3, 150.1 (dd, J = 247, 12.3 Hz), 146.1

3

with CH

2

Cl

2

(3x30 mL). The organic phase was combined, dried over

(dd, J = 244, 12.2 Hz), 138.1(q, J = 8.4, 4.7 Hz), 134.5 (q, J = 10.7, 5.2

Hz), 129.9 (t, J = 2.2 Hz), 121.9 (t, J = 2.6 Hz), 113.8 (d, J =18.4 Hz),

102.2 (t, J = 24.7 Hz), 25.8.

Na SO , filtered, and concentrated under reduced pressure. The crude

2

4

product was purified by silica gel flash chromatography (ethyl

acetate/isopropanol/ammonium hydroxide (25 %), 8:2:0.5, v/v/v).

Evaporation of the solvent afforded O-TDMQ1 as a yellow oil (392 mg,

5,7-Difluoro-8-hydroxyquinoline-2-carbaldehyde (N-TDMQ3). The

8

0 %). O-TDMQ1 is not very stable upon storage at room temperature

procedure was similar to that described for the preparation of compound

N-TDMQ1. N-TDMQ3 was obtained as a yellow solid (80 %). H NMR

under air and light. Therefore, this compound was transformed to the salt

form TDMQ1 immediately after being purified.

1

(400 MHz, CDCl

3

): δ = 10.2 (s, 1H), 8.57 (d, J = 8.8 Hz, 1 H), 8.08 (d, J =

8.8 Hz, 1 H), 7.53 (brs, 1H), 7.31 (t, J = 10.4 Hz, 1 H)

TDMQ1 (Scheme 3, R = H). To a solution of O-TDMQ1 in diethyl ether

was added excess hydrogen chloride solution (2.0 N in diethyl ether).

The precipitate was filtered, washed with diethyl ether and dried under

2

-(((2-(Dimethylamino)ethyl)amino)methyl)-5,7-difluoroquinolin-8-ol

(

O-TDMQ-3). The procedure was similar to that described above for the

preparation of O-TDMQ1. O-TDMQ3 was obtained as a brown solid

80 %), which was transformed to the salt form TDMQ3 immediately after

reduced pressure to give TDMQ1 as a yellow solid (89 %). mp 205–

1

2

=

3

1

07 °C; H NMR (400 MHz, D

2

O): δ = 8.39 (d, J = 8.5 Hz, 1H), 7.54 (d, J

(

8.6 Hz, 1H), 7.51–7.43 (m, 2H), 7.20 (d, J = 7.2 Hz, 1 H), 4.70 (s, 2 H),

.73–3.58 (m, 4 H), 2.94 (s, 6 H). C NMR (100 MHz, D

49.1, 140.2, 128.9, 128.7, 120.6, 119.5, 113.4, 52.9, 50.8, 43.6, 42.1. IR

being purified.

13

2

O): δ = 150.3,

TDMQ3. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ3 was obtained as a yellow solid (86 %). mp 235–

(

1

2

C

KBr): 3414, 2962, 1632, 1602, 1544, 1507, 1468, 1393, 1304, 1239,

-

1

181, 1093, 992, 869, 839, 763 cm ; HRMS (EI) calcd for C14

H

19

N

3

O:

45.1528 ([M] ); found: 245.1521; Elemental analysis calcd (%) for

O·3HCl·0.5H O·0.07NH Cl (apparent MW = 367.45): C, 45.76;

1

237 °C; H NMR (400 MHz, D

2

O): δ = 9.93 (brs, 1H), 8.54 (d, J = 8. 8 Hz,

+

13

1

H), 7.70 – 7.65 (m, 2H), 4.71 (s, 2H), 3.61 (s, 4H), 2.88 (s, 6H);

O): δ = 151.4, 150.0 (dd, J = 223.1 Hz, J = 12.6 Hz),

= 217 Hz, J = 13.2 Hz), 137.1 – 137.0 (m), 134.0 – 133.8

m), 131.5, 119.2, 114.9 (d, J = 18.4 Hz), 102.8 (t, J = 25.6 Hz), 52.7,

C

H N

14 19 3

2

4

NMR (100 MHz, D

47.6 (dd, J

2

1

2

H, 6.39; N, 11.70; found: C, 45.77; H, 6.51; N, 11.71.

1

(

1

2

Synthesis of TDMQ-2

5

1

1.2, 43.4, 41.9; IR (KBr): 3420, 2935, 2720, 2657, 2610, 2416, 1650,

630, 1604, 1476, 1399, 1278, 1211, 1169, 1122, 1058, 1028, 844, 797,

-

1

+

5,7-Dichloro-8-hydroxyquinoline-2-carbaldehyde (N-TDMQ2, Scheme

763, 733 cm ; HRMS (EI) calcd for C14

281.1332; Elemental analysis calcd (%) for C14

17 2

H F N

3

O: 281.1340 ([M] ); found:

2

O•3HCl•0.8H O

3

, R = 5,7-Cl ). The procedure was similar to that described for the

2

H F N

17 2 3

preparation of N-TDMQ1, but starting from 2-methyl-5,7-dichloroquinolin-

-ol (M, Scheme 3, R = 5,7-Cl ). N-TDMQ2 was obtained as a yellow

solid (80 %). H NMR (300 MHz, DMSO-d ): δ = 11.22 (brs, 1H), 10.16 (s,

H), 8.65 (d, J = 8.7 Hz, 1 H), 8.09 (d, J = 8.7 Hz, 1 H), 7.99 (s, 1 H).

(apparent MW = 405.09): C, 41.51; H, 5.37; N, 10.37; found: C, 41.51; H,

5.39; N, 10.35.

8

2

1

6

1

Synthesis of TDMQ4

5

,7-Dichloro-2-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-8-ol

2

1

8

-Methylquinolin-8-amine (E-TDMQ4, Scheme 1, R = H). Iron (757 mg,

3.55 mmol) and acetic acid (3 mL) were added to a solution of 2-methyl-

-nitroquinoline (A-TDMQ4, 850 mg, 4.52 mmol) in ethanol (9 mL). The

(

O-TDMQ2, Scheme 3, R = 5,7-Cl

2

). The procedure was similar to that

described for the preparation of O-TDMQ1. O-TDMQ2 was obtained as a

yellow oil (92 %) O-TDMQ2 is not stable upon storage at room

temperature under air and light. Therefore, this compound was

transformed to the salt form TDMQ2 immediately after being purified.

mixture was stirred under reflux for 4 h. The reaction mixture was poured

into an aqueous saturated NaHCO solution (200 mL) and extracted with

CH Cl (3 x 100 mL). The combined organic layers were dried over

Na SO , filtered and concentrated under reduced pressure. The crude

3

2

4

TDMQ2. The same procedure as described above for the preparation of

product was purified by silica gel flash chromatography (ethyl

TDMQ1 afforded TDMQ2 as a yellow solid (92 %). Decompose at

acetate/petroleum ether, 1:10, v/v). Evaporation of the solvent afforded

1

~

247 °C; H NMR (400 MHz, D

2

O): δ = 8.43 (d, J= 8.7 Hz, 1 H), 7.56 (d,

E-TDMQ4 as a brown oil (628 mg, 88 %). H NMR (400 MHz, CDCl

3

): δ =

J= 8.8 Hz, 1 H), 7.50 (s, 1 H), 4.72 (s, 2H), 3.73 – 3.63 (m, 4 H), 2.96 (s,

7.93 (d, J = 8.4 Hz, 1 H), 7.25-7.21 (m, 2 H), 7.10 (d, J = 8.0 Hz, 1 H),

6.89 (d, J = 8.4 Hz, 1 H), 4.85 (brs, 2 H), 2.70 (s, 3 H).

13

6

1

2

1

6

2

H). C NMR (100 MHz, D O): δ = 150.8, 146.4, 136.7, 134.9, 127.6,

24.0, 120.9, 120.8, 116.4, 52.5, 51.2, 43.4, 41.9; IR (KBr): 3357, 3247,

938, 2721, 2587, 2411, 1650, 1599, 1499, 1451, 1401, 1340, 1301,

245, 1213, 1168, 1086, 1029, 1003, 967, 947, 857, 782, 726, 666,

N-(2-Methylquinolin-8-yl)acetamide (F-TDMQ4). To

a solution of

compound E-TDMQ4 (2.50 g, 15.8 mmol) in CH Cl (25 mL) was added

2

-

1

+

27,546 cm ; HRMS (ESI) calcd for C14

314.0822; Elemental analysis

O•3HCl•0.5H O (apparent MW = 432.59): C, 38.87; H, 4.89;

H

18Cl

2

N

3

O: 314.0827 ([M+H] );

o

acetyl chloride (4.5 mL) and N,N-diisopropylethylamine (25 mL) at 0 C.

found:

C

calcd (%) for

o

The reaction mixture was kept at 0 C for 15 min and stirred overnight at

14

H17Cl

N

2 3

2

room temperature. After the removal of solvents under reduced pressure,

the crude product was purified by silica gel flash column chromatography

N, 9.71; found: C, 38.89; H, 4.85; N, 9.72.

(

ethyl acetate/ petroleum ether, 1:20, v/v). After evaporation of the eluent,

1

Synthesis of TDMQ-3

F-TDMQ4 was obtained as a light yellow solid (3.15 g, 99 %). H NMR

400 MHz,CDCl ): δ = 9.83 (s, 1 H), 8.72 (d, J = 8.8 Hz, 1 H), 8.02 (d, J =

.4 Hz, 1 H), 7.45-7.44 (m, 2 H), 7.31 (d, J = 8.4 Hz, 1 H), 2.74 (s, 3 H),

.35 (s, 3 H).

(

8

2

3

5

,7-Difluoro-2-methylquinolin-8-ol (M-TDMQ3, Scheme 3, R = 4,6 -F

2

).

To a solution of 2-amino-4,6-difluorophenol (L, Scheme 3, R = 4,6-F

2

,

o

2

.90 g, 20 mmol) in HCl (12 M, 12 mL) at 0 C acetaldehyde was added

o

dropwise, under stirring. The reaction medium was kept at 0

C

for 15

N-(2-Formylquinolin-8-yl)acetamide (G-TDMQ4). The procedure was

similar to that described for the preparation of N-TDMQ1. G-TDMQ4 was

o

min, and was gradually raised to 75 C. The mixture was stirred at 75 C

1

0

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

1

obtained as a yellow solid (65 %). H NMR (400 MHz, CDCl

3

): δ = 10.25

8.31 (d, J = 8.0 Hz, 1 H), 7.42 (s, 1 H), 7.35 (d, J = 8.0 Hz，1 H), 5.36

(s, 1 H), 9.75 (s, 1 H), 8.87 (d , J = 7.6 Hz, 1 H), 8.33 (d, J = 8.4 Hz, 1 H),

(brs, 2 H), 2.76 (s, 3 H).

8.08 (d, J = 8.4 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1

H), 2.42 (s, 3 H).

N-Acetyl-N-(5,7-dichloro-2-methylquinolin-8-yl)acetamide (F-TDMQ5).

The procedure was similar to that described for the preparation of F-

TDMQ4. F-TDMQ4 was obtained as a yellow solid (70 %). H NMR (400

1

2

1

N -((8-Aminoquinolin-2-yl)methyl)-N ,N -dimethylethane-1,2-diamine

(

H-TDMQ4). To a solution of G-TDMQ4 (2.00 g, 9.34 mmol) in 1,2-

dichloroethane (30 mL) was added N,N-dimethyl-1,2-ethanediamine

3.29 g, 4.08 mL, 37.34 mmol) under argon. The reaction mixture was

stirred at room temperature for 1 h, and sodium triacetoxyborohydride

7.92 g, 37.34 mmol) was added. The resulting mixture was stirred for

additional 12 h and diluted with 100 mL CH Cl , followed by the addition

3

MHz, CDCl ): δ 8.41 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.42 (d, J=8.0 Hz,

1H), 2.71 (s, 3H), 2.29 (s, 6H).

(

N-Acetyl-N-(5,7-dichloro-2-formylquinolin-8-yl)acetamide (G-TDMQ5).

(

The procedure was similar to that described for the preparation of N-

1

2

TDMQ1. G-TDMQ5 was obtained as a yellow solid (71 %). H NMR (400

of saturated aqueous sodium bicarbonate solution (40 mL). The organic

phase was separated. The aqueous phase was added 2 mL ammonium

3

MHz, CDCl ): δ = 10.13 (s, 1 H), 8.76 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 8.0

Hz, 1 H), 7.92 (s, 1 H), 2.32 (s, 6 H).

hydroxide, extracted with CH

combined, dried over Na SO

pressure. To the crude product in CH

2

Cl

, filtered, and concentrated under reduced

Cl (5 mL) was added 6N HCl (2

2

(3 x 30 mL). The organic phase was

2

4

1

2

N -((8-Amino-5,7-dichloroquinolin-2-yl)methyl)-N ,N -

2

dimethylethane-1,2-diamine (H-TDMQ5). The procedure was similar to

mL), which was stirred at 50 °C for 4 h. Water (50 mL) was added,

followed by addition of extra aqueous 25% ammonium hydroxide. The

that described for the preparation of compound H-TDMQ4. H-TDMQ5

1

was obtained as a yellow solid (78 %). H NMR (400 MHz, CDCl

3

): δ =

mixture was extracted with CH

2 2

Cl (3 x 30 mL). The combined organic

8

2

6

.35 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.43 (s, 1 H), 5.38 (brs,

H), 4.10 (s, 2 H), 2.75 (t, J = 6.0 Hz, 2 H), 2.55 (brs, 1 H), 2.48 (t, J =

.0 Hz, 2 H), 2.22 (s, 6 H).

layers were dried (Na SO ), filtered and concentrated under reduced

2

4

pressure. The crude product was purified by silica gel flash

chromatography (ethyl acetate/isopropanol/ammonium hydroxide (25%),

5

:1:0.2, v/v/v). Evaporation of the solvent afforded H-TDMQ4 as a yellow

1

TDMQ5. The procedure was similar to that described for the preparation

solid (683 mg, 93 %). H NMR (400 MHz, CDCl

H), 7.37 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 8.4

Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 4.97 (brs, 2 H), 4.09 (s, 2 H), 2.78 (t, J

6.0 Hz, 2 H), 2.49 (t, J = 6.0 Hz, 2 H), 2.23 (s, 6 H).

3

): δ = 8.01 (d, J = 8.4 Hz,

of compound TDMQ1. TDMQ5 was obtained as a yellow solid (98 %).

1

Decompose at ~269.5 °C; H NMR (400 MHz, DMSO-d

6

): δ = 8.48 (d, J =

8

2

1

4

9

3

.8 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 6.72 (s, 2H), 4.66 (s,

H), 3.51 (s, 4H), 2.82 (s, 6H); C NMR (100 MHz, CDCl ): δ = 159.1,

3

39.8, 137.8, 133.4, 126.9, 124.1, 121.3, 117.6, 113.6, 59.3, 55.4, 47.0,

=

13

TDMQ4. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ4 was obtained as a yellow solid (95 %). Decompose

at ~245 °C; H NMR (400 MHz, D

5.6 IR (KBr): 3426, 3253, 2947, 2715, 1630, 1596, 1465, 1373, 1322,

-1

95, 947, 861, 712, 539 cm ; HRMS (EI) calcd for

14 2 4

C H18Cl N :

1

2

O): δ = 8.38 (d, J = 8.8 Hz, 1H), 7.95

+

12.0909([M] ); found: 312.0900; Elemental analysis calcd (%) for

•3HCl•0.6H O·0.02NH Cl (apparent MW = 434.48): C, 38.70;

(d, J = 8.4 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.57

C

14

H18Cl

N

2 4

2

4

13

(

d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 3.78-3.71 (m, 4H), 2.99 (s, 6H);

O): δ = 152.1, 139.7, 138.7, 129.0, 128.1, 127.0,

26.7, 124.0, 121.0, 52.6, 51.43, 43.5, 41.9; IR (KBr): 3470, 3024, 2798,

542, 1630, 1601，1468, 1428, 1397, 1295, 1101, 1084, 1021, 997, 960,

C

H, 5.17; N, 12.96; found: C, 38.75; H, 5.18; N, 13.07.

NMR (100 MHz, D

2

1

2

8

2

C

4

Synthesis of TDMQ-6

-

1

20 4

44, 820, 781, 757, 644, 483 cm ; HRMS (EI) calcd for C14H N :

+

5,7-Difluoro-2-methyl-8-nitroquinoline (A-TDMQ6, Scheme 1, R = 5,7-

44.1688 ([M] ); found: 244.1684; Elemental analysis calcd (%) for

•2.9HCl•0.8H O•0.03CH COOC (apparent MW = 367.13): C,

6.20; H, 6.79; N, 15.26; found: C, 46.14; H, 6.81; N, 15.24.

2

F ). The procedure was similar to that described for the preparation of M-

H N

14 20 4

2

3

2 5

H

TDMQ3, but starting from 2-amino-4,6-difluoronitrobenzene (D, Scheme

1

, R = 4,6-F

2

). A-TDMQ6 was obtained as a brown solid (47 %). H NMR

) δ = 8.29 (d, J = 8.4 Hz, 1 H), 7.43 (d, J =8.4 Hz, 1 H),

.10 (t, J = 9.3 Hz, 1 H), 2.76 (s, 3 H).

(300 MHz, CDCl

3

Synthesis of TDMQ5

7

5

,7-Dichloro-2-methylquinoline (C-TDMQ5, Scheme 1, R = 5,7-Cl

The procedure was similar to that described for the preparation of M-

TDMQ3, but starting from 3,5-dichloroaniline (B, Scheme 1, R = 3,5-Cl ).

C-TDMQ5 was obtained as a yellow solid (69 %). H NMR (400 MHz,

CDCl ): δ = 8.40 (d, J = 8.0 Hz, 1 H), 7.96 (d, J = 2.0 Hz,1 H), 7.55 (d, J

2.0 Hz,1 H), 7.37 (d, J = 8.0 Hz,1 H), 2.76 (s, 3 H).

2

).

5

,7-Difluoro-2-methylquinoline-8-amine (E-TDMQ6). The procedure

was similar to that described for the preparation of compound E-TDMQ4.

E-TDMQ6 was obtained as a yellow solid (92%). H NMR (300 MHz,

CDCl

2

1

3

): δ = 8.18 (d, J = 9.0 Hz, 1 H), 7.26 (d, J = 6.0 Hz, 1 H), 6.98 (t, J =

3

12.0 Hz, 1 H), 4.63 (s, 2 H), 2.73 (s, 3 H ).

=

tert-Butyl-(5,7-difluoro-2-methylquinoline-8-yl)carbamate (F-TDMQ6).

To a solution of E-TDMQ6 (295 mg, 1.52 mmol) in 1,4-dioxane (15 mL),

was added di-tert-butyl dicarbonate (1.33g, 6.08 mmol) under Argon. The

5

,7-Dichloro-2-methyl-8-nitroquinoline (A-TDMQ5): To

a

stirred

solution of C-TDMQ5 (2.12 g, 10 mmol) in neat sulfuric acid (10 mL) was

added fuming nitric acid (2.0 mL) dropwise over a 1 h period at an

ambient temperature. The resulting mixture was stirred for an additional

hour, and was then poured onto ice. The mixture was allowed to warm to

ambient temperature, neutralized with aqueous ammonium. After

extraction with CH Cl , the organic phase was dried over Na SO , filtered,

2 2 2 4

and concentrated under reduced pressure. The crude mixture was

purified by silica gel flash column chromatography (ethyl

acetate/petroleum ether, 1/10, v/v). Evaporation of the solvent afforded

A-TDMQ5 as a yellow solid (2.34 g, 91%). H NMR (400 MHz, CDCl

=

3

0

reaction mixture was stirred at 90 C overnight. The resulting mixture was

cooled to room temperature, quenched with water, extracted with CH

2 2

Cl .

The organic phase was dried over MgSO , filtered and concentrated

4

under reduced pressure. The crude mixture was purified by silica gel

flash column chromatography (ethyl acetate/ petroleum ether, 1:10, v/v).

Evaporation of the solvent afforded F-TDMQ6 as a white solid (440 mg,

1

7

2 %). H NMR (400 MHz, CDCl

3

): δ = 8.24 (d, J = 12.0 Hz, 1 H), 7.37 (s,

1

1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.05 (t, J = 8.0 Hz, 1 H), 2.75 (s, 3H), 1.55

s, 9 H).

3

): δ

(

8.43 (d, J = 8.0 Hz, 1 H), 7.64 (s, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 2.76 (s,

H).

tert-Butyl-(5,7-difluoro-2-formylquinoline-8-yl)carbamate (G-TDMQ6).

The procedure was similar to that described for the preparation of N-

TDMQ1. G-TDMQ6 was obtained as a yellow solid (71 %). H NMR (400

5

,7-Dichloro-2-methylquinolin-8-amine (E-TDMQ5). The procedure

1

was similar to that described for the preparation of E-TDMQ4. E-TDMQ5

was obtained as a yellow solid (89 %). H NMR (400 MHz, CDCl ): δ =

3

1

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

MHz, CDCl

3

): δ = 10.25 (s, 1 H), 8.57 (d, J = 12.0 Hz, 1 H), 8.08 (d, J =

Hz, 1H), 7.79 – 7.76 (m, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.40 (t, J = 8.8 Hz,

1H), 4.77 (s, 2H), 3.73 – 3.70 (m, 4H), 2.98 (s, 6H); C NMR (100 MHz,

D2O): δ = 157.2 (d, J = 255 Hz), 153.2, 140.2 (d, J = 4.2 Hz), 132.2 (d, J

13

8.0 Hz, 1 H), 7.36 (s, 1 H), 7.31 (d, J = 12.0 Hz, 1 H), 1.57 (s, 9 H).

=

2

3.4 Hz), 123.9 (d, J = 9.8 Hz), 123.7, 121.2 (d, J = 2.1 Hz), 118.9 (d, J

18.6 Hz), 110.4 (d, J = 21.4 Hz), 52.5, 51.4, 43.5, 41.8; IR (KBr): 3372,

971, 2712, 2536, 2432, 1643, 1605, 1483, 1415, 1313, 1245, 1221,

H-TDMQ6. The procedure was similar to that described for the

preparation of compound H-TDMQ4. In particular, the deprotection of N-

Boc amine was achieved using trifluoroacetic acid (TFA, 0.5 M in DCM),

-

1

1102, 1046, 1025, 998, 849, 831, 787, 581,457 cm ; HRMS (EI) calcd

for C14

calcd (%) for C14

instead of HCl. TDMQ-6 was obtained as a yellow solid (78 %). H NMR

+

H19FN

4

: 262.1594 ([M] ); found: 262.1587; Elemental analysis

•2.7HCl•2.3H O•0.06C OC (apparent MW =

(400 MHz, CDCl

3

): δ = 8.25 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H),

H19FN

4

2

H

2 5

H

7

2

=

1

.01 (t, J = 10.4 Hz, 1H), 4.70 (brs, 2H), 4.11 (s, 2H), 2.78 (t, J = 6.0 Hz,

H), 2.49 (t, J = 6.0 Hz, 2H), 2.23 (s, 6H); C NMR (100 MHz, CDCl ): δ

3

159.9, 149.3 (dd, J = 208.6, 13.5 Hz), 146.9 (dd, J = 200.5, 13.4 Hz),

37.8 (dd, J = 10.2, 3.8 Hz), 129.7 (t, J = 2.5 Hz), 126.5 (dd, J = 12.4, 4.7

13

406.65): C, 42.06; H, 6.67; N, 13.78; found: C, 42.13; H, 6.73; N, 13.78.

Synthesis of TDMQ-9

Hz), 119.8 (t, J = 2.8 Hz), 114.8 (d, J = 17.6 Hz), 101.8 – 101.3 (m), 59.3,

5.6, 47.0, 45.6.

5

6-Fluoro-2-methyl-8-nitroquinoline (A-TDMQ9, Scheme 1, R = 6-F).

The procedure was similar to that described for the preparation of M-

TDMQ3, but starting from 2-amino-5-fluoronitrobenzene (D, Scheme 1, R

= 5-F). A-TDMQ9 was obtained as a light yellow solid (73%). H NMR

TDMQ6. The procedure was similar to that described for the preparation

1

of TDMQ1. TDMQ6 was obtained as a yellow solid (99 %). Decompose

1

at ~246 °C; H NMR (400 MHz, D

2

O): δ = 8.53 (d, J = 8.8 Hz, 1H), 7.55

(400 MHz, CDCl

3

): δ = 8.00 (d, J = 8.4 Hz, 1 H), 7.70 (dd, J =8.0, 2.8 Hz,

(

4

1

d, J = 8.4 Hz, 1H), 7.34 (t, J = 10.8 Hz, 1H), 4.73 (s, 2H), 3.72 – 3.68 (m,

1 H), 7.55 (dd, J =8.0, 2.8 Hz, 1 H), 7.40 (d, J= 8.4 Hz, 1 H), 2.69 (s, 3 H);

C NMR (100 MHz, CDCl ): δ = 161.5 (d, J = 2.7 Hz), 157.5 (d, J = 249

3

Hz), 148.6, 136.3 (d, J = 1.6 Hz), 135.2 (d, J = 5.1 Hz), 127.9(d, J = 9.4

Hz), 124.6, 114.7 (d, J = 21 Hz), 113.8 (d, J = 30 Hz), 25.6.

13

H), 2.97 (s, 6H); IR (KBr): 3420, 3036, 2801, 2539, 1655, 1605, 1474,

-

1

416, 1393, 1209, 1165, 1119, 1054, 858, 808, 477 cm ; HRMS (EI)

+

calcd for

analysis calcd (%) for

apparent MW = 408.70): C, 40.30; H, 5.86; N, 13.28; found: C, 40.36; H,

.95; N, 13.30.

14 18 2 4

C H F N :

280.1500 ([M] ); found: 280.1496; Elemental

C

14

H

19ClN

4

•3HCl•0.7H O•0.09CH COOC H

2

3

2 5

(

5

6-Fluoro-2-methylquinolin-8-amine (E-TDMQ9). The procedure was

similar to that described for the preparation of E-TDMQ4. E-TDMQ9 was

1

3

obtained as a light yellow solid (92%). H NMR (400 MHz, CDCl ): δ =

Synthesis of TDMQ-8

-Fluoro-2-methyl-8-nitroquinoline (A-TDMQ8, Scheme 1, R = 5-F).

The procedure was similar to that described for the preparation of M-

TDMQ3, but using 2-amino-4-fluoronitrobenzene (D, Scheme 1, R = 4-F)

7.87 (d, J= 8.4 Hz, 1 H), 7.25 (d, J =8.4 Hz, 1 H), 6.95 (dd, J =10.8, 2.8

Hz, 1 H), 6.63 (dd, J =10.8, 2.8 Hz, 1 H), 5.13 (brs, 2 H), 2.69 (s, 3 H).

13

C NMR (100 MHz, CDCl

Hz), 145.5 (d, J = 12.9 Hz), 135.6 (d, J = 5.5 Hz), 135.1, 127.3 (d, J =

2.1 Hz), 123.1, 99.3 (d, J = 27 Hz), 98.5 (d, J = 22.3 Hz), 25.0.

3

): δ = 161.1 (d, J = 241 Hz), 155.1 (d, J = 2.5

5

1

as starting material. A-TDMQ8 was obtained as a yellow-brown solid

1

(

62 %). H NMR (400 MHz, CDCl

3

): δ = 8.37 (d, J = 8.0 Hz, 1 H), 8.02

tert-Butyl (6-fluoro-2-methylquinolin-8-yl)carbamate (F-TDMQ9). The

dd, J = 8.0 Hz, 4.0 Hz, 1 H), 7.48 (d, J = 12.0 Hz, 1 H), 7.20 (t, J = 8.0

Hz, 1 H), 2.80 (s, 3 H).

procedure was similar to that described for the preparation of F-TDMQ6.

1

F-TDMQ9 was obtained as a white solid (89%). H NMR (400 MHz,

CDCl

H), 7.31 (d, J =8.4 Hz, 1 H), 6.97 (dd, J =8.8, 2.8 Hz, 1 H), 2.72 (s, 3H),

.59 (s, 9 H).

3

): δ = 9.08 (s, 1 H), 8.21 (d, J = 10.4 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1

5

-Fluoro-2-methylquinolin-8-amine (E-TDMQ8). The procedure was

1

similar to that described for the preparation of E-TDMQ4. E-TDMQ8 was

obtained as a yellow solid (74 %). H NMR (400 MHz, CDCl ): δ = 8.21 (d,

3

1

J = 8.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 6.95 (dd, J = 8.0 Hz, 4.0 Hz, 1

H), 6.77 (dd, J = 8.0 Hz, 4.0 Hz, 1 H), 4.78 (s, 2 H), 2.71 (s, 3 H).

tert-Butyl (6-fluoro-2-formylquinolin-8-yl)carbamate (G-TDMQ9). The

procedure was similar to that described for the preparation of N-TDMQ1.

1

G-TDMQ9 was obtained as a light yellow solid (50%). H NMR (400 MHz,

3

CDCl ): δ = 10.23 (s, H), 9.04 (s, 1 H), 8.36 (d, J = 10.8 Hz, 1 H), 8.23 (d,

tert-Butyl-(5-fluoro-2-methylquinolin-8-yl)carbamate (F-TDMQ8). The

J = 8.4 Hz, 1 H), 8.07 (d, J =8.4 Hz, 1 H), 7.11 (dd, J =8.4, 2.4 Hz, 1 H),

1.62 (s, 9 H).

procedure was similar to that described for the preparation of F-TDMQ6.

F-TDMQ6 was obtained as a white solid (80 %). H NMR (400 MHz,

1

acetone-d

Hz, 4.0 Hz, 1 H), 7.59 (d, J = 12.0 Hz, 1 H), 7.24 (dd, J = 8.0 Hz, 4.0 Hz,

H), 2.76 (s, 3 H), 1.57 (s, 9 H).

6

): δ = 8.87 (s, 1 H), 8.38 (d, J = 8.4 Hz, 1 H), 8.33 (dd, J = 8.0

1

2

N -((8-Amino-6-fluoroquinolin-2-yl)methyl)-N ,N -dimethylethane-

1,2-diamine (H-TDMQ9). The procedure was similar to that described for

1

the preparation of H-TDMQ6. H-TDMQ9 was obtained as a yellow solid

1

(

79 %). H NMR (400 MHz, CDCl

3

): δ = 7.93 (d, J = 8.4 Hz, 1 H), 7.39 (d,

tert-Butyl-(5-fluoro-2-formylquinolin-8-yl)carbamate (G-TDMQ8). The

J = 8.4 Hz, 1 H), 6.71 (dd, J = 10.4, 2.8 Hz, 1 H), 6.64 (dd, J = 10.4, 2.8

Hz, 1 H), 5.20 (brs, 2H), 4.07 (s, 2 H), 2.85 (brs, 1 H), 2.78 (t, J = 6.0 Hz,

procedure was similar to that described for the preparation of compound

N-TDMQ1. G-TDMQ8 was obtained as a yellow solid (42 %). H NMR

1

13

2

H), 2.49 (t, J = 6.0 Hz, 2 H), 2.23 (s, 6 H). C NMR (100 MHz, CDCl

3

):

(

400 MHz, CDCl

H), 8.46 (dd, J = 8.0 Hz, 4.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 7.34 (t, J

12.0 Hz, 1 H), 1.61 (s, 9 H).

3

): δ = 10.26 (s, 1 H), 8.80 (s, 1 H), 8.57 (d, J = 8.0 Hz, 1

δ = 161.3 (d, J = 242 Hz), 156.4 (d, J = 2.6 Hz), 145.8 (d, J = 13.1 Hz),

1

2

35.9 (d, J = 5.6 Hz), 134.9, 128.2 (d, J = 12.1 Hz), 121.7, 99.4 (d, J =

8.9 Hz), 98.5 (d, J = 22.3 Hz), 59.3, 55.5, 47.0, 45.6

=

1

2

N -((8-Amino-5-fluoroquinolin-2-yl)methyl)-N ,N -dimethylethane-

,2-diamine (H-TDMQ8). The procedure was similar to that described for

the preparation of H-TDMQ-6. H-TDMQ8 was obtained as a yellow-

TDMQ9. The procedure was similar to that described for the preparation

1

of TDMQ1. TDMQ9 was obtained as a yellow solid (98 %). Decompose

1

at ~260 °C; H NMR (400 MHz, D O): δ = 8.32 (d, J = 8.8 Hz, 1H), 7.53

brown solid (81 %). H NMR (400 MHz, CDCl

3

): δ = 8.22 (d, J = 8.0 Hz,

2

(

d, J = 8.4 Hz, 1H), 7.36 – 7.29 (m, 2H), 4.68 (s, 2H), 3.71 – 3.68 (m, 4H),

1

=

2

H), 7.39 (d, J = 8.0 Hz, 1H), 6.92 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 6.72 (d, J

8.0 Hz, 4.0 Hz, 1H), 4.78 (s, 2H), 4.04 (s, 2H), 2.72 (t, J = 8.0 Hz, 2H),

.42 (t, J = 8.0 Hz, 2H), 2.18 (s, 6H).

2

1

2

C

4

.97 (s, 6H); IR (KBr): 3426, 3018, 2959, 2730, 1631, 1581, 1501, 1480,

-1

4

399, 1358, 1129, 1090, 784 cm ; HRMS (EI) calcd for C14H19FN :

+

62.1594 ([M] ); found: 262.1586; Elemental analysis calcd (%) for

•2.8HCl•1.65H O•0.05C OC (apparent MW = 397.85): C,

2.87; H, 6.49; N, 14.08; found: C, 42.86; H, 6.51; N, 14.11.

14

H

19FN

4

2

H

2 5

H

TDMQ8. The procedure was similar to that described for the preparation

of compound TDMQ1. The product was obtained as a yellow solid (98 %).

Decompose at ~235 °C; H NMR (400 MHz, D2O): δ = 8.63 (d, J = 8.8

1

2

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

1

Synthesis of TDMQ-10

TDMQ6. F-TDMQ11 was obtained as a white solid (71 %). H NMR (400

MHz, CDCl

3

): δ = 9.00 (s, 1 H), 8.40 (d, J = 8.6 Hz, 1 H), 8.31 (d, J = 7.6

Hz, 1 H), 7.48 (d, J = 8.3 Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1 H), 2.76 (s, 3H),

5

,6-Dichloro-2-methyl-8-nitroquinoline (A-TDMQ10, Scheme 1, R =

13

1

2

3

.59 (s, 9 H). C NMR (100 MHz, CDCl ) δ 157.69, 152.80, 138.18,

33.87, 133.32, 126.12, 124.15, 123.10, 122.88, 114.31, 80.64, 28.42,

5.06.

5,6-Cl ). The procedure was similar to that described for the preparation

2

of M-TDMQ3, but starting from 2-amino-4,5-dichloronitrobenzene (D,

Scheme 1, R = 4,5-Cl ). A-TDMQ10 was obtained as a light yellow solid

54%). H NMR (400 MHz, CDCl ): δ = 8.51 (d, J = 8.8 Hz, 1 H), 8.03 (s,

2

1

(

3

1

H), 8.16 (d, J =8.8 Hz, 1 H), 2.79 (s, 3 H).

tert-Butyl (5-chloro-2-formylquinolin-8-yl)carbamate (G-TDMQ11).

The procedure was similar to that described for the preparation of N-

TDMQ1. Compound G-TDMQ11 was obtained as a yellow solid (55 %).

H NMR (400 MHz, CDCl ): δ = 10.28 (s, 1 H), 8.95 (s, 1 H), 8.71 (d, J =

3

5

,6-Dichloro-2-methylquinolin-8-amine (E-TDMQ10): The procedure

1

was similar to that described for the preparation of E-TDMQ4. E-

TDMQ10 was obtained as a light yellow solid (86%). H NMR (400 MHz,

CDCl ): δ = 10.25 (s, H), 8.91 (s, 1 H), 8.34 (d, J = 8.8 Hz, 1 H), 7.37 (d,

3

J =8.8 Hz, 1 H), 6.93 (s, 1 H), 2.71 (s, 3 H).

1

8.7 Hz, 1H), 8.47 (d, J = 8.4 Hz, 1 H), 8.15 (d, J = 8.7 Hz, 1 H), 7.72 (d, J

1

3

=

1

3

8.5 Hz, 1 H), 1.61 (s, 9 H). C NMR (100 MHz, CDCl ) δ 192.61,

52.48, 150.43, 138.17, 135.44, 134.97, 130.11, 127.86, 123.04, 118.37,

15.32, 81.38, 28.37.

tert-Butyl(5,6-dichloro-2-methylquinolin-8-yl)carbamate (F-TDMQ10):

1

2

N -((8-Amino-5-chloroquinolin-2-yl)methyl)-N ,N -dimethylethane-

1,2-diamine (H-TDMQ11). The procedure was similar to that described

The procedure was similar to that described for the preparation of F-

1

TDMQ6. F-TDMQ10 was obtained as a white solid (84%). H NMR (400

for the preparation of compound H-TDMQ6. H-TDMQ11 was obtained as

a yellow solid (77 %). H NMR (400 MHz, CDCl

MHz, CDCl

3

): δ = 8.98 (s, 1 H), 8.50 (s, 1 H), 8.40 (d, J = 8.4 Hz, 1 H),

1

3

): δ = 8.40 (d, J = 8.7 Hz,

7.42 (d, J =8.4 Hz, 1 H), 2.75 (s, 3H), 1.59 (s, 9 H).

1

H), 7.50 (d, J = 8.7 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 6.81 (d, J = 8.1

Hz, 1 H), 5.03 (brs, 2 H), 4.11 (s, 2 H), 2.76 (t, J = 6.1 Hz, 2 H), 2.47 (t, J

tert-Butyl(5,6-dichloro-2-formylquinolin-8-yl)carbamate (G-TDMQ10):

13

=

6.1 Hz, 2 H), 2.44 (brs, 1 H), 2.22 (s, 6 H). C NMR (100 MHz, CDCl

δ = 158.15, 142.97, 138.03, 133.31, 126.60, 125.47, 121.44, 118.09,

09.66, 59.35, 55.46, 47.00, 45.63.

3

):

The procedure was similar to that described for the preparation of N-

1

TDMQ1. G-TDMQ10 was obtained as a light yellow solid (56 %). H NMR

1

(400 MHz, CDCl

3

): δ = 10.25 (s, 1 H), 8.91 (s, 1 H), 8.69 (d, J = 8.4 Hz, 1

H), 8.65 (s, 1 H), 8.16 (d, J =8.4 Hz, 1 H), 1.62 (s, 9 H).

TDMQ11. The procedure was similar to that described for the preparation

1

2

of compound TDMQ1. TDMQ11 was obtained as a yellow solid (90 %).

N -((8-amino-5,6-dichloroquinolin-2-yl)methyl)-N ,N -

1

mp 204–206 °C; H NMR (400 MHz, D

2

O): δ = 8.68 (d, J = 8.8 Hz, 1H),

dimethylethane-1,2-diamine (H-TDQM10). The procedure was similar

to that described for the preparation of H-TDMQ6. H-TDMQ10 was

obtained as a light yellow solid (72%). H NMR (400 MHz, CDCl

.41 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 8.8 Hz, 1 H), 6.94 (s, 1 H), 5.06 (s,

H), 4.10 (s, 2 H), 2.76 (d, J = 6.0 Hz, 2 H), 2.48 (d, J = 6.0 Hz, 2 H),

.23 (s, 6 H); C NMR (100 MHz, CDCl

30.9, 126.3, 122.2, 115.5, 110.5, 59.3, 55.3, 47.0, 45.6.

7.68 – 7.63 (m, 2H), 7.45 – 7.42 (m, 1H), 4.73 (s, 2 H), 3.72 – 3.67 (m, 4

1

H), 2.97 (s, 6H); IR (KBr): 3426, 3241, 2992, 2921, 2720, 1629, 1602,

3

): δ =

1

577, 1503, 1475, 1440, 1424, 1396, 1349, 1308, 1227, 1202, 1157,

8

2

1

-

1

1090, 1058, 1024, 992, 952, 933, 853, 837, 783, 597, 483 cm ; HRMS

+

13

(EI) calcd for C14

analysis calcd (%) for C14

apparent MW = 424.01): C, 40.45; H, 6.22; N, 13.21; found: C, 40.47; H,

.29; N, 13.22.

H19ClN

4

: 278.1298 ([M] ); found: 278.1290; Elemental

3

): δ = 158.1, 143.4, 136.8, 133.5,

H19ClN

4

•2.9HCl•1.85H O•0.07CH COOC H

2

3

2 5

(

6

TDMQ10. The procedure was similar to that described for the preparation

of compound TDMQ1. TDMQ10 was obtained as a yellow solid (98 %).

1

Synthesis of TDMQ12

-Chloro-2-methyl-8-nitroquinoline (A-TDMQ12, Scheme 1, R = 6-Cl).

The procedure was similar to that described for the preparation of M-

TDMQ3, but using 2-amino-5-chloronitrobenzene (D, Scheme 1, R = 5-Cl)

6

Decompose at ~260 °C; H NMR (400 MHz, DMSO-d ): δ = 11.10 (brs,

1H), 9.96 (s, 2H), 8.47 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.98

6

(

2

s, 1H), 4.64 (s, 2H), 3.59 (s, 4H), 2.87 (s, 6H); IR (KBr): 3420, 2926,

-

711, 1631, 1598, 1506, 1464, 1366, 1173, 1140, 973, 843, 777, 649 cm

1

+

;

HRMS (EI) calcd for C14

Elemental analysis

•2.9HCl•1.65H O•0.05CH

2 4

H18Cl N : 312.0909 ([M] ); found: 312.0905;

as starting material. A-TDMQ12 was obtained as a light yellow solid

calcd

COOC

(%)

for

=

1

(

54%). H NMR (400 MHz, CDCl

3

): δ = 8.04 (d, J = 8.4 Hz, 1 H), 7.94 (d,

C

14

H18Cl

N

2 4

2

3

H

2 5

(apparent MW

J = 2.1 Hz, 1 H), 7.92 (d, J = 2.2 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 2.76

s, 3 H).

4

56.61): C, 37.77; H, 5.50; N, 12.27; found: C, 37.80; H, 5.54; N, 12.29.

Synthesis of TDMQ-11

-Chloro-2-methyl-8-nitroquinoline (A-TDMQ11, Scheme 1, R = 5-Cl).

(

6-Chloro-2-methylquinolin-8-amine (E-TDMQ12). The procedure was

similar to that described for the preparation of E-TDMQ4. E-TDMQ12

5

1

was obtained as a light yellow solid (81%). H NMR (400 MHz, CDCl

= 7.84 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 2.0 Hz,

H), 6.83 (d, J = 2.0 Hz, 1H), 5.05 (brs, 2H), 2.68 (s, 3H).

3

): δ

The procedure was similar to that described for the preparation of M-

TDMQ3. A-TDMQ11 was obtained as a yellow solid (40 %). H NMR

1

(

7

(

400 MHz, CDCl

.61 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 2.80 (s, 3H). C NMR

100 MHz, CDCl ): δ = 162.90, 146.95, 139.80, 135.18, 132.92, 125.46,

3

): δ = 8.50 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H),

13

N-(6-Chloro-2-formylquinolin-8-yl)acetamide

(F-TDMQ12).

The

3

procedure was similar to that described for the preparation of F-TDMQ4.

E-TDMQ12 was obtained as a light yellow solid (81%). H NMR (400

124.56, 124.36, 123.10, 25.64.

1

MHz, CDCl

3

): δ = 9.79 (s, 1H), 8.75 (s,1H), 7.94 (d, J = 8.0 Hz, 1H), 7.43

5

-Chloro-2-methylquinolin-8-amine (E-TDMQ11). The procedure was

(s, 1H), 7.34 (d, J = 8.0 Hz, 1H,), 2.73 (s, 3H), 2.36 (s, 3H)

similar to that described for the preparation of E-TDMQ4. E-TDMQ11

was obtained as a yellow solid (99 %). H NMR (400 MHz, CDCl

1

3

): δ =

N-(6-Chloro-2-formylquinolin-8-yl)acetamide

procedure was similar to that described for the preparation of N-TDMQ1.

G-TDMQ12 was obtained as a light yellow solid (45%). H NMR (400

MHz, CDCl

(G-TDMQ12).

The

8.34 (d, J = 8.6 Hz, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 1

13

H), 6.80 (d, J = 8.1 Hz, 1 H), 4.98 (brs, 2 H), 2.72 (s, 3 H). C NMR (100

MHz, CDCl ): δ = 156.75, 142.67, 138.22, 133.02, 126.18, 124.69,

22.91, 118.18, 109.62, 25.05.

1

3

): δ = 10.23 (s, 1H), 9.71 (s, 1H), 8.90 (s, 1H), 8.24 (d, J =

1

8.0Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 2.42 (s, 3H)

tert-Butyl (5-chloro-2-methylquinolin-8-yl)carbamate (F-TDMQ11).

The procedure was similar to that described for the preparation of F-

1

3

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

1

2

N -((8-Amino-6-chloroquinolin-2-yl)methyl)-N ,N -dimethylethane-

Synthesis of TDMQ-14

1,2-diamine (H-TDMQ12). The procedure was similar to that described

for the preparation of H-TDMQ4. H-TDMQ12 was obtained as a light

2

,5,7-Trimethylquinoline (C-TDMQ14, Scheme 1, R = 5,7-CH

procedure was similar to that described for the preparation of M-TDMQ3,

but starting from 3,5-dimethylaniline (B, Scheme 1, R = 5,7-CH ). C-

TDMQ14 was obtained as a yellow oil (64 %). H NMR (400 MHz, CDCl ):

δ = 8.08 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 1 H), 7.03 (s, 1H), 2.72

3

). The

1

yellow solid (81%). H NMR (400 MHz, CDCl

H), 7.39 (d, J = 8.4 Hz, 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 6.83 (d, J = 2.0 Hz,

H), 5.14 (brs, 2 H), 4.06 (s, 2 H), 2.81 (brs, 1 H), 2.77 (t, J = 6.0 Hz, 2

3

): δ = 7.89 (d, J = 8.4 Hz, 1

3

1

3

H), 2.48 (t, J = 6.0 Hz, 2 H), 2.22 (s, 6 H).

13

3

(s, 3 H), 2.52 (s, 3 H), 2.32 (s, 3 H). C NMR (100 MHz, CDCl ): δ =

TDMQ12. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ12 was obtained as a yellow solid (90 %). mp 253–

155.6, 138.8, 138.1, 132.6, 129.4, 124.3, 121.6, 120.6, 117.9, 25.1, 17.8,

17.5.

1

2

1

4

1

3

1

55 °C; H NMR (400 MHz, D

2

O): δ = 8.14 (d, J = 8.4 Hz, 1H), 7.68 (s,

H), 7.62 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 4.69 (s, 2 H), 3.78-3.71 (m,

H), 2.99 (s, 6H); C NMR (100 MHz, D O): δ = 152.0, 137.9, 137.6,

2

31.8, 130.0, 128.4, 126.0, 123.2,121.8, 52.6, 51.4, 43.5, 41.9; IR (KBr):

334, 3022, 2968, 2914, 2697, 2533, 2429, 1630, 1601, 1495, 1475,

399, 1320, 1303, 1242, 1090, 1021, 999, 967, 876, 828, 784, 653, 534

cm-1; HRMS (EI) calcd for C14

Elemental analysis calcd (%) for C14

415.18): C, 40.45; H, 6.07; N, 13.49; found: C, 40.48; H, 6.07; N, 13.48.

2,5,7-Trimethyl-8-nitroquinoline (A-TDMQ14). The procedure was

13

similar to that described for the preparation of A-TDMQ5. A-TDMQ14

1

was obtained as a yellow solid (33 %). H NMR (400 MHz, CDCl

3

): δ =

8

.16 (d, J = 8.8 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.17 (s, 1H), 2.71 (s, 3

13

H), 2.65 (s, 3 H), 2.46 (s, 3 H). C NMR (100 MHz, CDCl

3

): δ = 160.93,

46.90, 139.60, 136.48, 132.12, 129.30, 127.95, 124.36, 122.51, 25.46,

8.54, 17.24.

+

H

19ClN

4

: 278.1298 ([M] ); found: 278.1290;

1

4 2

H19ClN •3HCl•1.5H O (apparent MW

=

2

,5,7-Trimethylquinolin-8-amine (E-TDMQ14). The procedure was

Synthesis of TDMQ-13

-Chloro-2-methyl-8-nitroquinoline (A-TDMQ13, Scheme 1, R = 7-Cl).

similar to that described for the preparation of E-TDMQ4. E-TDMQ14

was obtained as a yellow solid (80 %). H NMR (400 MHz, CDCl

8.07 (d, J = 8.8 Hz, 1 H), 7.21 (d, J = 8.8 Hz, 1 H), 7.02 (s, 1 H), 4.79 (br

s, 2 H), 2.70 (s, 3 H), 2.51 (s, 3 H), 2.32 (s, 3 H). C NMR (100 MHz,

CDCl ): δ = 155.61, 138.80, 138.12, 132.61, 129.35, 124.24, 121.56,

1

3

): δ =

7

13

The procedure was similar to that described for the preparation of M-

TDMQ3, but starting from 2-amino-6-chloronitrobenzene (D, Scheme 1,

3

1

R = 6-Cl). A-TDMQ13 was obtained as a light yellow solid (80%).

NMR (400 MHz, CDCl

1

H

120.63, 117.81, 25.14, 17.76, 17.55.

3

): δ = 8.08 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.8 Hz,

H), 7.52 (d, J = 8.8 Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1 H), 2.74 (s, 3 H).

tert-Butyl(2,5,7-trimethylquinolin-8-yl)carbamate (F-TDMQ14). The

procedure was similar to that described for the preparation of F-TDMQ6.

1

7-Chloro-2-methylquinolin-8-amine (E-TDMQ13). The procedure was

F-TDMQ14 was obtained as a yellow solid (89 %). H NMR (400 MHz,

similar to that described for the preparation of E-TDMQ4. A-TDMQ13

CDCl

3

): δ = 8.09 (d, J = 8.8 Hz, 1 H), 7.80 (brs, 1 H), 7.23 (d, J = 8.8 Hz,

1

was obtained as a light yellow solid (86%). H NMR (400 MHz, CDCl

3

): δ

.84 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 6.83 (s, 1H),

.05 (brs, 2H), 2.68 (s, 3H).

1 H), 7.15 (s, 1 H), 2.71 (s, 3 H), 2.57 (s, 3 H), 2.45 (s, 3 H), 1.54 (s, 9 H).

1

3

7

5

C NMR (100 MHz, CDCl

130.11, 129.91, 129.66, 123.98, 120.83, 79.84, 28.39, 25.31, 19.64,

8.16.

3

): δ = 157.29, 154.08, 142.40, 132.49, 132.36,

1

N-(7-Chloro-2-methylquinolin-8-yl)acetamide

(F-TDMQ13).

The

procedure was similar to that described for the preparation of F-TDMQ4.

F-TDMQ13 was obtained as a light yellow solid (42%). H NMR (400

tert-Butyl(2-formyl-5,7-dimethylquinolin-8-yl)carbamate (G-TDMQ14).

The procedure was similar to that described for the preparation of N-

TDMQ1. G-TDMQ14 was obtained as a light-yellow solid (57 %), which

was conducted for the next step without further purification.

1

MHz, CDCl

3

): δ = 8.04 (d, J=8.4 Hz, 1 H), 7.79 (d, J=8.8 Hz, 1 H), 7.57 (d,

J=8.8 Hz, 1 H), 7.32 (d, J=8.4 Hz, 1 H), 2.688(s, 3H), 2.30 (s, 6 H).

1

2

N-(7-Chloro-2-formylquinolin-8-yl)acetamide

(G-TDMQ13).

The

N -((8-Amino-5,7-dimethylquinolin-2-yl)methyl)-N ,N -

procedure was similar to that described for the preparation of N-TDMQ1.

G-TDMQ13 was obtained as a light yellow solid (64%). H NMR (400

dimethylethane-1,2-diamine (H-TDMQ14). The procedure was similar

1

to that described for the preparation of H-TDMQ6. H-TDMQ14 was

1

MHz, CDCl

3

): δ = 10.13 (s, 1 H), 8.39 (d, J=8.8 Hz, 1 H), 8.10 (d, J=8.8

obtained as a yellow solid (87 %). H NMR (400 MHz, CDCl

3

): δ = 8.15 (d,

Hz, 1 H), 7.96 (d, J=8.8 Hz, 1 H), 7.81 (d, J=8.8 Hz, 1H), 2.33 (s, 6 H).

J = 8.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 4.82 (br s, 2H),

4

2

1

.09 (s, 2H), 2.77 (t, J = 6.1 Hz, 2H), 2.53 (s, 3H), 2.48 (t, J = 6.1 Hz, 2H),

.33 (s, 3H), 2.22 (s, 6H). C NMR (101 MHz, CDCl ): δ = 156.4, 139.0,

3

37.9, 133.0, 129.9, 125.1, 121.6, 119.2, 118.0, 59.1, 55.3, 46.8, 45.5,

7.8, 17.5.

13

1

2

N -((8-Amino-7-chloroquinolin-2-yl)methyl)-N ,N -dimethylethane-

,2-diamine (H-TDMQ13). The procedure was similar to that described

for the preparation of H-TDMQ4. H-TDMQ-13 was obtained as a light

1

yellow solid (91%). H NMR (400 MHz, CDCl

3

): δ = 7.99 (d, J = 8.4 Hz, 1

H), 7.39 (d, J = 8.4 Hz, 1 H), 7.34 (d, J = 8.7 Hz, 1 H), 7.05 (d, J = 8.7 Hz,

TDMQ14. The procedure was similar to that described for the preparation

1

6

H), 5.35 (brs, 2 H), 4.09 (s, 2 H), 2.76 (t, J = 6.0 Hz, 2 H), 2.48 (t, J =

.0 Hz, 2 H), 2.46 (brs, 1 H), 2.23 (s, 6 H).

of TDMQ1. TDMQ14 was obtained as a yellow solid (90 %). mp 189–

1

191 °C; H NMR (400 MHz, D

2

O): δ = 8.55 (d, J = 8.4 Hz, 1H), 7.56 (d, J

=

2

8.8 Hz, 1H), 7.43 (s, 1H), 4.72 (s, 2H), 3.73 – 3.68 (m, 4H), 2.98 (s, 6H),

.63(s, 3H), 2.51(s, 3H); IR (KBr): 3328, 3057, 2959, 2694, 2423, 1629,

TDMQ13. The procedure was similar to that described for the preparation

-

1

602, 1516, 1463, 1402, 1384, 1345, 1241, 1015, 886, 829, 592, 563 cm

of compound H-TDMQ1. TDMQ13 was obtained as a yellow solid (90 %).

1

+

1

;

HRMS (EI) calcd for C16

H

24

N

4

: 272.2001 ([M] ); found: 272.1994;

mp 239–241 °C; H NMR (400 MHz, D

2

O): δ = 8.12 (d, J = 8.8 Hz, 1H),

Elemental analysis calcd (%) for

(apparent MW = 459.75): C, 43.37; H, 6.84; N, 12.19; found: C, 43.35; H,

.79; N, 12.18.

16 4 4 2 2 2

C H N •3HCl•1.5H O•0.6CH Cl

7

.41 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H),

13

2

4.65 (s, 2 H), 3.75-3.61 (m, 4H), 2.94 (s, 6H); C NMR (100 MHz, D O):

6

δ = 13C NMR (100 MHz, D2O): δ = 151.4, 138.7, 138.5, 130.5, 128.0,

1

7

2

C

4

26.4, 124.3, 124.0, 120.4, 52.6, 51.3, 43.5, 41.8; IR (KBr): 3375, 2925,

630, 1602, 1553, 1459, 1400, 1327, 1243, 1143, 1035, 1008, 957, 865,

Synthesis of TDMQ-15

-

1

+

87 cm ; HRMS (EI) calcd for C14

78.1290; Elemental analysis

•3HCl•0.7H O•0.09CH COOC

2.20; H, 5.95; N, 13.71; found: C, 42.23; H, 5.92; N, 13.72.

H

19ClN

4

: 278.1298 ([M] ); found:

calcd (%) for

2 5

H (apparent MW = 408.70): C,

2,5,6-Trimethyl-8-nitroquinoline (A-TDMQ15, Scheme 1, R = 5,6-CH ).

3

14

H

19ClN

4

2

3

The procedure was similar to that described for the preparation of M-

TDMQ3, but starting from 2-amino-4,5-dimethylnitroquinoline (D, Scheme

1

4

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

1

, R = 4,5-CH

NMR (400 MHz, CDCl

J = 8.8 Hz, 1H), 2.73 (s, 3H), 2.60 (s, 3H), 2.50 (s, 3H). C NMR (100

MHz, CDCl ) δ 160.24, 145.87, 138.11, 136.78, 132.20, 132.18, 126.53,

26.01, 123.14, 25.43, 20.31, 14.77.

3

). A-TDMQ15 was obtained as a yellow oil (69 %).

H

TDMQ4. F-TDMQ16 was obtained as a light yellow solid (78 %). H NMR

3

) δ 8.27 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.37 (d,

3

(400 MHz, CDCl ): δ = 9.85 (s, 1 H), 8.97 (s,1 H), 8.12 (d, J = 8.4 Hz,1

H), 7.76 (s,1 H), 7.42 (d, J = 8.4 Hz, 1 H), 2.79 (s, 3H), 2.38 (s, 3 H).

13

3

1

N-(2-Formyl-6-(trifluoromethyl)quinolin-8-yl)acetamide (G-TDMQ16).

The procedure was similar to that described for the preparation of N-

1

2,5,6-Trimethylquinolin-8-amine (E-TDMQ15). The procedure was

TDMQ1. G-TDMQ16 was obtained as a light yellow solid (50 %). H NMR

similar to that described for the preparation of E-TDMQ4. E-TDMQ15

(400 MHz, CDCl

3

): δ 10.28 (s, 1 H), 9.77 (s, 1 H), 9.12 (s, 1 H), 8.45 (d, J

1

was obtained as a brown solid (60 %). H NMR (400 MHz, CDCl

3

): δ =

= 8.0 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 7.90 (s, 1H), 2.43 (s, 3 H).

8

2

.14 (d, J = 8.8 Hz, 1 H), 7.25 (d, J = 8.8 Hz, 1 H), 6.78 (s, 1H), 4.78 (brs,

13

H), 2.69 (s, 3 H), 2.43 (s, 3 H), 2.38 (s, 3 H). C NMR (100 MHz,

): δ = 154.5, 140.9, 137.3, 133.3, 132.3, 126.1, 121.6, 119.4, 113.6,

4.9, 20.6, 13.3.

1

2

N -((8-Amino-6-(trifluoromethyl)quinolin-2-yl)methyl)-N ,N -

CDCl

2

3

dimethylethane-1,2-diamine (H-TDMQ16). The procedure was similar

to that described for the preparation of H-TDMQ4. H-TDMQ16 was

obtained as a light yellow solid (85 %). H NMR (400 MHz, CDCl

1

3

) δ 8.07

tert-Butyl(2,5,6-trimethylquinolin-8-yl)carbamate (F-TDMQ15). The

(d, J = 8.4 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.01 (s, 1 H),

5.23 (br s, 2 H), 4.11 (s, 2 H), 2.77 (t, J = 6.0 Hz, 2 H), 2.55 (brs, 1 H),

2.48 (t, J = 6.0 Hz, 2 H), 2.23 (s, 6 H).

procedure was similar to that described for the preparation of F-TDMQ6.

1

F-TDMQ15 was obtained as a white solid (90 %). H NMR (400 MHz,

CDCl

.7 Hz, 1H), 2.71 (s, 3H), 2.48 (s, 3H), 2.46 (s, 3H), 1.59 (s, 9H).

NMR (100 MHz, CDCl ) δ 155.19, 153.11, 136.73, 133.53, 132.56,

32.05, 125.53, 123.50, 121.84, 117.37, 80.11, 28.49, 24.87, 20.87,

3.64.

3

) δ 9.01 (s, 1H), 8.23 (s, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.28 (d, J =

13

8

C

TDMQ16. The procedure was similar to that described for the preparation

3

of TDMQ1. TDMQ16 was obtained as a yellow solid (88 %). Decompose

1

at ~209 °C; H NMR (400 MHz, DMSO-d

6

): δ = 8.23 (d, J = 8. 4 Hz, 1 H),

7

4

.55 (s, 1H), 7.47 (d, J = 8. 4 Hz, 1 H), 7.20 (s, 1H), 4.47 (s, 2H), 3.47 (s,

H), 2.89 (s, 6H); IR (KBr): 3374, 3302, 3169, 2976, 2794, 2718, 1630,

tert-Butyl(2-formyl-5,6-dimethylquinolin-8-yl)carbamate (G-TDMQ15).

The procedure was similar to that described for the preparation of N-

TDMQ1. G-TDMQ15 was obtained as a yellow solid (53 %), which was

conducted for the next step without further purification.

1604, 1508, 1439, 1365, 1292, 1265, 1231, 1159, 1141, 1110, 1041,

-

1

19 3 4

1020, 925, 865, 849, 835, 790, 712 cm ; HRMS (EI) calcd for C15H F N :

+

312.1562 ([M] ); found: 312.1559; Elemental analysis calcd (%) for

•2.9HCl•0.4H O•0.08CH COOC (apparent MW = 432.32):

15 19 3

C H F N

4

2

3

2 5

H

C, 42.56; H, 5.44; N, 13.18; found: C, 42.53; H, 5.42; N, 13.18.

1

2

N -((8-Amino-5,6-dimethylquinolin-2-yl)methyl)-N ,N -

dimethylethane-1,2-diamine (H-TDMQ15). The procedure was similar

to that described for the preparation of H-TDMQ6. H-TDMQ-15 was

obtained as a brown solid (43 %). mp. 52-54℃. H NMR (400 MHz,

Synthesis of TDMQ-18

1

4-Chloro-2-methyl-8-nitroquinoline (A-TDMQ18, Scheme 1, R = 4-Cl).

CDCl

3

) δ 8.20 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.78 (s, 1H),

The procedure was similar to that described for the preparation of A-

4

2

1

2

.08 (s, 2H), 2.78 (t, J = 6.1 Hz, 2H), 2.48 (t, J = 6.1 Hz, 2H), 2.43 (s, 3H),

TDMQ5, but starting from 4-chloro-2-methylquinoline (C, Scheme 1, R =

13

.37 (s, 3H), 2.22 (s, 6H). C NMR (101 MHz, CDCl

3

) δ = 155.7, 141.2,

1

4-Cl). A-TDMQ18 was obtained as a light yellow solid (51 %). H NMR

37.1, 133.9, 132.6, 127.0, 120.2, 119.4, 113.6, 59.4, 55.4, 47.0, 45.6,

0.6, 13.4.

3

(400 MHz, CDCl ): δ = 8.37 (dd, J = 7.6, 1.2 Hz, 1 H), 7.98 (dd, J = 7.6,

1.2 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.52 (s, 1 H), 2.74 (s, 3 H).

TDMQ15. The procedure was similar to that described for the preparation

4

-Chloro-2-methylquinolin-8-amine (E-TDMQ18). The procedure was

of compound TDMQ1. TDMQ15 was obtained as a yellow solid (92 %).

similar to that described for the preparation of E-TDMQ4. A-TDMQ18

1

Decompose at ~206 °C; H NMR (400 MHz, D

2

O): δ = 8.63 (d, J = 8.8 Hz,

was obtained as a light yellow solid (95 %). H NMR (400 MHz, CDCl

3

): δ

7.46 (dd, J = 8.0, 1.2 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H), 7.32 (s, 1 H),

.93 (dd, J =8.0, 1.2 Hz, 1 H), 5.07 (s, 2 H), 2.68 (s, 3 H).

1

4

1

H), 7.65 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 4.70 (s, 2H), 3.73 – 3.68 (m,

=

6

H), 2.97 (s, 6H), 2.55(s, 3H), 2.46(s, 3H); IR (KBr): 3354, 2961, 2714,

-

1

631, 1596, 1502, 1401, 1314, 1248, 1108, 1020, 961, 838, 791 cm ;

+

HRMS (EI) calcd for

Elemental analysis

•2.9HCl•1.2H O•0.09CH

8.20; H, 7.42; N, 13.74; found: C, 48.25; H, 7.47; N, 13.76.

C

16

H

24

N

4

:

272.2001 ([M] ); found: 272.1994;

calcd (%) for

COOC (apparent MW = 407.67): C,

tert-Butyl (4-chloro-2-methylquinolin-8-yl)carbamate (F-TDMQ18).

The procedure was similar to that described for the preparation of F-

TDMQ6. A-TDMQ18 was obtained as a light yellow solid (35 %). H NMR

C

4

H N

16 24 4

2

3

H

2 5

1

(400 MHz, CDCl

3

): δ = 9.08 (s, 1 H), 8.45 (d, J = 7.6 Hz, 1 H), 7.75 (d, J

=

8.0 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.41 (s, 1 H), 1.59 (s, 9 H).

Synthesis of TDMQ-16

tert-Butyl (4-chloro-2-formylquinolin-8-yl)carbamate (G-TDMQ18).

2

-Methyl-8-nitro-6-(trifluoromethyl)quinoline (A-TDMQ16, Scheme 1,

R = 6-CF ). The procedure was similar to that described for the

preparation of M-TDMQ3, but using 2-amino-5-trifluoromethyl

nitrobenzene (D, Scheme 1, R = 5-CF ). A-TDMQ16 was obtained as a

light yellow solid (59 %). H NMR (400 MHz, CDCl ): δ = 8.28 (s, 1 H),

.22 (d, J = 8.4 Hz, 1 H), 8.12 (s, 1 H), 7.54 (d, J = 8.4 Hz, 1 H), 2.81 (s,

The procedure was similar to that described for the preparation of N-

1

3

TDMQ1. G-TDMQ18 was obtained as a light yellow solid (56 %). H NMR

(400 MHz, CDCl

3

): δ = 10.21 (s, 1 H), 8.59 (d, J = 7.6 Hz, 1 H), 8.11 (s, 1

3

H), 7.87 (d, J = 7.6 Hz, 1 H), 7.75 (t, J = 8.0 Hz, 1 H), 1.61 (s, 9 H).

1

3

8

3

1

2

N -((8-Amino-4-chloroquinolin-2-yl)methyl)-N ,N -dimethylethane-

,2-diamine (H-TDMQ18). The procedure was similar to that described

for the preparation of H-TDMQ6. H-TDMQ-18 was obtained as a brown

H).

1

2-Methyl-6-(trifluoromethyl)quinolin-8-amine

(E-TDMQ16).

The

1

solid (73 %). HNMR (400 MHz, CDCl

.44 (s, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 5.02 (s, 2

H), 4.12 (s, 2 H), 2.94 (t, J = 6.0 Hz, 2 H), 2.70 (t, J = 6.0 Hz, 2 H), 2.38

3

): δ = 7.46 (d, J = 8.4 Hz, 1 H),

procedure was similar to that described for the preparation of E-TDMQ4.

E-TDMQ16 was obtained as a light yellow solid (74 %). H NMR (400

MHz, CDCl

7

1

3

): δ = 8.02 (d, J=8.4 Hz, 1 H), 7.39 (s, 1 H), 7.33 (d, J = 8.4

13

(

s, 6 H); C NMR (100 MHz, CDCl

3

): δ = 157.1, 144.0, 142.8, 138.3,

Hz, 1 H), 7.01 (s, 1 H), 5.15 (br s, 2 H), 2.74 (s, 3 H).

127.8, 126.0, 120.7, 112.1, 111.0, 59.2, 55.2, 46.8, 45.5.

N-(2-Methyl-6-(trifluoromethyl)quinolin-8-yl)acetamide (F-TDMQ16).

The procedure was similar to that described for the preparation of F-

TDMQ18. The procedure was similar to that described for the preparation

of compound TDMQ1. TDM18 was obtained as a yellow solid (91 %).

1

5

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

1

Decompose at ~287 °C; H NMR (400 MHz, DMSO-d

H), 7.82 (s, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.12

d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 3.61 (s, 2H), 2.87 (s, 6H); IR (KBr): 3426,

6

): δ = 10.04 (brs,

3-(Dimethylamino)-1-propylamine (1.03 g, 10.1 mmol) was added to an

suspension of G’-TDMQ19 in dry 1,2-dichloroethane (35 mL) under

argon. The mixture was stirred at room temperature for 15 min and the

solution became yellow and limpid. To this, was added sodium

triacetoxyborohydride (2.14 g, 10.1 mmol) and the reaction mixture was

further stirred for 48 h. After, the mixture was diluted with methylene

chloride, washed with water and the organic phase was dried with over

2

(

3

1

025, 2929, 2670, 2563, 2475, 1630, 1592, 1496, 1467, 1390, 1288,

218, 1161, 1110, 1027, 953, 910, 830, 764, 527 cm ; HRMS (EI) calcd

-

1

+

for C14

calcd (%) for C15

MW = 411.26): C, 42.52; H, 6.03; N, 13.62; found: C, 42.46; H, 6.04; N,

3.61.

H

19cClN

4

: 278.1298 ([M] ); found: 278.1294; Elemental analysis

H F

19 3

N

4

•2.9HCl•0.8H O•0.14CH COOC (apparent

2

3

2 5

H

Na

which was purified by column chromatography on silica gel (10%

MeOH/NH OH 25% (70/30, v/v) in CH Cl ). Evaporation of the eluate to

dryness provided H-TDMQ19 as a yellow oil (0.89 g, 75%). H NMR (400

MHz, CDCl ): δ = 8.37 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44

s, 1H), 5.34 (br, 2H), 4.10 (br, 2H), 2.77 (t, J = 8.0 Hz, 2H), 2.37 (t, J =

2 4

SO and filtered. The solvent was evaporated to provide the yellow oil

1

4

2

1

Synthesis of TDMQ-19

3

(

8

N-(5,7-Dichloro-2-methylquinolin-8-yl)-2-hydroxy-2-

13

.0 Hz, 2H), 2.24 (s, 6H), 2.21 (br, 1H), 1.75 (q, J = 8.0 Hz, 2H).

C

methylpropanamide (F-TDMQ19, Scheme S1). To a solution of 5,7-

dichloro-2-methylquinolin-8-ol (2.28 g, 10 mmol) in anhydrous 1,4-

dioxane (50 mL) under argon was added sodium hydride (1.2 g, 60% in

mineral oil, 30 mmol), cesium carbonate (9.78 g, 30 mmol) and 2-bromo-

NMR (100 MHz, CDCl

21.3, 117.7, 113.6, 58.1, 55.4, 48.2, 45.6, 28.2. MS (ESI ): m/z = 327.1

3

): δ = 159.2, 139.6, 137.7, 133.4, 126.8, 124.1,

+

1

+

[M+H] .

2

-methylpropionamide (4.98 g, 30 mmol). The reaction mixture was

stirred for 20 h at 110°C. Then, 1-methyl-2-pyrrolidinone (NMP, 55 mL,

.57 mol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 6

TDMQ19 (Scheme S1). Compound H-TDMQ19 (0.84 g, 2.57 mmol) was

treated with HCl 6 M (10 mL) for 30 min and the solvent was removed

0

under vacuum to give TDMQ19 as brown yellow solid (1.13 g, 95%).

mL, 50 mmol) and sodium hydride (0.5 g, 60% in mineral oil, 12.5 mmol)

were added and the resulting mixture was further stirred for 24 h at

1

Decompose at ~293 °C; H NMR (400 MHz, DMSO-d

6

): δ = 10.79 (br s,

1

H), 9.84 (s, 2H), 8.47 (d, J = 8.0 Hz), 7.70 (d, J = 8.0 Hz, 1H), 7.68 (s,

1

30°C. After cooling, water (200 mL) was added and the solution was

extracted with ethyl acetate (4 x 400 mL). The combined organic layers

were washed with water, dried over Na SO , filtered and concentrated

13

1H), 4.61 (m, 2H), 3.19 (m, 4H), 2.75 (s, 6H), 2.23 (m, 2H). C NMR

): δ = 151.5, 141.9, 136.9, 134.2, 128.3, 124.5,

(100 MHz, DMSO-d

6

2

4

1

2

1

3

22.1, 114.6, 112.1, 53.9, 50.2, 44.3, 42.4, 20.9; IR (KBr): 3348, 3015,

under reduced pressure. The crude brown oil was purified by using silica

923, 2706, 1597, 1507, 1456, 1395, 1369, 1317, 1282, 1194, 1108,

gel flash chromatography (petroleum ether/AcOEt from 100/0, v/v to

-

1

+

1

039, 946, 862, 775 cm ; HRMS (ESI) calcd for C15

2 4

H21Cl N ([M+H] ):

2

0/80, v/v) to give F-TDMQ19 as a white solid (1.95 g, 62%). H NMR

27.1139, found 327.1143. Elemental

analysis

for

(

1

400 MHz, DMSO-d

H), 7.63 (d, J = 8.0 Hz, 1H), 5.84 (s, 1H), 2.70 (s, 3H), 1.45 (s, 6H).

6

): δ = 9.60 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.89 (s,

13

^C15^H20Cl N •3HCl•0.31H O• 0.25 CH Cl (apparent MW

=

462.3):

C

2

4

2

calculated C 39.62, H 5.25, N 12.12; found C 39.64, H 5.27, N 11.95.

NMR (100 MHz, DMSO-d

6

): δ = 175.8, 161.0, 144.3, 133.2, 132.1, 131.2,

+

1

28.7, 126.9, 124.2, 123.5, 73.2, 28.2, 25.5. MS (ESI ): m/z = 313

+

[M+H] .

Synthesis of TDMQ-20

N-(5,7-Dichloro-2-formylquinolin-8-yl)-2-hydroxy-2-

5,7-Dichloro-8-nitro-2-vinylquinoline (I-TDMQ20, Scheme 2, R = 5,7-

methylpropanamide (G-TDMQ19).

Cl

in DMA (5 mL) was added FeCl

1.05 g, 7.8 mmol). The mixture was stirred at 110℃ for 1.5 h and

quenched with water. After extraction with CH Cl , the organic phase was

dried over Na SO , filtered, and concentrated under reduced pressure.

2

). To a solution of A-TDMQ5 (Scheme 2, R = 5,7-Cl

2

, 1.0 g, 3.9 mmol)

3

(19.0 mg, 0.117 mmol) and K

2 2 8

S O

(

2

Previously dried SeO (0.81 g, 7.34 mmol) was added to a suspension of

F-TDMQ19 (1.9 g, 6.07 mmol) in anhydrous 1,4-dioxane (40 mL) under

argon. The reaction mixture was stirred overnight at 85°C and, after

cooling, passed through a Celite 521 filter cake. The Celite was washed

2

4

The crude mixture was purified by silica gel flash column

chromatography (EtOAc/petroleum ether, 1:10, v/v). After evaporation of

with a solution of CH

under reduced pressure, the obtained residue was purified by using silica

gel flash chromatography (CH Cl /iPrOH from 100/0, v/v to 90/10, v/v) to

yield G-TDMQ19 as a yellow solid (1.7 g, 85%). H NMR (400 MHz,

DMSO-d ): δ = 10.09 (d, J = 0.8 Hz, 1H), 9.81 (br, 1H), 8.81 (dd, J = 8.0,

.8 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 1.47 (s,

2 2

Cl /iPrOH (9/1). After evaporation of the filtrate

the eluent, compound I-TDMQ20 was obtained as a brown solid (430.3

1

mg, 41%). H NMR (400 MHz, CDCl

3

) δ 8.52 (d, J = 8.8 Hz, 1 H), 7.73 (d,

2

1

J = 8.8 Hz, 1 H), 7.65 (s, 1 H), 6.97 (dd, J = 17.6, 10.8 Hz, 1 H), 6.46 (d,

J = 17.6 Hz, 1 H), 5.79 (d, J = 10.8 Hz, 1 H).

6

0

6

+

1

2

H). MS (ESI ): m/z = 327 [M+H] .

N -(2-(5,7-Dichloro-8-nitroquinolin-2-yl)ethyl)-N ,N -dimethylethane-

,2-diamine (J-TDMQ20, Scheme 2, R = 5,7-Cl , R = CH -N(CH ). To

a mixture of I-TDMQ20 (780.3 mg, 2.9 mmol) and K CO (481 g, 3.48

1

2

1

2

3 2

)

8-Amino-5,7-dichloroquinoline-2-carbaldehyde (G’-TDMQ19). G-

2

3

mmol) in 1, 4-dioxane (10 mL) was added N,N-dimethyl-1,2-

ethanediamine (511.2 mg, 5.8 mmol). The reaction mixture was stirred at

room temperature for 1 h, and quenched with water. After extraction with

TDMQ19 (1.7 g, 5.18 mmol) was dissolved in HCl 37 wt% (17 mL) and

was stirred for 90 min at 50°C. After cooling, the reaction mixture was

added dropwise over cold water, and the pH was adjusted to 7 with a 3 M

2 2 2 4

CH Cl , the organic phase was dried over Na SO , filtered, and

aqueous NaOH solution. The aqueous phase was extracted with CH

3 x 400 mL). The combined organic layers were dried over Na SO

filtered and concentrated under reduced pressure. The crude product

was purified by using silica gel flash chromatography (CH Cl /iPrOH from

00/0, v/v to 90/10, v/v) to yield G’-TDMQ19 as a brown powder (0.89 g,

2 2

Cl

concentrated under reduced pressure. The crude mixture was purified by

silica gel flash column chromatography ethyl acetate/isopropanol/25%

ammonium hydroxide, 8/2/0.5, v/v/v). After evaporation of the eluent, J-

(

2

4

,

2

1

TDMQ20 was obtained as yellow solid (777 mg, 75 %). H NMR (400

1

MHz, CDCl ): δ = 8.46 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.54 (d, J = 8.8

71%). H NMR (400 MHz, DMSO-d

6

): δ = 10.14 (d, J = 0.8 Hz, 1H), 8.60

3

Hz, 1H), 3.22 (t, J = 6.0 Hz, 2H), 3.12 (t, J = 6.0 Hz, 2H), 2.74 (t, J = 6.4

Hz, 2H), 2.43 (t, J = 6.4 Hz, 2H), 2.23 (s, 6H).

(

2

1

dd, J = 8.0, 0.8 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 6.62 (br,

13

H). C NMR (100 MHz, DMSO-d

6

): δ = 193.3, 150.6, 142.7, 137.3,

): m/z = 241.0

34.8, 130.7, 126.9, 118.9 , 114.9, 112.6. MS (DCI, NH

3

+

1

2

[M+H] .

N -(2-(8-Amino-5,7-dichloroquinolin-2-yl)ethyl)-N ,N -

dimethylethane-1,2-diamine (K-TDMQ20). The procedure was similar

1

to that described for the preparation of M-TDMQ3. K-TDMQ20 was

N -[(8-Amino-5,7-dichloroquinolin-2-yl)methyl]propane-1,3-diamine

(

1

obtained as a light yellow solid (90%). H NMR (400 MHz, CDCl

3

): δ =

H-TDMQ19).

8.33 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 5.40 (brs,

1

6

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2

H), 3.19-3.12 (m, 4 H), 2.77 (t, J = 6.0 Hz, 2H), 2.44 (t, J = 6.0 Hz, 2H),

.22 (s, 6H).

2 2

(142.5 mg, 0.4 mmol), SnCl •2H O (270.8 mg, 1.2 mmol) in ethanol (5

mL) was added HCl (12 M, 1 mL) dropwise at room temperature, and the

o

mixture was stirred at 50 C for 1 h. Water (50 mL) was added, followed

by addition of extra aqueous 25% ammonium hydroxide. The mixture

TDMQ20. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ20 was obtained as a yellow solid (90 %). mp 189–

was extracted with CH

were dried (Na SO ), filtered and concentrated under reduced pressure.

The crude product was purified by silica gel flash chromatography (ethyl

acetate/isopropanol/25% ammonium hydroxide, 50/1/1, v/v/v).

Evaporation of the solvent afforded K-TDMQ22 as a light yellow solid

2 2

Cl (3 x 30 mL). The combined organic layers

1

3

1

4

1

91 °C; H NMR (400 MHz, D

2

O): δ = 8.32 (d, J = 8.4 Hz, 1H), 7.46 (s,

2

4

H), 7.44 (d, J = 8.8 Hz, 1H), 3.71 (t, J = 6.8 Hz, 2H), 3.55 – 3.48 (m, 4H),

.39 (t, J = 6.8 Hz, 2H), 2.90 (s, 6H); C NMR (100 MHz, DMSO-d ): δ =

6

56.7, 141.3, 137.4, 133.6, 127.5, 123.9, 123.8, 115.2, 112.1, 52.8, 45.3,

2.9, 41.9, 33.7; IR (KBr): 3441, 3354, 3194, 3015, 1676, 1632, 1593,

545, 1468, 1403, 1376, 1310, 763 cm ; HRMS (ESI) calcd for

13

1

(

96.6 mg, 74%). H NMR (400 MHz, CDCl

H), 7.38 (s, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.01 (s, 1 H), 5.24 (brs, 2 H),

.21-3.11 (m, 4 H), 2.78 (t, J = 6.0 Hz, 2 H), 2.45 (t, J = 6.0 Hz, 2 H), 2.21

s, 6 H).

3

): δ = 8.04 (d, J = 8.4 Hz, 1

-

1

+

3

(

C

15

H

21Cl

20Cl

2

N

4

: 327.1143 ([M+H] ); found: 327.1148; Elemental analysis for

•3HCl•0.2H O (apparent MW = 440.24): calculated C, 40.93;

15

H

2

4

2

H, 5.36; N, 12.73; found C, 40.71; H, 5.24; N, 12.78.

TDMQ22. The procedure was similar to that described for the preparation

of compound TDMQ1. TDMQ22 was obtained as a yellow solid (90 %).

Synthesis of TDMQ-21

1

mp 180–182 °C; H NMR (400 MHz, D

2

O): δ = 8.36 (d, J = 8.8 Hz, 1H),

1

3

7.58 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.07 (s, 1H), 3.65 (s, 2H), 3.50 (s,

N -(2-(5,7-Dichloro-8-nitroquinolin-2-yl)ethyl)-N ,N -

13

4

1

2

H), 3.42 (t, J = 7.2 Hz, 2H), 2.85 (s, 6H); C NMR (100 MHz, D O): δ =

59.9, 140.5, 138.9, 130.6, 127.3 (q, J = 26.5 Hz), 126.8, 124.9, 124.4,

23.4 (q, J = 216.1 Hz), 117.3, 52.4, 46.2, 43.4, 42.0, 33.4; IR (KBr):

2 1

dimethylpropane-1,3-diamine (J-TDMQ21, Scheme 2, R = 5,7-Cl , R =

CH ) -N(CH ) ). The procedure was similar to that described for the

2 2 3 2

preparation of J-TDMQ20, but using N,N-dimethyl-1,3-propanediamine.

J-TDMQ21 was obtained as a light yellow solid (87%). H NMR (400

(

1

3423, 3140, 2962, 2762, 2560, 1647, 1604, 1535, 1479, 1427, 1359,

-

1

287, 1260, 1215, 1165, 1123, 1087, 986, 903, 834, 790, 715, 504 cm ;

MHz, CDCl

3

): δ = 8.24 (d, J = 8.8 Hz, 1H), 7.40 (s, 1H), 7.39 (d, J = 8.8

+

HRMS (ESI) calcd for C16

Elemental analysis for C16

H F N

22 3 4

: 327.1797 ([M+H] ); found: 327.1792;

•3HCl•0.9H O•0.1NH Cl (apparent MW

Hz, 1H), 3.61 (t, J = 6.8 Hz, 2H), 3.32 (t, J = 6.8 Hz, 2H), 3.14 – 3.05 (m,

H), 2.79 (s, 6H), 2.08 – 2.02 (m, 2H).

H F N

21 3 4

2

4

=

1

457.32): calculated C 42.02, H 5.78, N 12.56; found C 41.95, H 5.52, N

2.49.

1

3

N -(2-(8-Amino-5,7-dichloroquinolin-2-yl)ethyl)-N ,N -

dimethylpropane-1,3-diamine (K-TDMQ21). The procedure was similar

Synthesis of TDMQ-23

to that described for the preparation of H-TDMQ5. K-TDMQ21 was

1

obtained as a light yellow solid (87%). H NMR (400 MHz, CDCl

3

): δ =

1

3

N ,N -Dimethyl-N -(2-(8-nitro-6-(trifluoromethyl)quinolin-2-

3

yl)ethyl)propane-1,3-diamine (J-TDMQ23, Scheme 2, R = 6-CF , R1 =

8

2

1

.38 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.48 (brs,

H), 3.39 – 3.35 (m, 4H), 2.97 (t, J = 6.0 Hz, 2H), 2.39 (t, J = 6.4 Hz, 2H),

.97 (s, 6H), 1.84 – 1.81 (m, 2H).

2 2 3 2

(CH ) -N(CH ) ). The procedure was similar to that described for the

preparation of J-TDMQ21. J-TDMQ23 was obtained as a yellow solid

1

(

1

60 %). H NMR (400 MHz, CDCl

H), 8.17 (s, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 3.26 (t, J = 6.4 Hz, 2 H),

3.13 (t, J = 6.4 Hz, 2 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.33 (t, J = 7.2 Hz, 2 H),

3

): δ = 8.30 (s, 1 H), 8.25 (d, J = 8.8 Hz,

TDMQ21. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ21 was obtained as a yellow solid (90 %). mp 207–

1

2

1

2

(

1

3

09 °C; H NMR (400 MHz, D

2

O): δ = 8.36 (d, J = 8.8 Hz, 1H), 7.51 (s,

13

2

.21 (s, 6 H), 1.70 (t, J = 7.2 Hz, 2 H); C NMR (100 MHz, CDCl

3

): δ =

H), 7.47 (d, J = 8.8 Hz, 1H), 3.66 (t, J = 6.8 Hz, 2H), 3.39 (t, J = 6.8 Hz,

13

160.0, 144.4, 138.6, 137.1, 128.5 (q, J = 31.8 Hz), 126.2, 124.3 (q, J =

H), 3.19 – 3.15 (m, 4H), 2.84 (s, 6H), 2.15 – 2.07 (m, 2H); C NMR

O): δ = 156.8, 137.3, 134.7, 134.2, 126.6, 123.2, 122.8,

21.6, 118.4, 54.2, 45.7, 44.5, 42.8, 33.0, 21.2; IR (KBr): 3464, 3351,

271 Hz), 123.1, 113.0 (q, J = 4.6 Hz), 105.0 (q, J = 3.1 Hz), 58.0, 48.9,

100 MHz, D

2

48.3, 45.4, 38.7, 27.9.

-

1

084, 1630, 1611, 1593, 1492, 1465, 1396, 1046, 864, 820, 782 cm ;

1

3

+

N -(2-(8-Amino-6-(trifluoromethyl)quinolin-2-yl)ethyl)-N ,N -

HRMS (EI) calcd for C16

Elemental analysis for

apparent MW = 462.22): C, 41.89; H, 5.85; N, 12.12; found: C, 41.87; H,

.90; N, 12.12.

H22Cl

2 4

N

: 340.1222 ([M] ); found: 340.1219;

dimethylpropane-1,3-diamine (K-TDMQ23): The procedure was similar

16

C H

22Cl

2 4

N

•2.8HCl•0.9H O•0.03CH COOC

2

3

2 5

H

to that described for the preparation of K-TDMQ22. K-TDMQ23 was

(

5

1

obtained as a brown solid (41 %). H NMR (400 MHz, CDCl

3

): δ = 8.05 (d,

J = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.01 (s, 1 H),

5

7

.18 (br s, 2 H), 3.20-3.12 (m, 4 H), 2.72 (t, J = 7.2 Hz, 2 H), 2.29 (t, J =

.2 Hz, 1 H), 2.16 (s, 6 H), 1.66 (t, J = 7.2 Hz, 2 H).

Synthesis of TDMQ-22

8

=

-Nitro-6-(trifluoromethyl)-2-vinylquinoline (I-TDMQ22, Scheme 2, R

6-CF ). The procedure was similar to that described for the preparation

). I-

TDMQ22 was obtained as a brown solid (45 %). H NMR (400 MHz,

CDCl ): δ = 8.30-8.28 (m, 2H), 8.15 (s, 1H), 7.76 (d, J = 8.4 Hz, 1 H),

.02 (dd, J = 17.6 Hz, 10.8 Hz, 1 H), 6.52 (d, J = 17.6 Hz, 1 H), 5.82 (d,

J = 10.8 Hz, 1 H).

TDMQ23. The procedure was similar to that described for the preparation

3

of compound TDMQ1. TDMQ23 was obtained as a yellow solid (91 %).

of I-TDMQ20, but starting from A-TDMQ16 (Scheme 2, R = 6-CF

3

1

mp 141–143 °C; H NMR (400 MHz, D

2

O): δ = 8.39 (d, J = 8. 4 Hz, 1 H),

8

2

1

.12 (s, 1H), 7.73 (s, 1H), 7.61 (d, J = 8. 4 Hz, 1 H), 3.70 (t, J = 6.8 Hz,

H), 3.47 (t, J = 6.8 Hz, 2H), 3.23 – 3.18 (m), 2.86 (s, 6H), 2.19 – 2.11 (m,

3

7

H); IR (KBr): 3402, 3100, 2961, 2788, 1630, 1607, 1476, 1431, 1400,

-

1

361, 1294, 1227, 1163, 1129, 1088, 1010, 961, 888, 802, 712 cm ;

+

HRMS (ESI) calcd for C17

Elemental analysis for

apparent MW = 487.49): calculated C, 43.07; H, 6.29; N, 11.49; found C,

3.02; H, 6.25; N, 11.45.

H

24

F

3

N

4

: 341.1953 ([M+H] ); found: 341.1948;

1

2

N ,N -Dimethyl-N -(2-(8-nitro-6-(trifluoromethyl)quinolin-2-

yl)ethyl)ethane-1,2-diamine (J-TDMQ22). The procedure was similar to

that described for the preparation of J-TDMQ20. J-TDMQ22 was

obtained as a yellow solid (80 %). H NMR (400 MHz, CDCl

C

17

H

23

F

3

N

4

•3HCl•1.6H O•0.12C OC

2

H

5

2 5

H

(

4

1

3

): δ = 8.29 (s,

1

3

2

H), 8.24 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 7.56 (d, J = 8.4 Hz, 1 H),

.26 (t, J = 6.4 Hz, 2 H), 3.16 (t, J = 6.4 Hz, 2 H), 2.77 (t, J = 6.4 Hz, 2 H),

.44 (t, J = 6.4 Hz, 2 H), 2.22 (s, 6 H).

Synthesis of TDMQ24

2-(8-Nitro-6-(trifluoromethyl)quinolin-2-yl)-N-(pyridin-2-

1

2

ylmethyl)ethan-1-amine (J-TDMQ24, Scheme 2, R = 6-CF , R = 2-

pyridyl). The procedure was similar to that described for the preparation

of J-TDMQ20, but starting from 2-(aminomethyl)pyridine. J-TDMQ24 was

3 1

N -(2-(8-Amino-6-(trifluoromethyl)quinolin-2-yl)ethyl)-N ,N -

dimethylethane-1,2-diamine (K-TDMQ22). To a mixture of J-TDMQ22

1

7

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FULL PAPER

1

obtained as a yellow solid (63 %). H NMR (400 MHz, CDCl

H), 8.30 (s, 1 H), 8.24 (d, J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 7.65 (t, J = 7.6,

Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 1 H), 7.15 (t, J =

.8 Hz, 1 H), 3.99 (s, 2 H), 3.30 (t, J = 6.4 Hz, 2 H), 3.20 (t, J = 6.0 Hz, 2

H).

3

) δ = 8.54 (s,

Synthesis of TDMQ27

1

2-(8-Nitro-6-(trifluoromethyl)quinolin-2-yl)-N-(pyrimidin-2-

6

ylmethyl)ethanamine (J-TDMQ27, Scheme 2, R = 6-CF

pyrimidyl). The procedure was similar to that described for the

3 1

, R = 2-

preparation of J-TDMQ20, but using 2-(aminomethyl)pyrimidine as

1

2

-(2-((Pyridin-2-ylmethyl)amino)ethyl)-6-(trifluoromethyl)quinolin-8-

starting material. J-TDMQ27 was obtained as a yellow solid (53 %).

NMR (400 MHz, CDCl

H

amine (K-TDMQ-24). To a mixture of J-TDMQ24 (227 mg, 0.60 mmol),

3

) δ ppm: 8.71-8.69 (m, 2 H), 8.29 (s, 1 H), 8.25 (d,

Na

2

S•9H

2

O (432 mg, 1.80 mmol) in methanol (10 mL) was added NH

4

Cl

J = 8.8 Hz, 1 H), 8.16 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.17 (t, J = 4.8

Hz, 1 H), 4.14 (s, 2 H), 3.33 (t, J = 6.4 Hz, 2 H), 3.25 (t, J = 5.2 Hz, 2 H).

(96 mg, 1.80 mmol) at room temperature, and the mixture was stirred at

o

6

5

C for 2 h. Water (400 mL) was added, followed by addition of extra

aqueous 25% ammonium hydroxide. The mixture was extracted with

CH Cl (3 x 30 mL). The combined organic layers were dried (Na SO ),

filtered and concentrated under reduced pressure. The crude product

was purified by silica gel flash chromatography (ethyl

2-(2-((Pyrimidin-2-ylmethyl)amino)ethyl)-6-(trifluoromethyl)quinolin-

2

4

8-amine (K-TDMQ27). The procedure was similar to that described for

the preparation of K-TDMQ24. K-TDMQ26 was obtained as a brown solid

1

(

60 %). mp 121–123 °C; H NMR (400 MHz, CDCl

3

): δ = 8.70-8.69 (m, 2

acetate/isopropanol/ 25% ammonium hydroxide, 50/2/2, v/v/v).

H), 8.04 (d, J = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.18

Evaporation of the solvent afforded K-TDMQ24 as a brown solid (116 mg,

(

t, J = 4.8 Hz, 1 H), 7.02 (s, 1 H), 5.33 (brs, 2 H), 4.16 (s, 2 H), 3.28-3.20

1

56%). H NMR (400 MHz, CDCl

3

): δ = 8.55 (s, 1 H), 8.04 (d, J = 8.4 Hz, 1

13

(m, 4 H). C NMR (100 MHz, CDCl

3

): δ = 169.1, 160.1, 157.0, 144.5,

38.6, 137.0, 128.4 (q, J = 31.6 Hz), 126.2, 124.3 (q, J = 270.3 Hz),

23.1, 119.2, 112.9 (q, J = 4.4 Hz), 104.9 (q, J = 4.4 Hz), 55.8, 48.1, 38.6;

H), 7.63 (t, J = 6.0 Hz, 1 H), 7.38 (s, 1 H), 7.35 (d, J = 8.4Hz, 1 H), 7.28

d, J = 8.0 Hz, 1 H), 7.16 (d, J = 6.8 Hz, 1 H), 7.02 (s, 1 H), 5.31 (brs, 2

1

(

1

3

H), 4.00 (s, 2 H), 3.26-3.18 (m, 4 H); C NMR (100 MHz, CDCl

3

): δ =

60.1, 159.7, 149.3, 144.5, 138.6, 137.1, 136.5, 128.4 (q, J = 31.7 Hz),

IR (KBr): 3414, 3298, 3185, 3039, 2816, 1630, 1604, 1560, 1504, 1480,

1

6

3

421, 1391, 1293, 1269, 1147, 1102, 998, 930, 879, 849, 808, 763, 709,

26.2, 124.3 (q, J = 271 Hz), 123.1, 122.4, 122.0, 112.9 (q, J = 4.6 Hz),

05.0 (q, J = 3.1 Hz), 55.2, 48.2, 38.5.

-1

+

26 cm ; HRMS (ESI) calcd for C17

H

17

F

H

3

N

5

: 348.1436 ([M+H] ); found:

•0.5H O•0.03C OC

48.1435; Elemental analysis for C17

16

F

3

N

5

2

H

5

2 5

H

(apparent MW = 358.58): calculated C, 57.35; H, 4.86; N, 19.53; found C,

TDMQ24. The procedure was similar to that described for the preparation

57.36; H, 4.89; N, 19.52.

of TDMQ1. TDMQ24 was obtained as a yellow solid (93 %). mp 183–

1

=

(

4

3

1

C

85 °C; H NMR (400 MHz, D

2

O): δ = 8.60 (d, J = 4.4 Hz, 1 H), 8.42 (d, J

TDMQ27. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ27 is highly hygroscopic and absorbs water very

quickly from the air. Therefore, this compound is stocked as its base form,

K-TDQM27.

6.8 Hz, 1 H), 8.27 (s, 1 H), 8.14 (t, J = 6.0 Hz, 1 H), 7.88 (s, 1 H), 7.73

d, J = 6.0Hz, 1 H), 7.66 (d, J = 6.0 Hz, 1 H), 7.63 (t, J = 6.8 Hz, 1 H),

.59 (s, 2 H), 3.79 (t, J = 5.2 Hz, 2 H), 3.53 (t, J = 5.2 Hz, 2 H); IR (KBr):

423, 3307, 2893, 2753, 2634, 1630, 1547, 1477, 1433, 1403, 1296,

-

1

251, 1160, 1119, 1086, 907, 798, 780, 528 cm ; HRMS (ESI) calcd for

Stability of TDMQ ligands.

+

18

H

18

F

3

N

4

: 347.1405 ([M+H] ); found: 347.1400; Elemental analysis for

•3HCl•0.6H O (apparent MW = 464.54): calculated C, 46.34;

18

17

3

4

2

TDMQ5, -20 and -22 were kept in open-air flasks at room temperature

H, 4.58; N, 12.01; found C, 46.32; H, 4.59; N, 12.01.

(

25~35°C in Guangzhou China) for 6 months. Aliquots were analyzed by

1

HPLC each month and by H NMR spectroscopy at the end of the period.

TDMQ5, -20 and -22 in D O were kept at room temperature under air and

light for weeks, and were rechecked by HPLC and

Synthesis of TDMQ26

2

1

4

H NMR

N-(Furan-2-ylmethyl)-2-(8-nitro-6-(trifluoromethyl)quinolin-2-

yl)ethanamine (J-TDMQ26, Scheme 2, R = 6-CF , R = 2-furanyl). The

3 1

procedure was similar to that described for the preparation of J-TDMQ20,

spectroscopy at the end of the period. Analyses were compared to those

of the starting materials.

but using 2-(aminomethyl)furane as starting material. J-TDMQ26 was

Preparation of single crystals for X-ray diffraction

1

obtained as a yellow solid (74 %). H NMR (400 MHz, CDCl

3

): δ = 8.29

(

7

s, 1 H), 8.24 (d, J = 8.4 Hz, 1 H), 8.18 (s, 1 H), 7.54 (d, J = 8.4 Hz, 1 H),

.35 (s, 1 H), 6.31 (t, J = 2.8 Hz, 1 H), 6.22 (d, J = 2.8 Hz, 1 H), 3.86 (s, 2

II

Cu -TDMQ5. CuCl

2

(5µL, 12 µmol) in ethanol (2.39 M) was added to

TDMQ5 (10.1 mg, 24 µmol) dissolved in a mixture of water (0.3 mL) and

ethanol (0.4 mL). The resulting green solution was filtered through a

polyester syringe filter (Chromafil GF/PET-45/25). Crystals suitable for

X-ray analysis were obtained by the slow vapour diffusion of acetone into

the filtered solution placed at 4°C. The X-ray diffraction analysis exhibited

H), 3.26 (t, J = 6.4 Hz, 2 H), 3.15 (t, J = 6.0 Hz, 2 H).

2

-(2-((Furan-2-ylmethyl)amino)ethyl)-6-(trifluoromethyl)quinolin-8-

amine (K-TDMQ26). The procedure was similar to that described for the

preparation of K-TDMQ24. K-TDMQ26 was obtained as a brown solid

(

II

a Cu -TDMQ5 complex structure with a 1:1 molar ratio.

1

65 %). mp 68–71 °C; H NMR (400 MHz, CDCl

3

): δ = 8.04 (d, J = 8.4

Hz, 1 H), 7.39 (s, 1 H), 7.35-7.33 (m, 2 H), 7.02 (s, 1 H), 6.32 (t, J = 3.2

Hz, 1 H), 6.18 (t, J = 3.2 Hz, 1 H), 5.13 (brs, 2 H), 3.85 (s, 2 H), 3.21-3.13

II

Cu - TDMQ19. CuCl

2

(10 µL, 0.031 mmol) in ethanol (3.1 M) was added

13

to TDMQ19 (10.1 mg, 0.022 mmol) dissolved in a mixture of water (0.3

mL) and ethanol (0.4 mL). The resulting green solution was filtered

through a polyester syringe filter (Chromafil GF/PET-45/25). After few

days, blues crystals suitable for X-ray analysis were obtained by the slow

vapour diffusion of acetone into the filtered solution placed at 4°C. The X-

(

1

m, 4 H) ; C NMR (100 MHz, CDCl

3

): δ = 159.9, 153.9, 144.4, 141.8,

38.6, 137.2, 128.5 (q, J = 31.8 Hz), 126.2, 124.3 (q, J = 271 Hz), 123.1,

13.0 (q, J = 4.6 Hz), 110.2, 107.0, 105.0 (q, J = 3.2 Hz), 47.7, 46.1, 38.5;

IR (KBr): 3429, 3283, 3128, 1630, 1596, 1504, 1474, 1429, 1394, 1343,

-

1

292, 1177, 1108, 1010, 915,864, 846, 817, 742, 712, 599 cm ; HRMS

II

+

ray diffraction analysis exhibited a Cu - TDMQ19 complex structure with

a 1:1 molar ratio.

(ESI) calcd for

C

H F N

17 17 3 3

O: 336.1324 ([M+H] ); found: 336.1322;

O•0.7H O (apparent MW = 347.94):

Elemental analysis for C17

H F N

16 3 3

2

calculated C, 58.68; H, 5.04; N, 12.08; found C, 58.60; H, 5.09; N, 12.07.

II

Cu - TDMQ22. CuCl

2

(5µL, 4.85 µmol) in ethanol (0.97 M) was added to

a solution of TDMQ22 (4.45 mg, 9.7 µmol) in ethanol (0.4 mL) containing

Et N (3 mol equiv.). The resulting brown solution was filtered through a

polyester syringe filter (Chromafil GF/PET-45/25). Crystals suitable for

X-ray analysis were obtained by the slow vapour diffusion of CH Cl into

TDMQ26. The procedure was similar to that described for the preparation

of TDMQ1. TDMQ26 is highly hygroscopic and absorbs water very

quickly from the air. Therefore, this compound is stocked as its base form,

K-TDQM26.

3

2

1

8

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

the filtered solution placed at 4°C. The X-ray diffraction analysis exhibited

a Cu - TDMQ22 complex structure with a 1:1 molar ratio.

Direct method (ligands with “low” affinity). From the titration of TDMQ

II

2+

ligands by Zn

(for the conditions, see the above paragraph

2+

“

Ligand/metal stoichiometry of TDMQ in the presence of Cu or Zn ”),

the affinity of TDMQ for Zn(II) was calculated as reported in Reference

8.

II

Zn -TDMQ5. ZnCl

2

(5µL, 12 µmol) in ethanol (2.39 M) was added to a

2

solution of TDMQ5 (10.1 mg, 24 µmol) in ethanol (0.8 mL) and methanol

0.4 mL) containing Et N (3 mol equiv.) at 50°C. The resulting solution

(

3

was filtered through a polyester syringe filter (Chromafil GF/PET-45/25).

Crystals suitable for X-ray analysis were obtained by the slow

evaporation of the filtered solution in air at room temperature. The X-ray

diffraction analysis exhibited a Zn -TDMQ5 complex structure with a 1:1

molar ratio.

Transfer of copper from Cu-A1-16 to TDMQ22

The Cu-Aβ complex was first prepared by mixing equimolar amounts of

II

Aβ1-16 (1.26 mM in Hepes 100 mM, pH 7.4) and CuCl

HEPES buffer 100 mM, pH 7.4, in a UV-visible cuvette, under continuous

magnetic stirring. The solution of TDMQ22 (5 mM in H O) was then

added (1 mol equiv). The reaction was monitored by UV-visible

spectroscopy. Final concentrations were [Aβ1-16]=[Cu ]=[TDMQ22]=20

μM.

2 2

(3 mM in H O) in

2

II

Zn -TDMQ19. ZnCl

2

(5.6 µL, 5.4 µmol) in ethanol (0.97 M) was added to

2+

a solution of TDMQ19 (5 mg, 10.8 µmol) in ethanol (0.8 mL) and water

0.4 mL) containing Et N (3 mol equiv.) at 50°C. The resulting solution

(

3

was filtered through a polyester syringe filter (Chromafil GF/PET-45/25).

Crystals suitable for X-ray analysis were obtained by the slow

evaporation of the filtered solution in air at room temperature. The X-ray

Demetalation of TDMQ22 in the presence of glutathione

II

diffraction analysis exhibited a Zn - TDMQ19 complex structure with a

The following stock solutions were prepared: TDMQ22 (5 mM in H

2

O),

1:1 molar ratio.

CuCl (3 mM in H O), and GSH (50, 100, and 250 mМ in Hepes 100 mM,

2

pH 7.4). For each experiment, a fresh solution of GSH was prepared.

The complexes Cu -TDMQ22 was prepared by addition of adequate

II

Zn -TDMQ20. ZnCl

2

(7.6 µL, 11.4 µmol) in ethanol (1.5 M) was added to

II

a solution of TDMQ20 (5 mg, 11.4 µmol) in a mixture of ethanol (0.5 mL),

acetonitrile (0.2 mL) and methanol (0.2 mL) containing Et N (3 mol

equiv.). The resulting solution was filtered through a polyester syringe

2

volumes of the CuCl and TDMQ22 solution in a UV-visible cuvette

3

containing Hepes buffer 100 mM, pH 7.4. Concentrations in the cuvette

2+

were: [TDMQ22] = [Cu ] = 20 µM, [Hepes] = 100 mM). Aliquots of the

filter (Chromafil GF/PET-45/25). Crystals suitable for X-ray analysis

GSH solution (10 to 200 mol equiv with respect to copper) were then

added into the cuvette, under continuous stirring, using the 50 mM

solution for 10 mol equiv, the 100 mM solution for 30 and 50 mol equiv,

and the 250 mM solution for 100-200 mol equiv of GSH. The total

variation of volume in the cuvette was below 3.2 % upon addition of 200

mol equiv of GSH. A UV-visible spectrum was recorded 1 min after each

addition of GSH.

were obtained by the slow evaporation of the filtered solution in air at

II

room temperature. The X-ray diffraction analysis exhibited

TDMQ20 complex structure with a 1:1 molar ratio.

a

Zn -

2+

Ligand/metal stoichiometry of TDMQ in the presence of Cu or Zn

To a solution of 15 µM of TDMQ ligand in 20 mM Tris•HCl pH 7.4, 150 mM

II

NaCl, aliquots of aqueous solutions of CuSO

to 10 mol equiv). The concentration of the solutions of metal salts was

.75 mM or 37.5 mM, for 0.25 to 3.5 mol equiv, or 5-10 mol equiv,

4

, or ZnSO

4

were added (1

Oxidative reactivity of Cu -TDMQ complexes

3

Oxidation of ascorbic acid. The kinetic of ascorbate oxidation was

monitored by UV-visible at 265 nm, as a classical test to detect in vitro

ROS production induced by Cu(II) in presence of molecular oxygen.

Stock solutions were prepared as follows: TDMQ ligands (3 or 5 mM in

respectively, of metal ion with respect to ligand. Total variation of volume

in the cuvette was below 2% upon addition of 10 mol equiv of metal. UV-

visible spectrum was recorded after each addition of metal salt. Titrations

were made in duplicate.

H

2

O), Aβ1-16 (1.31 or 1.66 mM in DMSO, CuCl

2 2

(3 mM in H O) and

sodium ascorbate (30 mM in H O). For each experiment, a fresh solution

2

II

Evaluation of Cu(II) or Zn(II) to ligand affinity constants

of ascorbate was prepared. The copper complexes Cu /Ligand (molar

II

ratio 1/1 or 1/2) and Cu /Aβ1-16 (molar ratio 1/1.1) were prepared by

mixing adequate volumes of the metal salt and ligand stock solutions,

and incubated for 30 min at room temperature. Where a TDMQ was

Competitive method (ligands with “high” affinity). The following

mother solutions were prepared: (1) TDMQ ligand, 300 M in H

competitor ligand (C = EDTA, EDDA, EGTA, CDTA, EDA or NTA), 300

M in 20 mM Tris·HCl pH 7.4, 150 mM NaCl; (3) CuSO , or ZnSO , 15 mM

in H O. In the UV-vis cuvette, 100 L of (1), 100 L of (2), 1800 L of 20

2

O; (2)

II

added to Cu -Aβ1-16, the mixture was incubated for a further 30 min. Final

II

concentrations in the cuvette were: [Cu ] = [TDMQ] = 10 µM, [Aβ1-16] = 11



4

2

µM. The copper complexes (or CuCl , final concentration 10 µM, as a

positive control) were then added to the UV cuvette containing sodium

ascorbate (final concentration 100 µM) in Hepes buffer (50 mM, pH 7.4,

2

mM Tris·HCl pH 7.4, 150 mM NaCl, and 2 L of (3) were added in this

order. Final concentration of TDMQ, competitor, and metal ion was 15 M.

Spectrum was recorded from 200 to 600 nm at 20 °C, and compared to

25 °C) under continuous stirring (final volume = 1.5 mL). The DMSO

2+

concentration was below 1 vol%. Monitoring of ascorbate absorbance

the spectra of TDMQ [2 L of H

TDMQ [100 L of 20 mM Tris·HCl pH 7.4, 150 mM NaCl, instead of 100

L of (2)]. All ligands and complexes studied followed the Beer-Lambert

2

O instead of 2 L of (3)], and of M -

-

1

-1 [31]

(

λ

max = 265 nm,  = 14500 M x cm )

was immediately started and

continued over 30 min. The experiments without ascorbate were also

performed in the same conditions and resulting absorbance was

subtracted from measurements with ascorbate.



law in the experimental conditions used. UV-vis spectra were monitored

at a wavelength where the absorbances of both C and M-C are negligible.

In this case, the absorbance of the competitive chelation mixture (Amix),

2+

the absorbance of TDMQ in the absence of M (ATDMQ), and the

absorbance of M-TDMQ in the absence of C (AM-TDMQ) allowed to

determine the affinity of TDMQ for the metal ion as

Production of H

9, 10, 13, or -16) (10 µM in H

O) and sodium ascorbate (100 µM in H

2

Cu /TDMQ (molar ratio 1/1 or 1/2) and Cu /Aβ1-16 (molar ratio 1/1) were

prepared by mixing adequate volumes of the metal salt and ligand stock

solutions in Hepes buffer 50 mM pH 7.4, and incubated for 30 min at

2

O

2

. Stock solutions were prepared as follows: TDMQ5,

O), Aβ1-16 (10 µM in H O), CuCl (10 µM in

O). The copper complexes

2

H

2

II

x

^l^o^g^Kapp [M-TDMQ] ⁼^l^o^g^Kapp [M-C] + 2 log

1-x

II

room temperature. Final concentrations were [Cu ] = [Aβ1-16] = 1 µM,

where

x

is

the

[

TDMQ] = 1 or 2 µM and [ascorbate] = 10 µM. Where a TDMQ was

proportion of M(II) chelated by TDMQ [x = (ATDMQ – Amix) / (ATDMQ – AM-

II

[

24]

added to Cu -Aβ1-16 complex, the mixture was incubated for a further 30

min. At the end of the incubation time, sodium ascorbate was added and

the reaction was immediately started and continued over 30 min. The

TDMQ)]. Experiments were performed in triplicate.

1

9

ChemMedChem

10.1002/cmdc.201700734

FULL PAPER

production of H

Hydrogen Peroxide Assay kit according to the protocol of the supplier

exc.= 540 nm, λem.= 550-700 nm). After addition of the reagents from the

kit, the reaction mixtures were incubated for 30 min protected from light,

before the fluorescence measurement. The experiments without

ascorbate (controls) were also performed in the same conditions. The

reactions were made in triplicate.

2

O

2

was then quantified by fluorescence using the Red

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This work was supported by the NSFC (grant 21502023), the

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[

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10.1002/cmdc.201700734

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Copper

homeostasis

Alzheimer’s

disease

II

Cu –Ab

II

Oxidative

stress

Ab

Cu –L

L

complex

New tetradendate ligands as regulators of copper homeostasis for Alzhei mer’s disease therapy.

2

+

New tetradendate ligands (TDMQ) based on 8-aminoquinoline are specific chelators of copper(II) ions and are able to extract Cu

from toxic copper-loaded amyloids. These ligands can transfer copper ions to physiological copper acceptors. They should be

considered as poetential regulators of copper homeostasis for Alzheimer’s disease therapy.

2

1

Article Doi

Preparation of Tetradentate Copper Chelators as Potential Anti-Alzheimer Agents

DOI: 10.1002/cmdc.201700734

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Article abstract of DOI:10.1002/cmdc.201700734

Full text of DOI:10.1002/cmdc.201700734

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