Synthesis of novel 7-substituted pyrido[2′,3′:4,5]furo[3,2-d] pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases

Article abstract of DOI:10.1016/j.bmcl.2013.10.019

The efficient synthesis of 7-substituted pyrido[2′,3′:4,5] furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2- carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki-Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC₅₀ value of 49 nM and proved to be specific to CLK1 among the panel of tested kinases.

Full text of DOI:10.1016/j.bmcl.2013.10.019

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of novel 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimi-
din-4-amines and their N-aryl analogues and evaluation of their
inhibitory activity against Ser/Thr kinases
Emmanuel Deau a, Yvonnick Loidreau a, Pascal Marchand b, Marie-Renée Nourrisson b,
Nadège Loaëc c,d, Laurent Meijer d, Vincent Levacher a, Thierry Besson a,
⇑
a Normandie Univ, COBRA, UMR 6014 & FR 3038; Univ Rouen; INSA Rouen; CNRS, Bâtiment IRCOF, 1 rue Tesnière, 76821 Mont St Aignan Cedex, France
b Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections et du Cancer, IICiMed EA 1155, UFR des Sciences
Pharmaceutiques et Biologiques, 1 rue Gaston Veil, 44035 Nantes, France
c CNRS, USR3151, Station Biologique de Roscoff, 29680 Roscoff, France
d Manros Therapeutics, Centre de Perharidy, 29680 Roscoff, France
a r t i c l e i n f o
a b s t r a c t
The efficient synthesis of 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl
analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-
2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of
the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed
Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized
by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final
products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1d/
Article history:
Received 2 September 2013
Revised 7 October 2013
Accepted 8 October 2013
Available online xxxx
Keywords:
Microwave-assisted chemistry
Dimroth rearrangement
Formamide degradation
Suzuki–Miyaura cross-coupling
Serine/threonine kinases inhibitors
e, CLK1, DYRK1A, GSK3a/b). Compound 35 showed the best inhibitory activity with an IC50 value of
49 nM and proved to be specific to CLK1 among the panel of tested kinases.
Ó 2013 Elsevier Ltd. All rights reserved.
In the course of our work aiming to synthesize new polyaro-
matic heterocycles with a potent inhibitory activity on serine/thre-
onine kinases,1 we wished to examine the potential of compounds
bearing a pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amine core. In-
deed, a recent study performed by our group demonstrated that
N ’-(2-cyanofuro[3,2-b]pyridin-3-yl)-N,N-dimethylformimidamide
1 may undergo cyclisation to yield pyrido[20,30:4,5]furo[3,2-d]pyr-
imidin-4-amine 2 or its N-phenyl analogues 3–11 (series A)2 by
microwave-assisted formamide degradation3 or Dimroth rear-
rangement,4 respectively, as presented in Scheme 1.
amide dimethylacetal (DMFDMA)-mediated formylation,6 Suzu-
ki–Miyaura cross-coupling, formamide degradation and Dimroth
rearrangement were associated. This protocol allowed the prepara-
tion of novel 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-
amines (series B) and their N-aryl analogues (series C) for which
relevant biological properties were expected.
The main part of the chemistry described in this Letter was real-
ized under microwaves in an eco-compatible chemistry approach.7
The evaluation of kinase inhibition was performed with five serine/
threonine kinases: a cyclin-dependent kinase (CDK5/p25), casein
Moreover, our recent investigations on the synthesis of 8-aryl-
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4-amines confirmed that
Suzuki–Miyaura cross-coupling could be achieved on a thieno
derivative of 1 to functionalize position 8 with an aryl moiety.5
In light of these elements, and with the purpose of assessing the
kinase inhibitory potential of pyrido[20,30:4,5]furo[3,2-d]pyrimi-
din-4-amine skeleton, we focused on the synthesis of a library of
7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines and
their N-aryl analogues. This Letter describes the development of
a reliable strategy where microwave-assisted N,N-dimethylform-
kinase 1 (CK1d/
sine phosphorylation regulated kinase (DYRK1A), glycogen syn-
thase kinase 3 (GSK3 /b). The latter were chosen for their strong
e), cdc2-like kinase 1 (CLK1), dual-specificity, tyro-
a
implication in various regulation processes, especially Alzheimer’s
disease (AD).8
Owing to the reactivity of intermediate 1, we considered the
synthesis of 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-
amines (series B) and their N-aryl analogues (series C) from a
brominated precursor 12 according to the retrosynthetic pathway
presented in Scheme 2. In order to complete the synthesis of
potentially bioactive products of series B and C, we initially consid-
ered the synthesis of the common precursor 12 of both series B and
C, starting from commercially available 3,5-dibromopyridine 13.
⇑
Corresponding author. Tel.: +33 (0)235 522 904; fax: +33 (0)235 522 962.
E-mail address: thierry.besson@univ-rouen.fr (T. Besson).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.10.019
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2
E. Deau et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
Path B
Dimroth
Path A
Formamide
degradation
H2N
N
rearrangement
R
NH2CHO
N
N
neat
170 °C (µw), 30 min.
72%
AcOH
118 °C (µw), 10 min.
77-97%
CN
O
1
N
N
N
N
N
Series A
N
3
4
5
R = H ( ), 4-OMe ( ), 3,4-diOMe ( ),
6
7
3,5-diOMe ( ), 3,4,5-triOMe ( ),
3,4-dioxolane (8), 3,4-dioxine (9),
3-Cl-4-F (10), 4-Br-2-F (11)
O
O
R
NH2
HN
2
3-11
Scheme 1. Previous work: synthesis of pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amine 2 or its N-aryl analogues 3–11 (series A) by formamide degradation (path A) or Dimroth
rearrangement (path B).
Some of the steps of this previously described synthetic sequence9
were optimized using microwave technology as presented in
Scheme 3.
methane complex (for cyanoamidines 21–27) or tetrakis(triphen-
ylphosphine)palladium(0) (for cyanoamidine 28), the appropriate
phenylboronic acid, and sodium carbonate at 150 °C as shown in
Scheme 4. Noteworthy, the coupling reaction with some of the
haloarylboronic acids gave moderate yields due to purification
problems while alkyl- and alkoxyphenylboronic acids gave
coupling products in good to excellent yields. Cyclisation of cyano-
amidine intermediates 21–28 into the final 7-substituted pyr-
ido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines 29–36 was conducted
according to our previously described methodology using a high
temperature microwave-assisted degradation of formamide in
moderate yields (Table 1).3
Based on preceding work of several groups demonstrating the
importance of associating the 3,4-benzodioxolane ring to kinase
inhibitors,11 we decided to conceive series C from the structures
of products 28 and 36. Therefore the foreseen molecules (39–47
in Table 2) were designed with a constant 3,4-benzodioxolane moi-
ety at position 7 while modulations were achieved at position 4 of
the pyrimidin-4-amine ring. In an attempt to optimize the overall
yields, we investigated the best sequence for formylation, Suzuki–
Miyaura cross-coupling and Dimroth rearrangement. Activated
anilines bearing a methoxy substituent are known for improving
Dimroth rearrangement,4 we therefore chose to use 3,4-dime-
thoxyaniline for this short study. As presented in Scheme 5, path
B (DMFDMA-mediated formylation + Suzuki–Miyaura cross-cou-
pling + Dimroth rearrangement) gave the best overall yield for
the conversion of precursor 12 into product 42.
3,5-Dibromopyridine 13 was first desymmetrized into 3-bro-
mo-5-methoxypyridine 14 in an excellent 88% yield using an
excess of sodium methoxide in warm DMF. Optimization of this
reaction by microwave irradiation at atmospheric pressure re-
duced the reaction time from 24 hours for conventional heating
to 2 h in microwave oven. In the presence of boron tribromide in
DCM at low temperature, 3-bromo-5-methoxypyridine 14 was
efficiently deprotected into 5-bromopyridin-3-ol 15 in good 81%
yield. Regioselective iodination of compound 15 was achieved with
iodine in the presence of sodium carbonate, in water at room
temperature, to afford the iodo intermediate 16 in good yield.
The latter was successfully converted into corresponding 3-pyr-
idyloxyacetonitrile derivative 17 using bromoacetonitrile. Substi-
tution of iodine by
afforded the intermediate 18. Finally,
a
cyano group using copper(I) cyanide
microwave-assisted
a
cyclisation of compound 18 in the presence of potassium carbonate
in warm DMF furnished 3-amino-6-bromofuro[3,2-b]pyridine-2-
carbonitrile 12 in 31% overall yield.
We then performed the synthesis of 7-substituted pyr-
ido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines (series B). The absence
of structure–activity relationship features among the studied pyr-
ido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines series prompted us to
employ the Topliss scheme for selecting substitution patterns on
the aromatic substituent.10 In order to accomplish the synthesis
with the best overall yields, a previous study based on the synthe-
sis of thieno analogues5 led us to propose the following functional-
ization sequence: DMFDMA-mediated formylation, palladium-
catalyzed Suzuki–Miyaura cross-coupling, and cyclisation with
formamide. Accordingly, precursor 12 was reacted with DMFDMA
using microwave irradiation at atmospheric pressure, and con-
verted into 6-bromodimethylformimidamide derivative 19 in 87%
yield along with traces of the 6-bromoformimidate 20. Functional-
ization at position 7 of the intermediate 19 into the aryl adducts
21–28 was completed by a microwave-assisted Suzuki–Miyaura
cross-coupling in the presence of a catalytic amount of [1,10-
bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloro-
Conforming to this optimized sequence, intermediate 28 was
reacted with various anilines in refluxing acetic acid to provide
products 39–47 in moderate to excellent yields (Table 2) as pre-
sented in Scheme 6.
Products of series A (2–11), series B (29–36) and series C
(39–47) were tested on five different in vitro kinase assays
(CDK5/p25, CK1d/
inhibition potency.12–14 All compounds were first tested at a final
concentration of 10 M. Compounds showing less than 50% inhibi-
tion were considered as inactive (IC50 >10 M). Compounds
displaying more than 50% inhibition at 10 M were next tested
e, GSK3a/b, DYRK1A and CLK1) to evaluate their
l
l
l
over a wide range of concentrations (usually 0.01–10 lM), and
Suzuki-Miyaura
Suzuki-Miyaura
DMFDMA-mediated
N
N
NH2
CN
N
N
N
DMFDMA-mediated
cross-coupling
cross-coupling
formylation
+
formylation
+
N
N
Br
formamide
degradation
Dimroth
O
O
O
rearrangement
R1
R1
NHR2
NH2
12
Series B
Series C
Scheme 2. Retrosynthetic pathway and access to novel 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines and N-arylpyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-
amines from precursor 12.
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E. Deau et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
MeONa
N
N
N
BBr3
I2, Na2CO3
N
I
(30 wt.-% in MeOH)
DMF
80 °C (µw), 2h
88%
DCM
-78°C to r.t., 48h
81%
H2O
r.t., 3h
71%
Br
OMe
Br
Br
Br
OH
Br
OH
13
14
15
16
N
NH2
CN
N
CN
N
I
K2CO3
BrCH2CN, K2CO3
CuCN
Br
DMF
80 °C (µw), 10 min.
80%
Py.
100 °C, 1h
85%
acetone
r.t., 18h
91%
Br
O
CN
Br
O
CN
O
18
12
17
Scheme 3. Derivatization sequence of 3,5-dibromopyridine 13 into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile 12.
N
N
N
N
N
Br
Br
CN
R1PhB(OH)2
Pd(dppf)Cl2•DCM or Pd(PPh3
Na2CO3
O
19
87%
N
N
)4 (10 wt.-%)
N
NH2
CN
N
N
NH2CHO
N
DMFDMA
N
Br
neat
DMF
neat
170 °C (µw), 30 min.
47-67%
O
O
R1
90 °C (µw), 25 min.
150 °C (µw), 90 min.
39-99%
O
CN
NH2
O
R1
12
21 28
-
Series B: 29 36
-
CN
O
R1 = H (21), 4-Me (22), 4-OMe (23),
R1 = H (29), 4-Me (30), 4-OMe (31), 3-Cl (32),
20
3-Cl (24), 3,4-diCl (25), 4-Cl (26),
3,4-diCl (33), 4-Cl (34), 2,4-diCl (35),
13%
27
28
36
3,4-dioxolane ( )
2,4-diCl ( ), 3,4-dioxolane (
)
Scheme 4. Microwave-assisted synthesis of cyanoamidine 19 with DMFDMA, aryl adducts 21–28 by palladium-catalyzed Suzuki–Miyaura cross-coupling, and 7-substituted
pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines 29–36 by formamide degradation. For detailed yields, see Table 1.
Table 1
Yields for the synthesis of the aryl adduct intermediates 21–28 and 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines 29–36 (series B)
Product
R1
Yielda (%)
Product
N
N
N
N
N
N
R1
Yielda (%)
O
R1
NH2
CN
O
R1
21
22
23
24
25
26
27
28
H
4-Me
4-OMe
3-Cl
3,4-DiCl
4-Cl
99
79
89
76
48
39
44
66
29
30
31
32
33
34
35
36
H
4-Me
4-OMe
3-Cl
3,4-DiCl
4-Cl
51
47
57
53
61
56
54
67
2,4-DiCl
3,4-Dioxolane
2,4-DiCl
3,4-Dioxolane
a
Isolated yield.
Table 2
Isolated yields for 7-substituted N-arylpyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines 39–47
Product
R2
Reaction time (min)
Yielda (%)
N
N
N
O
O
O
R2
HN
39
40
41
42
43
44
45
46
47
H
4-Me
4-OMe
3,4-DiOMe
3,4,5-TriOMe
3,4-DiCl
4-Cl
3-Cl-4-F
3,4-Dioxolane
20
45
20
20
40
120
40
120
80
91
99
89
78
67
36
53
75
88
a
Isolated yield.
IC50 values were determined from the dose-response curves (Sig-
ma-Plot).
Results given in Table 3 demonstrated that none of the tricyclic
derivatives of series A and C showed affinity against the series of
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4
E. Deau et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
N
N
N
N
NH2
CN
N
DMFDMA
Br
3,4-diOMe-aniline
N
N
OMe
OMe
Br
O
neat
AcOH
118 °C (µw), 10 min.
67%
Br
HN
O
90 °C (µw), 25 min.
CN
O
87%
19
12
37
Benzo[d][1,3]dioxol-5-yl-
boronic acid
Pd(PPh3)4
Benzo[d][1,3]dioxol-5-yl-
boronic acid
Pd(PPh3)4
Benzo[d][1,3]dioxol-5-yl-
boronic acid
Pd(PPh3)4
Na2CO3
PATH B
Na2CO3
PATH C
Na2CO3
PATH A
DMF
DMF
DMF
150 °C (µw), 90 min.
20%
150 °C (µw), 90 min.
66%
150 °C (µw), 90 min.
70%
N
N
NH2
CN
N
N
N
N
N
DMFDMA
3,4-diOMe-aniline
OMe
O
O
O
neat
90 °C (µw), 25 min.
85%
AcOH
118 °C (µw), 20 min.
78%
O
HN
CN
O
O
O
OMe
O
Path A: 13% (3 steps)
Path B: 45% (3 steps)
Path C: 41% (3 steps)
O
38
28
42
Scheme 5. Optimization of the order of reaction sequence for DMFDMA-mediated formylation, palladium-catalyzed Suzuki–Miyaura cross-coupling, and Dimroth
rearrangement.
three dual-inhibitors were judged similar with a slightly better
activity for 36 (IC50 values of 0.32 and 2.3 lM for CLK1 and DYR-
N
N
H2N
R2
N
28
K1A, respectively).
O
O
R2
AcOH
Among the tested compounds, the pyrido[20,30:4,5]furo[3,2-
d]pyrimidin-4-amine substituted by a 2,4-dichlorophenyl group
(35) can be considered as the most active product because it was
the only one able to inhibit two kinases in the submicromolar
HN
118 °C (µw), 20-120 min.
36-99%
O
Series C: 39 47
-
R2 = H ( ), 4-Me ( ), 4-OMe ( ), 3,4-diOMe ( ),
39
40
41
42
43
44
45
3,4,5-triOMe ( ), 3,4-diCl ( ), 4-Cl ( ),
3-Cl-4-F (46), 3,4-dioxolane (47)
range (IC50 values of 0.049 and 0.60
respectively).
lM for CLK1 and DYRK1A,
Scheme
6. Microwave-assisted
synthesis
of
7-substituted
N-arylpyri-
With regard to this set of results on series A, B and C, it appears
that substitution by an N-aryl moiety in position 4 of the pyrimi-
dine ring reduces affinities for kinases. In contrast, the free amine
and substitution at position 7 might play an important role in the
interaction of the molecules with the target. In our case, the use of
Topliss list efficiently overcame the absence SAR studies. Hence, it
demonstrated its utility in the rapid discovery of a new hit com-
pound (e.g., compound 35).
do[20,30:4,5]furo[3,2-d]pyrimidin-4-amines 39–47 by Dimroth rearrangement. For
detailed yields and reaction times, see Table 2.
five kinases. The most promising results were obtained with prod-
ucts from the series B (29–36). Most of them displayed a rather
good inhibition of both CLK1 and DYRK1A kinases with micromolar
or submicromolar IC50 values. On a general aspect, series B deriva-
tives (29–36) were completely inactive toward CDK5/p25, CK1d/
e
CLK1 is one of the four isoforms of the cdc2-like kinase family. It
was described that inhibitors of CLK1 could prove to be useful
agents in disease phenotypes characterized by abnormal splicing.
In this sense CLK inhibitors may alter the splicing of microtu-
bule-associated protein tau implicated in Alzheimer’s disease and
Parkinson’s disease.15
and GSK3a/b.
Among the molecules of series B, three pyrido[20,30:4,5]furo[3,2-
d]pyrimidin-4-amines (29, 30, and 36) were judged relatively ac-
tive with submicromolar IC50 against CLK1 and with values against
kinase DYRK1A in the micromolar range. The IC50 values of these
Table 3
Kinase inhibitory activity of pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amine 2 and its N-aryl analogues 3–11 (series A), 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-
amines 29-36 (series B) and 7-substituted N-arylpyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines 39–47 (series C)
Series
Products
Ser/Thr kinasea,b
CDK5/p25
>10
CK1d/
e
CLK1
>10
DYRK1A
>10
GSK3
>10
a/b
A
B
2–11
>10
29
30
31
32
33
34
35
36
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
0.69
0.61
>10
1
3.1
4.4
>10
>10
>10
>10
>10
>10
>10
>10
>10
c
c
c
c
c
—
—
—
—
—
>10
>10
>10
>10
0.049
0.32
0.6
2.3
>10
>10
C
39–47
>10
>10
>10
>10
>10
a
b
c
IC50 values are reported in lM. The most significant results are presented in bold.
Kinases activities were assayed in triplicate. Typically, the standard deviation of single data points was below 10%.
Not determined.
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E. Deau et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
5
7. For latest advances in microwave-assisted organic synthesis (MAOS), see: Hoz,
De la Hoz; Loupy, A. Microwaves in Organic Synthesis, 3rd ed.; Wiley-VCH:
Weinheim, 2013.
In view of the results of this preliminary study, we consider that
the tricyclic pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amine ana-
logues (series B) constitute a promising source of inspiration for
the synthesis of novel bioactive molecules. Synthetic transforma-
tions will be explored and factors governing their dual activity
toward CLK1 and DYRK1A will be further investigated.
8. (a) Hunter, T. Cell 1995, 80, 225; (b) Harper, J. W.; Adams, P. D. Chem. Rev. 2001,
101, 2511; (c) Martí, E.; Altafaj, X.; Dierssen, M.; de la Luna, S.; Fotaki, V.;
Alvarez, M.; Pérez-Riba, M.; Ferrer, I.; Estivill, X. Brain Res. 2003, 964, 250; (d)
Ferrer, I.; Barrachina, M.; Puig, B.; Martínez de Lagrán, M.; Martí, E.; Avila, J.;
Dierssen, M. Neurobiol. Dis. 2005, 20, 392; (e) Wegiel, J.; Gong, Y.-W.; Hwang,
Y.-W. FEBS J. 2011, 278, 236; (f) Ionescu, A.; Dufrasne, F.; Gelbcke, M.; Jabin, I.;
Kiss, R.; Lamoral-Theys, D. Mini Rev. Med. Chem. 2012, 12, 1315; (g) Breland, S.;
Medda, F.; Gokhale, V.; Dunckley, T.; Hulme, C. ACS Chem. Neurosci. 2012, 3,
857.
Acknowledgments
This work was supported by a Ph.D. grant from the Région
Haute-Normandie (Y.L.). We thank the LABEX SynOrg (ANR-11-
LABX-0029) and AI-Chem Channel program for financial support.
We acknowledge Milestone s.r.l. (Italy) for technical support and
Anton Paar GmbH (Graz, Austria) for provision of the single-mode
microwave reactor (Monowave 300). It was also supported by the
EEC FP7-KBBE-2012 BlueGenics grant (L.M.), ‘Institut National con-
tre le Cancer’ (INCa) GLIOMER program and the ‘Fonds Unique
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assumption of the Hansch method that a particular substituent may modify
activity relative to the parent compound by virtue of resulting changes in
hydrophobic, electronic and steric effects. In the case of our study, using the
Topliss scheme allowed us to choose certain reagents to check the interest of
our methodology, while starting to build a list of molecules with potential
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1191; (c) Rosenthal, A. S.; Tanega, C.; Shen, M.; Mott, B. T.; Bougie, J. M.;
Nguyen, D.-T.; Misteli, T.; Auld, D. S.; Maloney, D. J.; Thomas, C. J. Bioorg. Med.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.10.
019.
References and notes
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Please cite this article in press as: Deau, E.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.10.019