Synthesis, anti-tubulin and antiproliferative SAR of steroidomimetic dihydroisoquinolinones

Article abstract of DOI:10.1002/cmdc.201400017

A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to

Full text of DOI:10.1002/cmdc.201400017

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DOI: 10.1002/cmdc.201400017
Synthesis, Anti-tubulin and Antiproliferative SAR of
Steroidomimetic Dihydroisoquinolinones
Mathew P. Leese,[a] Fabrice L. Jourdan,[a] Meriel R. Major,[a] Wolfgang Dohle,[a]
Mark P. Thomas,[a] Ernest Hamel,[b] Eric Ferrandis,[c] Mary F. Mahon,[d] Simon P. Newman,[e]
Atul Purohit,[e] and Barry V. L. Potter*[a]
A SAR translation strategy adopted for the discovery of tetra-
hydroisoquinolinone (THIQ)-based steroidomimetic microtu-
bule disruptors has been extended to dihydroisoquinolinone
(DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ
core was connected to methoxyaryl D-ring mimics through
methylene, carbonyl, and sulfonyl linkers, and the resulting
compounds were evaluated against two cancer cell lines. The
carbonyl-linked DHIQs in particular exhibit significant in vitro
antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-
(16 f) and 16g and their sulfamate derivatives 17 f and 17g (2-
(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihy-
droisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxy-
benzoyl)-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, re-
spectively) show excellent activity against the polymerization
of tubulin, close to that of the clinical combretastatin A-4, and
bind competitively at the colchicine binding site of tubulin.
Compounds 16 f and 17 f were also shown to demonstrate in
vitro anti-angiogenic activity. Additionally, X-ray and computa-
tional analyses of 17 f reveal that electrostatic repulsion be-
tween the two adjacent carbonyl groups, through conforma-
tional biasing, dictates the adoption of a “steroid-like” confor-
mation that may partially explain the excellent in vitro activi-
ties.
trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one
(16g):
GI50 51 nm in DU-145 cells). The broad anticancer activity of
DHIQ 16g was confirmed in the NCI 60-cell line assay giving
a mean activity of 33 nm. Furthermore, 6-hydroxy-2-(3,5-dime-
thoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one
Introduction
In previous studies we optimised sulfamoylated estratrienes
1a–b (Figure 1) as anticancer agents.[1–6] These compounds ex-
hibit antiproliferative activity against a range of human cancer
cell lines and are also capable of inhibiting angiogenesis. This
dual mechanism of action can be ascribed to their ability to in-
hibit normal microtubule dynamics and, in addition to good
oral bioavailability and excellent in vivo activity, they proved
capable of inhibiting the growth of cell lines resistant to exist-
ing microtubule disruptors such as the taxanes. To develop fur-
ther series of compounds that share this mechanism of action
we were drawn to investigate whether, by translating key
pharmacophoric elements from the steroidal series into non-
steroidal motifs, we could generate new microtubule disrup-
tors with further enhanced activity and/or physicochemical
properties. In initial studies[7,8] we used a tetrahydroisoquinoline
[a] Dr. M. P. Leese, Dr. F. L. Jourdan, Dr. M. R. Major, Dr. W. Dohle,
Dr. M. P. Thomas, Prof. Dr. B. V. L. Potter
Medicinal Chemistry, Department of Pharmacy & Pharmacology
University of Bath, Bath, BA2 7AY (UK)
E-mail: B.V.L.Potter@bath.ac.uk
[b] Dr. E. Hamel
Screening Technologies Branches, National Cancer Institute
Frederick, MD 21702 (USA)
[c] Dr. E. Ferrandis
Institut de Recherche Henri Beaufour, 91966 Les Ulis Cedex (France)
[d] Dr. M. F. Mahon
X-ray Crystallographic Suite, Department of Chemistry
University of Bath, Bath, BA2 7AY (UK)
[e] Dr. S. P. Newman, Dr. A. Purohit
Oncology Drug Discovery Group, Section of Investigative Medicine
Hammersmith Hospital, Imperial College London, London, W12 0NN (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201400017.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons
Attribution License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited.
Figure 1. Design of DHIQ-based steroidomimetic microtubule disruptors.
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(THIQ) decorated at C6 and C7 to mimic the steroidal A,B-ring
of the estratrienes tethered through N2 to a D-ring mimic, ini-
tially a benzyl group, which projects a hydrogen bond accept-
or into the appropriate region of space to address the pharma-
cophore for antiproliferative activity in that region. This deliv-
ered a series of microtubule disruptors with antiproliferative
activity in the micromolar range that could be further opti-
mised by introducing a substituent at C3 to sterically inhibit
the free rotation of the N-benzyl group and thus favour confor-
mational populations in which the N-benzyl group mimics the
steroidal D-ring. In this manner compounds displaying nano-
molar activity (equivalent to that of the steroid derivatives
upon which their design was based) were elaborated.[9] In
tandem, chimeric microtubule disruptors built from the THIQ
core and the trimethoxy aryl motif common to many colchi-
cine site binders were constructed.[10,11]
mide to furnish compound 5 in good yield. Reaction of 5 with
sodium azide and methanesulfonic acid in dichloromethane
gave dihydroisoquinolinone 6a. Some of the material was
transformed into the corresponding unprotected phenol 6b,
by treatment with hydrogen and palladium on charcoal, that
was subsequently protected with TIPSCl in dichloromethane to
afford compound 6c (Scheme 1).
N-Benzylation was then performed on compound 6c. Under
the conditions applied in these reactions TIPS-deprotection
and subsequent benzylation of the unprotected phenol was
also observed to give compounds 7a–c. In two further experi-
ments the more stable benzyl-protected compound 6a was re-
acted in the same manner to afford compounds 7d–e. These
were transformed into the corresponding unprotected phenols
8a–e either by treatment with hydrogen and Pd/C or with
TBAF (only for 7b) in good yields. Treatment of 8a–e with sul-
famoyl chloride in DMA[12] gave the corresponding sulfamates
9a–e (Scheme 2).
In the present work we sought to develop new microtubule
disruptors through integration of lessons learned in work on
the estratrienes and the THIQ-
based systems. By using an alter-
nate heterocyclic motif, the dihy-
droisoquinolinone (DHIQ) to
mimic the steroidal A,B-ring
system, we envisaged that some
conformational pre-organisation
Scheme 2. Synthesis of functionalised N-benzyl-substituted DHIQs. Reagents and conditions: a) NaH, 08C, DMF,
then benzyl halide, RT; b) H2, Pd/C, THF/MeOH, RT; c) TBAF, THF, RT; d) H2NSO2Cl, DMA, RT.
could be achieved through elec-
trostatic repulsion. Tethering the
D-ring-mimicking aryl group
through a carbonyl linkage, re-
pulsion of the two carbonyl groups of the imide should cause
adoption of a dihedral angle in which they minimise their elec-
trostatic clash; this should deliver a conformation in which the
D-ring mimic projects into a region of space broadly analogous
to a steroidal D-ring, thus decreasing rotation to achieve opti-
A second compound set was produced by N-sulfonylating
6a with various arylsulfonyl chlorides. Compounds 10a–
e were transformed into the corresponding unprotected phe-
nols 11 a–e, by treatment with hydrogen and Pd/C, that were
then reacted with sulfamoyl chloride in DMA to afford the cor-
responding sulfamates 12a–e (Scheme 3).
mal binding. To assess this strategy
a
series of
2’-, 3’- and 4’-methoxybenzoyl DHIQs was synthesised along-
side corresponding N-benzyl and N-arylsulfonyl DHIQ series for
which no positive conformational biasing is envisaged
(Figure 1).
For the synthesis of N-benzoylated compounds a direct
strategy starting from 6a proved not very successful. There-
fore, an alternate approach using benzyl-protected THIQ 13[8]
as starting material was adopted. N-Benzoylation using various
benzoyl chlorides followed by permanganate oxidation gave
access to the desired N-benzoylated dihydroisoquinolines
15a–g. These were reacted with hydrogen and Pd/C and the
product treated with sulfamoyl chloride in DMA to give sulfa-
mates 17a–g. Additionally, a set of control compounds with-
out the carbonyl at C1 was achieved by hydrogenation of com-
pounds 14e–g with Pd/C to give phenols 18a–c. Treatment
with sulfamoyl chloride in DMA then afforded sulfamates 19a–
c (Scheme 4).[8]
Results and Discussion
Chemistry
The synthetic strategy to access the dihydroisoquinolinone
core structure is outlined below (Scheme 1). 5,6-Dimethoxyin-
dan-1-one 3 was selectively demethylated in aqueous piperi-
dine and the product subsequently reacted with benzyl bro-
Biology
The compounds were then eval-
uated in vitro for their ability to
inhibit the proliferation of DU-
145 human prostate cancer cells
Scheme 1. Synthesis of the DHIQ core structure. Reagents and conditions: a) piperidine/H2O, 1408C; b) BnBr, K2CO3,
DMF, RT; c) NaN3, CH3SO3H, CH2Cl2, 08C!RT; d) H2, Pd/C, THF/MeOH, RT; e) TIPSCl, imidazole, CH2Cl2, RT.
and MDA MB-231 breast cancer
cells. As can be observed in
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this symmetric substitution adds
a further entropic advantage in
combination with the pre-organ-
isation we believed would derive
from the repulsion of the car-
bonyls of the imide discussed
above. In any case, the activity
of 16 f and 17 f is equal to that
of both the conformationally
biased THIQs and the steroidal
derivatives from which the non-
steroidal design was conceived.
Finally, 3’,4’,5’-trimethoxyben-
zoyl DHIQ derivatives 15g, 16g
and 17g were also evaluated.
From our understanding drawn
from experience with the THIQ
systems these compounds could
well act as chimeras addressing
both the steroidal A-ring binding
area and the trimethoxyaryl
binding area of the colchicine
binding site on tubulin. Phenol
16g and its sulfamate 17g
Scheme 3. Synthesis of functionalised N-arylsulfonyl-substituted DHIQs. Reagents and conditions: a) NaH, DMF,
508C, then ArSO2Cl, DMF, RT or 408C; b) H2, Pd/C, THF/EtOH, RT; c) H2NSO2Cl, DMA, RT.
Scheme 4. Synthesis of functionalised N-benzoyl-substituted DHIQs and THIQs. Reagents and conditions:
a) ArCOCl, Et3N, CH2Cl2, RT; b) KMnO4, 18-crown-6, CHCl3, RT; c) H2, Pd/C, THF/MeOH, RT; d) H2NSO2Cl, DMA, RT.
Table 1, the N-benzyl derivatives, regardless of the nature of
substitution of the benzyl motif, prove to be uniformly inactive
in contrast to the corresponding THIQ series in which the 3’-
methoxy compound 2 (Figure 1) exhibits a GI50 value of
2.1 mm.[7,8] The addition of a carbonyl at C1 in this case is clear-
ly detrimental, and it seems reasonable to suggest that this
group, through steric considerations, disfavours adoption of
a conformation in which the benzyl group can potentially
mimic the steroid D-ring. Likewise, the series of N-arylsulfonyl
derivatives prove to be inactive. The corresponding series of N-
arylsulfonyl THIQs also fails to display significant activity, a fact
that we ascribe to the likely unacceptable steric bulk of the
sulfonyl group at the site of binding.[8] The N-benzoyl DHIQs,
in contrast, provide interesting activity in both the 6-hydroxy
and 6-sulfamoyloxy series. Here, both the 2’- and 3’-methoxy
compounds give low micromolar GI50 values against the prolif-
eration of both DU-145 and MDA MB-231 cells. It is notable
that the 6-hydroxy compounds 16a–b display superior activity
to the 6-O-sulfamates 17a–b and that, as found for the N-
benzyl THIQs (with which we believed they should act in an
analogous manner), the 3’-substituted derivative displays the
highest activity. In contrast, as found in the N-benzyl THIQ
series, the 4’-substituted compounds 16d and 17d are inac-
tive. Several polymethoxylated compounds were also evaluat-
ed revealing that, although 4’-substitution alone did not afford
activity, it is tolerated as the 3’,4’-dimethoxy compounds 16e
and 17e display good activity and are more active than the 3’-
methoxy derivatives 16b and 17b. The major step forward in
activity was realised when the 3’,5’-dimethoxy derivative 16 f
and its sulfamate 17 f were evaluated, with roughly equivalent
activity (GI50 values of 215 and 179 nm for DU-145, respective-
ly). Compounds 16 f and 17 f are >10-fold more active than
the 3’-methoxy derivatives 16b and 17b. We postulate that
prove to be the most active compounds evaluated, with 16g
displaying respective GI50 values of 51 and 71 nm against the
proliferation of DU-145 and MDA MB-231 cells.
Comparing these results with those for related N-benzoylat-
ed THIQs (Table 2) it is evident that omitting the carbonyl at
C1 is in general detrimental towards in vitro antiproliferative
activity. Only polymethoxylated compounds are displayed
here. The series of 3’,4’-dimethoxy THIQ compounds shows
a different trend to the corresponding DHIQ series, because
here benzyl-protected compound 14e shows the best, but still
relatively modest, activity (GI50 26.7 mm in DU-145) with phenol
18a and sulfamate 19a being surprisingly completely inactive.
The 3’,5’-dimethoxy and 3’,4’,5’-trimethoxy derivatives were
also evaluated and show a similar trend as their DHIQ counter-
parts, with phenols 18b–c showing low micromolar activity
that is slightly better than that of the corresponding sulfa-
mates 19b–c, while benzyl-protected compounds 14 f–g dis-
play only modest activity. However, the most active com-
pounds 18c and 19c are still about 10- to 20-fold less active
than DHIQs 16g and 17g, showing the importance of the
combination of two carbonyl groups (at C1 and in the linker to
the D-ring mimic) to achieve compounds with low nanomolar
activity.
The most active compound 16g was also tested in the NCI
60-cell line assay (Table 3) that allows activity across a wide
range of cancer types to be assessed. Data from seven cell
lines are presented along with the mean activity across the
whole panel (MGM value). Screening was conducted at con-
centrations ranging from 10 nm upwards, with maximal activity
(where a 50% growth inhibition was obtained in all cell lines
at a concentration of 10 nm) being indicated by an MGM value
of 10 nm. The data obtained in the assay confirm the very high
potency of 16g against a broad range of cancer phenotypes.
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Table 1. Antiproliferative activity of DHIQs against DU-145 human pros-
tate cancer cells and MDA MB-231 human breast cancer cells in vitro.
Table 2. Antiproliferative activity of polymethoxylated N-benzoyl THIQs
against DU-145 human prostate cancer cells and MDA MB-231 human
breast cancer cells in vitro.
Compd
GI50 [mm][a]
Compd
GI50 [mm][a]
R1
H
X
R2
R3
R4
R5
DU-145 MDA MB-231
R1
R3
R4
R5
DU-145
26.7
>100
>100
46.8
MDA MB-231
8a
9a
8b
9b
8c
9c
7d
8d
9d
7e
8e
9e
CH2 OMe
H
H
H
H
H
H
H
H
>100
>100
>100
>100
>100
>100
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
14e
18a
19a
14 f
18b
19b
14g
18c[c]
19c[c]
Bn
H
SO2NH2
Bn
H
SO2NH2
Bn
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
ND[b]
18.9
SO2NH2 CH2 OMe
H
CH2
SO2NH2 CH2
CH2
SO2NH2 CH2
H
H
H
H
H
H
H
H
H
H
OMe H
OMe H
H
H
OMe H
OMe H
6.4
9
62.7
0.921
1.81
H
Bn
H
CH2
CH2
OMe H
OMe H
OMe H
OMe OMe OMe >100
OMe OMe OMe >100
OMe OMe OMe >100
H
H
H
OMe H
OMe H
OMe H
H
H
OMe >100
OMe >100
OMe >100
0.733
1.72
SO2NH2 CH2
Bn
H
SO2NH2 CH2
Bn
H
SO2NH2 SO2 OMe
Bn
H
SO2NH2
CH2
CH2
[a] Results are the mean of three determinations. [b] Not determined.
[c] Data for 18c and 19c are taken from the literature.[8]
10a
11 a
12a
10b
11 b
12b
11 c
12c
10d
11 d
12d
11 e
12e
15a
16a
17a
16b
17b
15c
16c
17c
15d
16d
17d
15e
16e
17e
15 f
16 f
17 f
15g
16g
17g
SO2 OMe
SO2 OMe
H
H
H
H
H
H
H
H
H
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
13.4
>100
SO2
SO2
H
H
H
H
H
H
H
H
>100
>100
>100
>100
>100
>100
>100
>100
>100
13
Table 3. GI50 and MGM values of compound 16g obtained for represen-
tative cell lines in the NCI-60 screening panel.
SO2NH2 SO2
SO2
SO2NH2 SO2
H
OMe H
OMe H
Cell Line
GI50 [mm][a]
Cell Line
GI50 [mm][a]
Bn
H
SO2
SO2
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Leukemia CCRF-CEM
Lung HOP-62
Colon HCT-116
CNS SF-539
0.0171
0.0295
0.0216
0.0102
Melanoma UACC-62
Ovarian OVCAR-3
Renal SN12-C
MGM
<0.01
<0.01
0.056
0.033
SO2NH2 SO2
H
SO2NH2 SO2 CO2Me H
Bn
H
SO2 CO2Me H
CO OMe
CO OMe
H
H
H
43.6
[a] Results are the mean of three determinations. The MGM value (in ital-
ics) represents the mean concentration that caused 50% growth inhibi-
tion in all 60 cell lines.
6.42
5.6
SO2NH2 CO OMe
CO
SO2NH2 CO
9.1
7.1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe H
OMe H
CN
CN
CN
H
3.63
5.3
1.89
3.5
Bn
H
CO
CO
H
H
H
>100
>100
37.4
>100
ND[b]
ND[b]
ND[b]
ND[b]
1.6
70
25
>100
>100
>100
>100
SO2NH2 CO
Bn
H
SO2NH2 CO
Bn
H
SO2NH2 CO
Bn
H
SO2NH2 CO
Bn
H
CO
CO
OMe H
OMe H
OMe H
H
H
CO
CO
OMe OMe H
OMe OMe H
OMe OMe H
OMe H
OMe H
OMe H
OMe OMe OMe >100
OMe OMe OMe
OMe OMe OMe
2.39
3.4
2.08
ND[b]
0.161
0.118
77.5
CO
CO
OMe >100
OMe
OMe
0.215
0.179
CO
CO
0.051
0.166
0.071
0.275
SO2NH2 CO
[a] Results are the mean of three determinations. [b] Not determined.
As with sulfamates in the tetrahydroisoquinoline series, sul-
famate 17 f also inhibits carbonic anhydrase (IC50 890 nm),
which may enhance the bioavailability of this compound.[13]
Compounds 16 f and 17 f were also assayed for anti-angiogen-
ic activity in an in vitro model of angiogenesis, wherein endo-
thelial cells co-cultured in a matrix of human dermal fibroblasts
are used to assess anti-angiogenic potential (Figure 2). When
stimulated with VEGF the endothelial cells proliferate and mi-
grate through the matrix to form tubule-like structures. The
extent of tubule formation was quantified after 11 days as de-
Figure 2. Activity of 16 f and 17 f in an in vitro model of angiogenesis.
scribed elsewhere.[14] Treatment with 25 nm and 50 nm concen-
trations of 16 f and 17 f almost completely inhibits the forma-
tion of tubule-like structures (Figure 2). Quantification carried
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out by calculating total pixel length reflects the lack of tubule
formation. Both phenol 16 f and its sulfamate 17 f are highly
potent.
angles in the crystal structure do not necessarily reflect condi-
tions in solution. However, the excellent in vitro antiprolifera-
tive activities obtained for this class of compound suggest that
adoptable conformations might be very restricted in solution
as well, mainly as a result of electrostatic repulsion between
the two carbonyl groups, and somewhere around the angle
observed in the crystal. Control compounds like 8d–e and 9d–
e without the carbonyl group in the linker to the D-ring mimic
and 18b–c and 19b–c without the carbonyl at C1 do not have
this favourable restriction and therefore show far less potency
than their counterparts 16 f–g and 17 f–g that have both car-
bonyl groups present.
With these excellent in vitro data in hand, we decided to ex-
plore further the microtubule disruptor activity in particular of
16 f–g and 17 f–g alongside the established potent agent
combretastatin A-4 (CA-4), currently in clinical trials. All the
tested novel compounds show excellent activity as inhibitors
of tubulin assembly, with IC50 values of 1.2–1.5 mm similar to
that of CA-4 (IC50 1.1 mm). Ultimately, as observed before, the
concentration required in tubulin-based assays far exceeds the
antiproliferative dose, and most likely it suffices to disrupt mi-
crotubule dynamics to arrest the cell cycle rather than cause
a catastrophic depolymerisation event. It should also be
stressed that the nominal compound concentration in antipro-
liferative assays is that of agent added to the culture medium,
rather than the actual concentration within cells, and drug
transport can also be a key determinant in reaching the con-
centration required to achieve an effect. We also determined
that 16 f–g and 17 f–g inhibit colchicine binding to tubulin
very effectively. Compound 17 f, which is the most active (89%
inhibition at 5 mm), was also tested at lower concentration and
shows 65% inhibition at 1 mm, approaching again the activity
of CA-4 (99 and 90%). It is thus reasonable to suggest that the
activity of the novel DHIQ derivatives can at least partially be
ascribed to their ability to disrupt the normal dynamic poly-
merisation of tubulin by interaction at, or around, the colchi-
cine binding site (Table 4).
Molecular structure 17 f was treated with a computational
energy minimisation procedure. These calculations showed, in
the minimal energy conformation, that a dihedral angle of
151.08 exists between the two carbonyl groups that is in good
agreement with the observed angle of 148.48 in the crystal
structure. As we postulated, the 3’,5’-dimethoxybenzoyl group
is projected into the area of space that is occupied by the ster-
oidal D ring and the C18 methyl group in the estratriene
series. This is illustrated in Figure 4 where the minimum
energy state of 17 f is overlaid with energy-minimised 1a. Ad-
ditionally, the D-ring is rotated 47.28 out of plane of the A,B-
ring system leading to one methoxy group being projected
into the space of the sulfamate group and the other into the
space of the C18 methyl group of 1a. Although not shown
here, the most potent DHIQs were subjected to the same con-
formational analysis and the results (angles) obtained were un-
surprisingly very similar (16g: 149.88 and 46.98; 17g: 150.58
and 47.18) to the ones for compound 17 f. These calculations
support our postulate that the presence of the imide sub-
structure favours adoption of a “steroid-like” conformation. It
seems reasonable to propose that the positive effects on activ-
ity can, to some degree, be ascribed to this conformational
biasing.
Table 4. Activity of selected DHIQs as inhibitors of tubulin polymerisation
(TP) and colchicine binding (CB) to tubulin.
Compd
TP IC50 [mm][a]
CB [% inhib.][a]
5 mm inhibitor
1 mm inhibitor
CA-4
1a[c]
1b[c]
1c[c]
16 f
16g
17 f
17g
1.1ꢀ0.1
2.2ꢀ0.3
1.3ꢀ0.08
1.3ꢀ0.01
1.5ꢀ0.1
1.3ꢀ0.1
1.3ꢀ0.01
1.2ꢀ0.03
99ꢀ0.6
28ꢀ3
90ꢀ0.2
ND[b]
78ꢀ0.9
45ꢀ4
ND[b]
ND[b]
ND[b]
Conclusions
81ꢀ0.7
83ꢀ2
ND[b]
In summary, dihydroisoquinolinone derivatives including their
sulfamate esters are compounds with activities in the low mi-
cromolar and nanomolar range against the proliferation of
prostate and breast cancer cells. The most potent DHIQ deriva-
tive synthesised 16g, is also confirmed as having very high po-
tency against a broad range of cancer phenotypes in the NCI
60-cell line assay. As anticipated, these compounds also display
anti-angiogenic activity in an in vitro angiogenesis assay and
appear to function as microtubule disruptors, as evidenced by
their ability to inhibit polymerisation of tubulin and compete
at the colchicine binding site. The most active DHIQs 16 f–g
and their sulfamates 17 f–g are nearly equipotent to combre-
tastatin A-4 (CA-4) as inhibitors of tubulin assembly and colchi-
cine binding. Additionally, X-ray analysis of 17 f reveals that
electrostatic repulsion between the two adjacent carbonyl
groups might partially explain the excellent in vitro activities of
this novel series of microtubule disruptors. This conclusion is
further supported by molecular modelling studies. Thus, com-
89ꢀ0.1
85ꢀ2
65ꢀ3
ND[b]
[a] Values are the mean ꢀSD of at least two determinations. [b] Not de-
termined. [c] Data for 1a–c are taken from the literature.[3]
Finally, an X-ray crystal structure of 17 f was obtained to ex-
plore conformational effects (Figure 3).[15] The crystal structure
shows that in the solid state the molecule adopts a “steroid-
like” conformation as planned with a dihedral angle of 148.48
between the two carbonyl groups (Figure 3a). In the single
crystal this fixed angle also appears as a result of positive inter-
molecular interactions (Figure 3b). The sulfamate group plays
a key role to stabilise the framework of the lattice structure by
acting as a hydrogen donor to the C3’-methoxy group of
a second molecular unit that is part of the same string and to
the carbonyl group at C1 of a third molecular unit that is part
of a second string running in the opposite direction. The
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(0.1 mgmLꢁ1). The effect of drugs
on tubule formation was assessed
using an angiogenesis kit (TCS-
Cellworks).
Antiproliferative assays: DU-145
and MDA MB-231 cells were
seeded into 96-well microtitre
plates (5000 cells per well) and
treated with compound (10ꢁ9
–
10ꢁ4 m) or with vehicle control. At
96 h post-treatment, live cell
counts were determined by WST-
1 cell proliferation assay (Roche,
Penzberg, Germany), as per the
manufacturer’s instructions. Viabili-
ty results were expressed as a per-
centage of mean control values re-
sulting in the calculation of the
50% growth inhibition (GI50). All
experiments were performed in
triplicate.
Anti-angiogenic assays: HUVECs
were cultured in a 24-well plate
within a matrix of human diploid
fibroblasts of dermal origin in opti-
mised medium supplied by the
company. The co-cultured cells
were incubated throughout the ex-
periment at 378C under 5% CO2 in
a humidified incubator. On day 1,
the culture medium was removed
and replaced with medium con-
taining the drug under investiga-
tion. On days 4, 7 and 9 the
medium was replaced with fresh
medium containing the drugs. Sur-
amin (20 mL) was used as a positive
anti-angiogenic control and vascu-
lar endothelial growth factor
(VEGF, 2 ngmLꢁ1) as a pro-angio-
genic control. Each compound was
tested in triplicate. On day 11, the
cells were washed (PBS) and 70%
EtOH (1 mL) added to each well
for 30 min to fix the cells. After fix-
ation the cells were washed with
blocking buffer (1 mL, PBS 1%
BSA; Sigma, UK) and stained for
Figure 3. a) Single-crystal X-ray structure of 17 f. Ellipsoids are depicted at 30% probability. b) Part of the crystal
lattice packing diagram of 17 f to illustrate the hydrogen-bonded linear arrangements present in the gross struc-
ture.
Figure 4. Overlay of the minimum energy conformation of DHIQ 17 f (cyan) with steroid 1a (pink) viewed from
two perspectives.
von Willebrand’s factor (manual scoring) for CD31 (computer analy-
sis) in accordance with the manufacturer’s instructions (TCS-Cell-
works). The extent of tubule formation was then quantified, either
manually by eye or using free software available through the Na-
tional Institutes of Health website (NIH image [Mac version] from
http://rsb.info.nih.gov/nih-image/download.html). For manual scor-
ing a grid was drawn on the back of the plate using a fine marker
pen. A 25-point Chalkley eyepiece graticule (Pyser SGI Ltd, UK) was
fitted to the microscope and 10x magnification was used to count
the tubules within five viewing fields (where the grid lines inter-
sect), the average and SE were then calculated. For computer anal-
ysis, eight fixed fields of view for each well (10x magnification)
were digitally photographed using a DC120 camera (Kodak, Ro-
chester, NY, USA) with the Photoshop (Adobe, USA) plug-in MDS
pounds derived from the DHIQ series are worthy of in vivo in-
vestigation and potential further pre-clinical development.
Experimental Section
In vitro studies
Cell lines: DU-145 (brain metastasis carcinoma of the prostate) and
MDA MB-231 (metastatic pleural effusion of breast adenocarcino-
ma) established human cell lines were obtained from ATCC Global
Bioresource Center. Cells were maintained in a 5% CO2 humidified
atmosphere at 378C in RPMI-1640 medium, supplemented with
10% fetal bovine serum, penicillin, (100 UmLꢁ1), and streptomycin
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120 software (Kodak). The pictures were copied to the NIH image
software using Quicktime (Apple, USA) translation. After correcting
for background the software counted the number of pixels repre-
senting tubules. The total pixel area within the eight fields was
then calculated for each well. The average total pixel area and SE
were then calculated. There was a significant correlation (r=0.94,
p<0.001) between manual and computer analysis of tubule forma-
tion.
point apparatus (Stanford Research Systems, Sunnyvale, CA, USA)
and are uncorrected. All compounds were ꢂ98% pure by re-
versed-phase HPLC run with CH3CN/H2O or MeOH/H2O (Sunfire C18
reversed-phase column, 4.6ꢁ150 mm, 3.5 mm pore size).
Crystallographic methods: Single crystals of compound 17 f were
analysed using a Nonius Kappa CCD diffractometer using Mo(Ka)
radiation. The structure was solved using SHELXS-97[22] and refined
using full-matrix least squares in SHELXL-97.[23] The hydrogen
atoms attached to N2 were located and refined subject to being
a distance of 0.89 ꢂ from the parent atom. CCDC 874341 contains
the crystallographic data for compound 17 f and can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.cam.ac.uk/data_request/cif.
Tubulin assays: Bovine brain tubulin, prepared as described previ-
ously,[16] was used in studies presented here. Assembly IC50 values
were determined as described in detail elsewhere.[17] Briefly,
1.0 mgmLꢁ1 (10 mm) tubulin was pre-incubated without GTP with
varying compound concentrations for 15 min at 308C. Reaction
mixtures were placed on ice, and GTP (final concentration, 0.4 mm)
was added. The reaction mixtures were transferred to cuvettes,
held at 08C in a recording spectrophotometer. Baselines were es-
tablished at 08C, and increase in turbidity was followed for 20 min
following a rapid (<30 s) jump to 308C. Compound concentrations
required to decrease the turbidity increase by 50% were deter-
mined. The method for measuring inhibition of the binding of
[3H]colchicine to tubulin was described in detail previously.[18] Reac-
tion mixtures contained 0.1 mgmLꢁ1 (1.0 mm) tubulin, 5.0 mm
[3H]colchicine, and potential inhibitor at 5.0 mm. Compounds were
compared with CA-4, a particularly potent inhibitor of the binding
of colchicine to tubulin.[19] Reaction mixtures were incubated for
10 min at 378C, a time point at which the binding of colchicine in
control reaction mixtures is generally 40–60% complete. A mini-
mum of two experiments were performed with each compound.
Computational methods: The Schrçdinger software running under
Maestro version 9.2.112 was used for all computational work. The
crystal structure of 17 f solved in this work was used. One mole-
cule was taken from this structure and run through a brief geome-
try optimisation procedure. Both dihedral angles were manually
and independently adjusted in steps of 308 and the energy of the
conformers was calculated. Compounds 16g and 17g were built
by altering the crystal structure of 17 f to yield the desired struc-
ture which was then run through a brief geometry optimisation
procedure. Conformers were generated and molecular energies
calculated as described above.
5-Hydroxy-6-methoxyindan-1-one (4): 5,6-Dimethoxy-indan-1-one
(25.93 g, 135.0 mmol) was placed in a 1 L round-bottom flask. Pi-
peridine (200 mL) and H2O (50 mL) were added and the reaction
mixture was stirred at 1408C for 8 days. The mixture was concen-
trated in vacuo and aqueous NaOH (2m, 400 mL) was added. The
mixture was extracted with EtOAc (200 mL) and CH2Cl2 (200 mL).
The aqueous layer was then acidified with HCl (12m, 100 mL) and
extracted with CH2Cl2 (3ꢁ200 mL). This organic layer system was
washed with H2O (200 mL), dried (MgSO4), filtered and concentrat-
ed in vacuo to give compound 4 as a yellow powder (16.87 g,
70%). 1H NMR (270 MHz, CDCl3): d=2.49–2.60 (2H, m), 2.86–2.98
(2H, m), 3.83 (3H, s), 6.86 (1H, s), 7.09 (1H, s), 8.03 ppm (1H, s, br).
Chemistry
General: All chemicals were either purchased from Aldrich Chemi-
cal Co. (Gillingham, UK) or Alfa Aesar (Heysham, UK). Organic sol-
vents of A.R. grade were supplied by Fisher Scientific (Loughbor-
ough, UK) and used as supplied. CHCl3, CH2Cl2, DMA, DMF and THF
were purchased from Aldrich and stored under a positive pressure
of N2 after use. Compounds 13, 18c and 19c were prepared ac-
cording to literature procedures.[8] Sulfamoyl chloride was prepared
by an adaptation of the method of Appel and Berger[20] and was
stored in the refrigerator under positive pressure of N2 as a solution
in toluene as described by Woo et al.[21] An appropriate volume of
this solution was freshly concentrated in vacuo immediately before
use. Reactions were carried out at room temperature unless stated
otherwise. Thin-layer chromatography (TLC) was performed on pre-
coated aluminum plates (Merck, silica gel 60 F254). Product spots
were visualised either by UV irradiation at 254 nm or by staining
with either alkaline KMnO4 solution or 5% dodecamolybdophos-
phoric acid in EtOH, followed by heating. Flash column chromatog-
raphy was performed using gradient elution (solvents indicated in
text) on either pre-packed columns (Isolute) on a Flashmaster II
system (Biotage, Uppsala, Sweden) or on a CombiFlash Rf Automat-
ed Flash Chromatography System (Teledyne Isco, Lincoln, NE, USA)
5-Benzyloxy-6-methoxyindan-1-one (5): Compound
4 (3.0 g,
16.8 mmol), benzyl bromide (2.1 mL, 17.7 mmol) and potassium
carbonate (4.70 g, 34.0 mmol) were suspended in DMF (20 mL) and
stirred at RT for 3 days. H2O (50 mL) was added and the mixture
was extracted with EtOAc (2ꢁ80 mL). The combined organics were
washed with H2O and brine, dried (MgSO4) and concentrated in
vacuo. Crystallisation from EtOAc/hexane 2:3 afforded compound
1
5 as a light-yellow powder (4.10 g, 91%), mp: 139–1408C. H NMR
(270 MHz, CDCl3): d=2.58–2.66 (2H, m), 2.93–3.01 (2H, m), 3.89
(3H, s), 5.22 (2H, s), 6.88 (1H, s), 7.18 (1H, s), 7.27–7.46 ppm (5H,
m).
6-Benzyloxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (6a):
Compound 5 (2.68 g, 10 mmol) was dissolved in CH2Cl2 (10 mL)
and methanesulfonic acid (10 mL) and the solution was cooled to
08C. Sodium azide (1.32 g, 20 mmol) was added portionwise over
0.5 h. The mixture was allowed to warm to RT and stirred for 16 h.
Aqueous NaOH (1.5m, 50 mL) was added dropwise at 08C. The
mixture was extracted with EtOAc (3ꢁ80 mL). The combined or-
ganics were washed with H2O and brine, dried (MgSO4) and con-
centrated in vacuo. Flash column chromatography (hexane/EtOAc
3:1 to EtOAc) and crystallisation from EtOAc afforded compound
6a as a white solid (1.45 g, 52%), mp: 177–1788C. 1H NMR
(270 MHz, CDCl3): d=2.87 (2H, t, J=7.6 Hz), 3.53 (2H, t, J=7.6 Hz),
3.94 (3H, s), 5.20 (2H, s), 6.03 (1H, s, br), 6.70 (1H, s), 7.29–7.46
(5H, m), 7.60 ppm (1H, s); LC–MS (FAB+): m/z 284.44 [M+H]+.
1
with RediSep Rf disposable flash columns. H and 13C NMR spectra
were recorded with either a Delta JMN-GX 270 (Jeol, Peabody, MA,
USA) at 270 and 67.5 MHz, respectively, or a Mercury VX 400 NMR
spectrometer (Varian, Paolo Alto, CA, USA) at 400 and 100 MHz, re-
spectively. Chemical shifts d are reported in parts per million (ppm)
relative to tetramethylsilane (TMS) as internal standard. Coupling
constants J are recorded to the nearest 0.1 Hz. Mass spectra were
recorded at the Mass Spectrometry Service Centre, University of
Bath, UK. FAB-MS was carried out using m-nitrobenzyl alcohol
(NBA) as the matrix. Melting points were determined using a Stuart
SMP3 or a Stanford research systems Optimelt MPA100 melting
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6-Hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one
(6b):
7-Methoxy-6-(triisopropylsilyloxy)-2-(4-methoxybenzyl)-3,4-dihy-
droisoquinolin-1(2H)-one (7c): Method as for 7a using compound
6c (524 mg, 1.5 mmol), sodium hydride (60%, 64 mg, 1.6 mmol)
and 4-methoxybenzyl bromide (0.26 mL, 1.8 mmol) in DMF (5 mL)
at 08C for 0.5 h and at RT for 6 h. Flash column chromatography
(hexane/EtOAc 10:1 to 5:1) afforded compound 7c as a colourless
Compound 6a (1.418 g, 5.0 mmol) was dissolved in MeOH (50 mL)
and filtered. The solution was sucked at 1.0 mLminꢁ1 into the H-
cube and treated with full hydrogen over Pd/C (10%, 140 mg car-
tridge) at RT. The resulting solution was concentrated in vacuo to
1
afford compound 6b as a pale-yellow solid (961 mg, 99%). H NMR
1
(270 MHz, CDCl3): d=2.72 (2H, t, J=6.7 Hz), 3.27–3.31 (2H, m),
3.77 (3H, s), 6.65 (1H, s), 7.33 (1H, s), 7.64 (1H, s, br), 9.65 ppm
(1H, s, br); LC–MS (ES+): m/z 194.2 [M+H]+.
oil (385 mg, 55%). H NMR (270 MHz, CDCl3): d=1.07 (18H, d, J=
6.9 Hz), 1.22 (3H, sept, J=6.9 Hz), 2.77 (2H, t, J=6.7 Hz), 3.42 (2H,
t, J=6.7 Hz), 3.78 (3H, s), 3.84 (3H, s), 4.68 (2H, s), 6.60 (1H, s), 6.84
(2H, dt, J=8.6, 2.4 Hz), 7.26 (2H, dt, J=8.5, 2.3 Hz), 7.60 ppm (1H,
s); LC–MS (APCI+): m/z 470.57 [M+H]+; HRMS (ES+): m/z found
470.2706; C27H40NO4Si+ [M+H]+ requires 470.2721.
7-Methoxy-(6-triisopropyloxy)-3,4-dihydro-2H-isoquinolin-1-one
(6c): Compound 6b (3.1 g, 16 mmol), TIPSCl (7.1 mL, 33 mmol) and
imidazole (2.4 g, 35 mmol) in DMF (30 mL) was stirred at RT for
16 h. H2O (30 mL) was added and the mixture was extracted with
EtOAc (2ꢁ80 mL). The combined organic layers were washed with
H2O and brine, dried (MgSO4), filtered and concentrated in vacuo.
Flash column chromatography (hexane to EtOAc) afforded com-
6-Benzyloxy-7-methoxy-2-(3,5-dimethoxybenzyl)-3,4-dihydroiso-
quinolin-1(2H)-one (7d): Method as for 7a using compound 6a
(425 mg, 1.5 mmol), sodium hydride (60%, 120 mg, 3.0 mmol) and
3,5-dimethoxybenzyl bromide (416 mg, 1.8 mmol) in DMF (10 mL)
at 08C for 0.5 h and at RT for 18 h. Flash column chromatography
(hexane/EtOAc 5:1 to 1:1) gave an oil that was stirred in Et2O
(50 mL) and hexane (20 mL), filtered and dried in vacuo to afford
compound 7d as a white powder (440 mg, 68%), mp: 82–838C.
1H NMR (270 MHz, CDCl3): d=2.79 (2H, t, J=6.7 Hz), 3.43 (2H, t,
J=6.7 Hz), 3.75 (6H, s), 3.93 (3H, s), 4.69 (2H, s), 5.17 (2H, s), 6.35
(1H, t, J=2.5 Hz), 6.45 (2H, d, J=2.5 Hz), 6.62 (1H, s), 7.27–7.45
(5H, m), 7.66 ppm (1H, s); LC–MS (ES+): m/z 456.03 ([M+Na]+,
100%), 434.05 [M+H]+; HRMS (ES+): m/z found 434.1956;
1
pound 6c as a white powder (5.0 g, 93%), mp: 112–1138C. H NMR
(270 MHz, CDCl3): d=1.07 (18H, d, J=6.9 Hz), 1.23 (3H, sept, J=
6.9 Hz), 2.85 (2H, t, J=6.7 Hz), 3.51 (2H, dt, J=6.7, 2.9 Hz), 3.82
(3H, s), 5.86 (1H, s, br), 6.66 (1H, s), 7.53 ppm (1H, s); LC–MS
(APCI+): m/z 350.50 [M+H]+.
7-Methoxy-2-(2-methoxybenzyl)-6-(2-methoxybenzyloxy)-3,4-di-
hydroisoquinolin-1(2H)-one (7a): Compound 6c (505 mg,
1.44 mmol) was dissolved in anhydrous DMF (5 mL) and cooled to
08C. Sodium hydride (60% in mineral oil, 115 mg, 2.88 mmol) was
added portionwise and the suspension was stirred at 08C for 0.5 h.
2-Methoxybenzyl chloride (0.24 mL, 1.73 mmol) was added drop-
wise and the reaction mixture was stirred at RT for 4 days. Ammo-
nium chloride (saturated, 10 mL) was added and the mixture was
extracted with EtOAc (80 mL). The organic layer was washed with
H2O and brine, dried (MgSO4), filtered and concentrated in vacuo.
Flash column chromatography (hexane/EtOAc 10:1 to 2:1) afforded
7a as a white powder (350 mg, 56%), mp: 133–1348C. 1H NMR
(270 MHz, CDCl3): d=2.81 (2H, t, J=6.7 Hz), 3.50 (2H, t, J=6.7 Hz),
3.83 (3H, s), 3.85 (3H, s), 3.93 (3H, s), 4.78 (2H, s), 5.22 (2H, s), 6.64
(1H, s), 6.84–6.95 (4H, m), 7.18–7.32 (3H, m), 7.44 (1H, dd, J=7.4,
1.5 Hz), 7.65 ppm (1H, s); LC–MS (APCI+): m/z 434.56 [M+H]+;
C26H28NO5 [M+H]+ requires 434.1962.
+
6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydroi-
soquinolin-1(2H)-one (7e): Method as for 7a using compound 6a
(425 mg, 1.5 mmol), sodium hydride (60%, 120 mg, 3.0 mmol) and
3,4,5-trimethoxybenzyl chloride (390 mg, 1.8 mmol) in DMF (10 mL)
at 08C for 0.5 h and at RT for 18 h. The residue was stirred in Et2O,
filtered and dried in vacuo to afford compound 7e as a white
1
powder (570 mg, 82%), mp: 136–1378C. H NMR (270 MHz, CDCl3):
d=2.80 (2H, t, J=6.8 Hz), 3.43 (2H, t, J=6.8 Hz), 3.82 (9H, s), 3.93
(3H, s), 4.68 (2H, s), 5.17 (2H, s), 6.52 (2H, s), 6.63 (1H, s), 7.26–7.43
(5H, m), 7.66 ppm (1H, s); LC–MS (ES+): m/z 486.26 ([M+Na]+,
100%), 464.28 [M+H]+; HRMS (ES+): m/z found 464.2064;
HRMS (ES+): m/z found 434.1960; C26H28NO5 [M+H]+ requires
C27H30NO6 [M+H]+ requires 464.2068.
+
+
434.1962.
6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-3,4-dihydroisoquino-
7-Methoxy-2-(3-methoxybenzyl)-6-(triisopropylsilyloxy)-3,4-dihy-
droisoquinolin-1(2H)-one (7b1) and 7-Methoxy-2-(3-methoxy-
benzyl)-6-(3-methoxybenzyloxy)-3,4-dihydroisoquinolin-1(2H)-
one (7b2): Method as for 7a using compound 6c (505 mg,
1.44 mmol), sodium hydride (60%, 115 mg, 2.88 mmol) and 3-me-
thoxybenzyl bromide (0.24 mL, 1.73 mmol) in DMF (5 mL) at 08C
for 0.5 h and at RT for 4 days. Flash column chromatography
(hexane/EtOAc 10:1 to 5:1 to 2:1) afforded 7b1 as a colourless oil
(120 mg, 18%) and 7b2 as a white powder (110 mg, 18%), mp:
85–868C. 7b1: 1H NMR (270 MHz, CDCl3): d=1.07 (18H, d, J=
6.7 Hz), 1.22 (3H, sept, J=6.7 Hz), 2.79 (2H, t, J=6.7 Hz), 3.44 (2H,
t, J=6.7 Hz), 3.77 (3H, s), 3.84 (3H, s), 4.73 (2H, s), 6.61 (1H, s), 6.80
(1H, ddd, J=8.1, 2.5, 0.8 Hz), 6.85–6.92 (2H, m), 7.23 (1H, t, J=
7.9 Hz), 7.61 ppm (1H, s); HRMS (ES+): m/z found 470.2709;
C27H40NO4Si+ [M+H]+ requires 470.2721. 7b2: 1H NMR (270 MHz,
CDCl3): d=2.77 (2H, t, J=6.6 Hz), 3.41 (2H, t, J=6.6 Hz), 3.75 (3H,
s), 3.77 (3H, s), 3.92 (3H, s), 4.72 (2H, s), 5.14 (2H, s), 6.61 (1H, s),
6.76–6.89 (4H, m), 6.94–7.01 (2H, m), 7.21 (1H, t, J=7.9 Hz), 7.25
(1H, t, J=8.1 Hz), 7.66 ppm (1H, s); LC–MS (APCI+): m/z 434.56
lin-1(2H)-one (8a): A mixture of compound 7a (290 mg,
0.67 mmol) and Pd/C (10%, 40 mg) in THF (20 mL) and MeOH
(20 mL) was stirred under hydrogen at RT for 4 h. After filtration
through Celite and evaporation under reduced pressure the resi-
due was stirred in Et2O, filtered and dried in vacuo to afford com-
pound 8a as a white powder (195 mg, 93%), mp: 164–1658C.
1H NMR (270 MHz, CDCl3): d=2.83 (2H, t, J=6.7 Hz), 3.51 (2H, t,
J=6.7 Hz), 3.83 (3H, s), 3.92 (3H, s), 4.78 (2H, s), 6.02 (1H, s), 6.68
(1H, s), 6.87 (1H, d, J=7.4 Hz), 6.91 (1H, dd, J=7.4, 1.0 Hz), 7.23
(1H, dt, J=7.4, 1.5 Hz), 7.30 (1H, dd, J=7.9, 1.5 Hz), 7.63 ppm (1H,
s); LC–MS (APCI+): m/z 314.17 [M+H]+; HRMS (ES+): m/z found
314.1384; C18H20NO4 [M+H]+ requires 314.1387.
+
6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-3,4-dihydroisoquino-
lin-1(2H)-one (8b): Method as for 8a using compound 7b2
(85 mg, 0.196 mmol) and Pd/C (10%, 20 mg) in THF (10 mL) and
MeOH (10 mL) under hydrogen at RT for 2 h. Flash column chroma-
tography (hexane/EtOAc 1:1) afforded compound 8b as a white
1
powder (52 mg, 76%), mp: 181–1828C. H NMR (270 MHz, CDCl3):
d=2.82 (2H, t, J=6.7 Hz), 3.44 (2H, t, J=6.7 Hz), 3.77 (3H, s), 3.93
(3H, s), 4.74 (2H, s), 6.03 (1H, s), 6.68 (1H, s), 6.80 (1H, dd, J=7.4,
1.7 Hz), 6.84 (1H, d, J=1.7 Hz), 6.90 (1H, d, J=7.7 Hz), 7.23 (1H, t,
J=7.9 Hz), 7.64 ppm (1H, s); LC–MS (APCI+): m/z 314.23 [M+H]+;
[M+H]+; HRMS (ES+): m/z found 434.1962; C26H28NO5 [M+H]+
+
requires 434.1962.
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HRMS (ES+): m/z found 314.1383, C18H20NO4 [M+H]+ requires
314.1387.
7-Methoxy-2-(3-methoxybenzyl)-6-sulfamoyloxy-3,4-dihydroiso-
quinolin-1(2H)-one (9b): Method as for 9a using compound 8b
(73 mg, 0.23 mmol) and sulfamoyl chloride (0.46 mmol) in DMA at
RT for 18 h. Flash column chromatography (hexane/EtOAc 1:1 to
2:3) afforded compound 9b as a white solid (60 mg, 67%), mp:
139–1408C. 1H NMR (270 MHz, CDCl3): d=2.86 (2H, t, J=6.7 Hz),
3.47 (2H, t, J=6.7 Hz), 3.78 (3H, s), 3.94 (3H, s), 4.73 (2H, s), 5.19
(2H, s), 6.79–6.89 (3H, m), 7.15 (1H, s), 7.24 (1H, dt, J=7.6, 1.0 Hz),
7.78 ppm (1H, s); LC–MS (APCI+): m/z 393.64 [M+H]+; HRMS
(ES+): m/z found 393.1118; C18H21N2O6S+ [M+H]+ requires
393.1115.
+
6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-3,4-dihydroisoquino-
lin-1(2H)-one (8b): Compound 7b1 (110 mg, 0.23 mmol) was dis-
solved in THF (20 mL). TBAF (1.0m in THF, 028 mL, 0.28 mmol) was
added dropwise and the reaction mixture was stirred at RT for 2 h.
H2O was added and the mixture extracted with EtOAc. The organic
layer was washed with H2O, brine, dried (MgSO4) and concentrated
in vacuo. The resulting yellow solid was stirred in Et2O, filtered and
dried in vacuo to afford compound 8b as a white powder (60 mg,
82%). Analytical data are identical as shown above.
7-Methoxy-2-(4-methoxybenzyl)-6-sulfamoyloxy-3,4-dihydroiso-
quinolin-1(2H)-one (9c): Method as for 9a using compound 8c
(82 mg, 0.26 mmol) and sulfamoyl chloride (0.78 mmol) in DMA
(1.0 mL) at RT for 24 h. Flash column chromatography (hexane/
EtOAc 3:1 to 1:1) gave a solid that was stirred in Et2O (10 mL), fil-
tered and dried in vacuo to afford compound 9c as a white solid
6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-3,4-dihydroisoquino-
lin-1(2H)-one (8c): Method as for 8b using compound 7c (0.24 g,
0.51 mmol) and TBAF (1.0m in THF, 0.61 mL, 0.61 mmol) in THF
(10 mL) at RT for 18 h. Flash column chromatography (hexane/
EtOAc 4:1 to 2:1) afforded compound 8c as a white powder
1
(110 mg, 69%), mp: 171–1728C. H NMR (270 MHz, CDCl3): d=2.78
1
(75 mg, 73%), mp: 159–1608C. H NMR (270 MHz, CDCl3/[D4]MeOH
(2H, t, J=6.7 Hz), 3.41 (2H, t, J=6.7 Hz), 3.77 (3H, s), 3.90 (3H, s),
4.69 (2H, s), 6.33 (1H, s, br), 6.66 (1H, s), 6.84 (2H, dt, J=8.7,
2.3 Hz), 7.24 (2H, dt, J=8.9, 2.3 Hz), 7.63 ppm (1H, s); LC–MS
(APCI+): m/z 314.42 [M+H]+; HRMS (ES+): m/z found 314.1381;
10:1): d=2.12 (2H, s), 2.81 (2H, t, J=6.7 Hz), 3.42 (2H, t, J=6.7 Hz),
3.76 (3H, s), 3.90 (3H, s), 4.67 (2H, s), 6.83 (2H, dt, J=8.9, 2.5 Hz),
7.14 (1H, s), 7.20 (2H, dt, J=8.9, 2.5 Hz), 7.72 ppm (1H, s); LC–MS
(APCI+): m/z 393.38 [M+H]+; HRMS (ES+): m/z found 393.1117;
C18H21N2O6S+ [M+H]+ requires 393.1115.
C18H19NO4 [M+H]+ requires 314.1387.
+
6-Hydroxy-7-methoxy-2-(3,5-dimethoxybenzyl)-3,4-dihydroiso-
quinolin-1(2H)-one (8d): Method as for 8a using compound 7d
(330 mg, 0.76 mmol) and Pd/C (10%, 40 mg) in THF (20 mL) and
MeOH (30 mL) under hydrogen at RT for 18 h. The resulting white
solid was stirred in Et2O, filtered and dried in vacuo to afford com-
pound 8d as a white powder (240 mg, 92%), mp: 166–1678C.
1H NMR (270 MHz, CDCl3): d=2.82 (2H, t, J=6.7 Hz), 3.44 (2H, t,
J=6.7 Hz), 3.75 (6H, s), 3.93 (3H, s), 4.70 (2H, s), 6.04 (1H, s), 6.35
(1H, t, J=2.5 Hz), 6.46 (2H, d, J=2.5 Hz), 6.68 (1H, s), 7.63 ppm
(1H, s); LC–MS (ESꢁ): m/z 342.09 [MꢁH]ꢁ; HRMS (ES+): m/z found
7-Methoxy-2-(3,5-dimethoxybenzyl)-6-sulfamoyloxy-3,4-dihy-
droisoquinolin-1(2H)-one (9d): Method as for 9a using compound
8d (100 mg, 0.29 mmol) and sulfamoyl chloride (0.87 mmol) in
DMA (1.0 mL) at RT for 24 h. The residue was stirred in Et2O, fil-
tered, washed with Et2O and dried in vacuo to afford compound
9d as a white powder (95 mg, 77%), mp: 164–1658C. 1H NMR
(270 MHz, CDCl3): d=2.90 (2H, t, J=6.6 Hz), 3.49 (2H, t, J=6.6 Hz),
3.74 (6H, s), 3.84 (3H, s), 4.64 (2H, s), 6.40–6.45 (3H, s), 7.26 (1H, s),
7.61 (1H, s), 8.08 ppm (2H, s, br); LC–MS (ESꢁ): m/z 421.13
[MꢁH]ꢁ; HRMS (ES+): m/z found 423.1215; C19H23N2O7S+ [M+H]+
requires 423.1220.
344.1477; C19H22NO5 [M+H]+ requires 344.1492.
+
6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydroiso-
quinolin-1(2H)-one (8e): Method as for 8a using compound 7e
(375 mg, 0.81 mmol) and Pd/C (10%, 50 mg) in THF (20 mL) and
MeOH (20 mL) under hydrogen at RT for 18 h. The resulting white
solid was stirred in Et2O, filtered and dried in vacuo to afford com-
pound 8e as a white powder (260 mg, 86%), mp: 168–1698C.
1H NMR (270 MHz, CDCl3): d=2.82 (2H, t, J=6.7 Hz), 3.44 (2H, t,
J=6.7 Hz), 3.82 (9H, s), 3.92 (3H, s), 4.69 (2H, s), 6.08 (1H, s, br),
6.53 (2H, s), 6.69 (1H, s), 7.63 ppm (1H, s); LC–MS (ESꢁ): m/z
7-Methoxy-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihy-
droisoquinolin-1(2H)-one (9e): Method as for 9a using compound
8e (100 mg, 0.27 mmol) and sulfamoyl chloride (0.8 mmol) in DMA
(1.0 mL) at RT for 24 h. After addition of H2O (20 mL), EtOAc
(100 mL) and THF (50 mL) the organics could not be dissolved. The
solvents were evaporated and the resultant solid in the aqueous
layer was washed, filtered, washed with H2O, Et2O, EtOAc and dried
in vacuo to afford compound 9e as a white powder (90 mg, 74%),
1
mp: 201–2038C. H NMR (270 MHz, [D6]DMSO): d=2.90 (2H, t, J=
372.07 [MꢁH]ꢁ; HRMS (ES+): m/z found 374.1590; C20H24NO6
+
6.6 Hz), 3.49 (2H, t, J=6.6 Hz), 3.63 (3H, s), 3.74 (6H, s), 3.84 (3H,
s), 4.64 (2H, s), 6.61 (2H, s), 7.26 (1H, s), 7.61 (1H, s), 8.08 ppm (2H,
s, br); LC–MS (ESꢁ): m/z 451.18 [MꢁH]ꢁ; HRMS (ES+): m/z found
453.1313; C20H25N2O8S+ [M+H]+ requires 453.1326.
[M+H]+ requires 374.1598.
7-Methoxy-2-(2-methoxybenzyl)-6-sulfamoyloxy-3,4-dihydroiso-
quinolin-1(2H)-one (9a): Sulfamoyl chloride (0.6m in toluene,
1.0 mL, 0.6 mmol) was concentrated in vacuo and dissolved in an-
hydrous DMA (1.0 mL). Compound 8a (94 mg, 0.3 mmol) was
added as a solid and the reaction mixture was stirred at RT for
18 h. H2O (10 mL) was added and the mixture was extracted with
EtOAc (2ꢁ50 mL). The combined organic layers were washed with
H2O, brine, dried (MgSO4), filtered and concentrated in vacuo. The
residue was stirred in Et2O, filtered and dried in vacuo to afford
compound 9a as a white solid (90 mg, 77%), mp: 142–1438C.
1H NMR (270 MHz, CDCl3): d=2.86 (2H, t, J=6.7 Hz), 3.54 (2H, t,
J=6.7 Hz), 3.84 (3H, s), 3.93 (3H, s), 4.77 (2H, s), 5.16 (2H, s), 6.87
(1H, d, J=8.2), 6.91 (1H, dt, J=7.4, 1.0 Hz), 7.14 (1H, s), 7.21–7.31
(2H, m), 7.77 ppm (1H, s); LC–MS (APCI+): m/z 393.45 [M+H]+;
HRMS (ES+): m/z found 393.1118; C18H21N2O6S+ [M+H]+ requires
393.1115.
6-Benzyloxy-7-methoxy-2-((2-methoxyphenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (10a): Sodium hydride (60% in mineral
oil, 46 mg, 1.9 mmol) was suspended in anhydrous DMF (5 mL).
Compound 6a (300 mg, 1.0 mmol) was added and the reaction
mixture was heated at 508C for 0.5 h. The reaction mixture was
cooled to RT and 2-methoxybenzenesulfonyl chloride (0.15 mL,
1.0 mmol) was added dropwise. The reaction mixture was stirred
for 3.5 h and turned from yellow to almost colourless after addition
of the sulfonyl chloride. A further 0.5 equiv (0.07 mL) of the sulfo-
nyl chloride was added and the reaction mixture stirred for a fur-
ther 2 h. The reaction mixture was poured into sodium bicarbonate
(sat., 100 mL) and extracted with CHCl3 (3ꢁ50 mL). The combined
organic layers were washed with H2O (4ꢁ50 mL) and brine
(50 mL), dried (MgSO4) and concentrated in vacuo. Flash column
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chromatography (hexane/EtOAc 2:1) afforded the compound 10a
as a colourless foam (314 mg, 65%), mp: 202–2038C. 1H NMR
(270 MHz, CDCl3): d=2.99 (2H, t, J=6.3 Hz), 3.80 (3H, s), 3.88 (3H,
s), 4.24 (2H, t, J=6.3 Hz), 5.19 (2H, s), 6.66 (1H, s), 6.96 (1H, d, J=
8.2 Hz), 7.14 (1H, dt, J=7.6, 1.0 Hz), 7.31–7.44 (6H, m), 7.52–7.58
(1H, m), 8.20 ppm (1H, dd, J=7.9, 1.7 Hz); LC–MS (ES+): m/z
454.46 [M+H]+; HRMS (ES+): m/z found 476.1124; C24H23NO6SNa+
[M+Na]+ requires 476.1144.
(3 mL) and EtOH (3 mL) under hydrogen at RT for 2 h. The residue
was crystallised from dichloromethane/hexane to afford compound
11 a as a colourless powder (145 mg, 57%), mp: 222–2248C.
1H NMR (270 MHz, CDCl3): d=3.02 (2H, t, J=6.3 Hz), 3.81 (3H, s),
3.88 (3H, s), 4.25 (2H, t, J=6.3 Hz), 6.07 (1H, s), 6.72 (1H, s), 6.96
(1H, d, J=8.4 Hz), 7.12 (1H, t, J=7.7 Hz), 7.42 (1H, s), 7.51–7.58
(1H, m), 8.19 ppm (1H, dd, J=7.9, 1.7 Hz); LC–MS (ESꢁ): m/z
362.33 [MꢁH]ꢁ; HRMS (ES+): m/z found 386.0651; C17H17NO6SNa+
[M+Na]+ requires 386.0674.
6-Benzyloxy-7-methoxy-2-((3-methoxyphenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (10b): Method as for 10a using com-
pound 6a (300 mg, 1.1 mmol), sodium hydride (60% in mineral oil,
64 mg, 1.9 mmol) and 3-methoxybenzenesulfonyl chloride
(0.22 mL, 1.6 mmol) in anhydrous DMF (5 mL) at 508C for 0.5 h and
at RT for 2 h and at 408C for 2 h. Flash column chromatography
(hexane/EtOAc 2:1) afforded compound 10b as a colourless foam
6-Hydroxy-7-methoxy-2-((3-methoxyphenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (11b): Method as for 8a using com-
pound 10b (369 mg, 0.81 mmol) and Pd/C (10%, 37 mg) in THF
(5 mL) and EtOH (5 mL) under hydrogen at RT for 2 h. Flash
column chromatography (hexane/EtOAc 1:1 to 1:2 to 1:3) afforded
compound 11 b as a colourless solid (203 mg, 69%), mp: 195–
1978C. 1H NMR (270 MHz, CDCl3): d=3.02 (2H, t, J=6.3 Hz), 3.84
(3H, s), 3.86 (3H, s), 4.19 (2H, t, J=6.3 Hz), 6.07 (1H, s), 6.71 (1H, s),
7.11 (1H, ddd, J=8.4, 2.6, 1.0 Hz), 7.41 (1H, t, J=8.1 Hz), 7.45 (1H,
s), 7.57–7.63 ppm (2H, m); LC–MS (ESꢁ): m/z 362.42 [MꢁH]ꢁ;
HRMS (ES+): m/z found 386.0657; C17H17NO6SNa+ [M+Na]+ re-
quires 386.0674.
1
(369 mg, 77%), mp: 140–1458C. H NMR (270 MHz, CDCl3): d=2.99
(2H, t, J=6.2 Hz), 3.84 (3H, s), 3.87 (3H, s), 4.18 (2H, t, J=6.2 Hz),
5.18 (2H, s), 6.64 (1H, s), 7.12 (1H, ddd, J=8.2, 2.7, 1.0 Hz), 7.31–
7.44 (6H, m), 7.47 (1H, s), 7.58–7.63 ppm (2H, m); LC–MS (ES+): m/
z
476.50 [M+Na]+; HRMS (ES+): m/z found 476.1116;
C24H23NO6SNa+ [M+Na]+ requires 476.1144.
6-Benzyloxy-7-methoxy-2-((4-methoxyphenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (10c): Method as for 10a using com-
pound 6a (300 mg, 1.0 mmol), sodium hydride (60% in mineral oil,
46 mg, 1.9 mmol) and 3-methoxybenzenesulfonyl chloride
(0.22 mL, 1.5 mmol) in anhydrous DMF (5 mL) at 508C for 0.5 h and
at RT for 6 h. Flash column chromatography (hexane/EtOAc 2:1) af-
6-Hydroxy-7-methoxy-2-((4-methoxyphenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (11c): Method as for 8a using com-
pound 10c (150 mg, 0.33 mmol) and Pd/C (10%, 15 mg) in THF
(5 mL) and EtOH (5 mL) under hydrogen at RT for 3 h. Flash
column chromatography (hexane/EtOAc 2:1) afforded compound
1
11 c as a colourless powder (74 mg, 62%), mp: 202–2048C. H NMR
1
forded compound 10c as a colourless oil (152 mg, 32%). H NMR
(270 MHz, CDCl3): d=3.00 (2H, t, J=6.3 Hz), 3.84 (3H, s), 3.85 (3H,
s), 4.17 (2H, t, J=6.2 Hz), 6.08 (1H, s), 6.70 (1H, s), 6.95–6.99 (2H,
m), 7.45 (1H, s), 7.99–8.03 ppm (2H, m); LC–MS (ESꢁ): m/z 362.33
[MꢁH]ꢁ; HRMS (ES+): m/z found 386.0651; C17H17NO6SNa+ [M+
Na]+ requires 386.0674.
(270 MHz, CDCl3): d=2.97 (2H, t, J=6.3 Hz), 3.82 (3H, s), 3.87 (3H,
s), 4.16 (2H, t, J=6.3 Hz), 5.17 (2H, s), 6.63 (1H, s), 6.95–6.99 (2H,
m), 7.28–7.41 (5H, m), 7.46 (1H, s), 7.98–8.03 ppm (2H, m); LC–MS
(ES+): m/z 454.60 [M+H]+; HRMS (ES+): m/z found 454.1320;
C24H24NO6S+ [M+H]+ requires 454.1324.
6-Hydroxy-7-methoxy-2-((3-chlorophenyl)sulfonyl)-3,4-dihydroi-
soquinolin-1(2H)-one (11d): Method as for 8a using compound
10d (240 mg, 0.53 mmol) and Pd/C (10%, 24 mg) in THF (5 mL)
and EtOH (5 mL) under hydrogen at RT for 1 h. Flash column chro-
matography (hexane to EtOAc) afforded compound 11 d as a col-
ourless solid (158 mg, 82%), mp: 178–1818C. 1H NMR (270 MHz,
CDCl3): d=3.03 (2H, t, J=6.2 Hz), 3.85 (3H, s), 4.19 (2H, t, J=6.3),
6.11 (1H, s), 6.72 (1H, s), 7.44 (1H, s), 7.44–7.50 (1H, m), 7.54–7.59
(1H, m), 7.96–8.00 (1H, m), 8.02 ppm (1H, t, J=1.5 Hz); LC–MS
(ESꢁ): m/z 366.46 [MꢁH]ꢁ; HRMS (ES+): m/z found 390.0160;
C16H14ClNO5SNa+ [M+Na]+ requires 390.0173.
6-Benzyloxy-7-methoxy-2-((3-chlorophenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (10d): Method as for 10a using com-
pound 6a (300 mg, 1.0 mmol), sodium hydride (60% in mineral oil,
46 mg, 1.9 mmol) and 3-methoxybenzenesulfonyl chloride
(0.22 mL, 1.5 mmol) in anhydrous DMF (5 mL) at 508C for 0.5 h and
at RT for 6 h. Flash column chromatography (hexane/EtOAc 2:1) af-
forded compound 10d as a yellow foam (259 mg, 54%), mp: 155–
1588C. 1H NMR (270 MHz, CDCl3): d=3.00 (2H, t, J=6.2 Hz), 3.83
(3H, s), 4.18 (2H, t, J=6.2 Hz), 5.18 (2H, s), 6.65 (1H, s), 7.27–7.49
(7H, m), 7.57 (1H, ddd, J=7.9, 2.0, 1.2 Hz), 7.96–8.01 ppm (2H, m);
LC–MS (ES+): m/z 458.52 [M+H]+; HRMS (ES+): m/z found
480.0621; C23H20ClNO5SNa+ [M+Na]+ requires 480.0643.
Methyl 2-((6-hydroxy-7-methoxy-1-oxo-3,4-dihydroisoquinolin-
2(1H)-yl)sulfonyl)benzoate (11e): Method as for 8a using com-
pound 10e (160 mg, 0.33 mmol) and Pd/C (10%, 90 mg) in THF
(5 mL) and EtOH (5 mL) under hydrogen at RT for 3 h. Flash
column chromatography (hexane to EtOAc) afforded compound
11 e as a colourless solid (99 mg, 76%), mp: 236–2398C. 1H NMR
(270 MHz, CDCl3): d=3.08 (2H, t, J=6.2 Hz), 3.83 (3H, s), 3.93 (3H,
s), 4.19 (2H, t, J=6.2 Hz), 6.08 (1H, s), 6.71 (1H, s), 7.44 (1H, s),
7.60–7.70 (3H, m), 8.54 ppm (1H, dd, J=6.2, 1.7 Hz); LC–MS (APCI-
): m/z 390.08 [MꢁH]ꢁ; HRMS (ES+): m/z found 414.0609;
C18H17NO7SNa+ [M+Na]+ requires 414.0618.
Methyl 2-((6-benzyloxy-7-methoxy-1-oxo-3,4-dihydroisoquinolin-
2(1H)-yl)sulfonyl)benzoate (10e): Method as for 10a using com-
pound 6a (300 mg, 1.0 mmol), sodium hydride (60% in mineral oil,
46 mg, 1.9 mmol) and 3-methoxybenzenesulfonyl chloride
(0.22 mL, 1.5 mmol) in anhydrous DMF (5 mL) at 508C for 0.5 h and
at RT for 6 h. Purification by flash column chromatography
(hexane/EtOAc 2:1) afforded compound 10e as
a colourless
1
powder (176 mg, 35%). H NMR (270 MHz, CDCl3): d=3.05 (2H, t,
J=6.2 Hz), 3.83 (3H, s), 3.92 (3H, s), 4.19 (2H, t, J=6.2 Hz), 5.18
(2H, s), 6.65 (1H, s), 7.28–7.41 (5H, m), 7.46 (1H, s), 7.61–7.71 (3H,
m), 8.55 ppm (1H, dd, J=6.4, 2.0 Hz); LC–MS (APCI-): m/z 482.29
[MꢁH]ꢁ; HRMS (ES+): m/z found 504.1075; C25H23NO7SNa+ [M+
Na]+ requires 504.1087.
7-Methoxy-2-((2-methoxyphenyl)sulfonyl)-6-(sulfamoyloxy)-3,4-
dihydroisoquinolin-1(2H)-one (12a): Method as for 9a using com-
pound 11 a (126 mg, 0.35 mmol) and sulfamoyl chloride
(0.69 mmol) in anhydrous DMA (1.0 mL) at RT for 22 h. Flash
column chromatography (hexane to EtOAc) afforded compound
12a as a white powder (115 mg, 75%), mp: 195–1978C. 1H NMR
(270 MHz, [D6]DMSO): d=3.09 (2H, t, J=6.2 Hz), 3.78 (3H, s), 3.89
6-Hydroxy-7-methoxy-2-((2-methoxyphenyl)sulfonyl)-3,4-dihy-
droisoquinolin-1(2H)-one (11a): Method as for 8a using com-
pound 10a (316 mg, 0.7 mmol) and Pd/C (10%, 32 mg) in THF
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(3H, s), 4.18 (2H, t, J=6.2 Hz), 7.18 (1H, t, J=7.7 Hz), 7.24 (1H, d,
J=8.4 Hz), 7.37 (1H, s), 7.44 (1H, s), 7.68 (1H, td, J=8.4, 1.6 Hz),
7.79 (1H, dd, J=7.8, 1.6 Hz), 8.14 ppm (2H, s, br); LC–MS (ESꢁ): m/
4.21–4.42 and 4.76–4.93 (2H, m), 5.11 (2H, s), 6.38 and 6.61 (1H, s),
6.67 and 6.69 (1H, s), 6.92 (1H, d, J=8.2 Hz), 6.99 (1H, t, J=7.4 Hz),
7.22–7.46 ppm (7H, m); LC–MS (APCI+): m/z 402.51 (M+-H), m/z
441.17 [MꢁH]ꢁ; HRMS (ES+): m/z found 465.0394;
404.46 [M+H]+; HRMS (ES+): m/z found 404.1856; C25H26NO4
+
z
C17H18N2O8S2Na+ [M+Na]+ requires 465.0402.
[M+H]+ requires 404.1856.
7-Methoxy-2-((3-methoxyphenyl)sulfonyl)-6-(sulfamoyloxy)-3,4-
dihydroisoquinolin-1(2H)-one (12b): Method as for 9a using com-
pound 11 b (200 mg, 0.55 mmol) and sulfamoyl chloride (2.2 mmol)
in anhydrous DMA (3.0 mL) at RT for 24 h. Flash column chroma-
tography (hexane to EtOAc) afforded compound 12b as a colour-
less powder (118 mg, 49%), mp: 164–1668C. 1H NMR (270 MHz,
[D6]DMSO): d=3.12 (2H, t, J=6.1 Hz), 3.78 (3H, s), 3.84 (3H, s),
4.21 (2H, t, J=6.1 Hz), 7.30 (1H, dt, J=7.6, 2.1 Hz), 7.36 (1H, s),
7.47 (2H, s, br), 7.52–7.61 (2H, m), 8.15 ppm (2H, s, br); LC–MS
(ESꢁ): m/z 441.38 [MꢁH]ꢁ; HRMS (ES+): m/z found 465.0382;
C17H18N2O8S2Na+ [M+Na]+ requires 465.0402.
6-Benzyloxy-2-(3-methoxybenzoyl)-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (14b): Method as for 14a using compound 13
(404 mg, 1.5 mmol), 3-methoxybenzoyl chloride (0.22 mL,
1.65 mmol) and Et3N (0.42 mL, 3.0 mmol) in CHCl3 (10 mL) at RT for
18 h. The reaction mixture was diluted with EtOAc (80 mL) and
washed with H2O and brine, dried (MgSO4), filtered and concentrat-
ed in vacuo. Flash column chromatography (hexane/EtOAc 10:1 to
1:1) afforded compound 14b as a thick colourless oil (500 mg,
83%). 1H NMR (270 MHz, CDCl3): d=2.66–2.76 and 2.76–2.88 (2H,
m), 3.52–3.64 and 3.72–3.98 (2H, m), 3.80 (6H, s), 4.49 and 4.79
(2H, s), 5.11 (2H, s), 6.40 and 6.69 (1H, br), 6.64 (1H, br), 6.92–7.05
(2H, m), 6.97 (1H, s), 7.26–7.46 ppm (6H, m); LC–MS (APCI+): m/z
402.45 (M+-H), m/z 404.46 [M+H]+; HRMS (ES+): m/z found
7-Methoxy-2-((4-methoxyphenyl)sulfonyl)-6-(sulfamoyloxy)-3,4-
dihydroisoquinolin-1(2H)-one (12c): Method as for 9a using com-
pound 11 c (45 mg, 0.13 mmol) and sulfamoyl chloride (0.5 mmol)
in anhydrous DMA (1.0 mL) at RT for 18 h. Flash column chroma-
tography (hexane to EtOAc) gave a colourless solid which was
stirred in hexane/CH2Cl2 to afford compound 12c as a colourless
404.1858; C25H26NO4 [M+H]+ requires 404.1856.
+
6-Benzyloxy-2-(3-cyanobenzoyl)-7-methoxy-1,2,3,4-tetrahydroi-
soquinoline (14c): Method as for 14a using compound 13
(300 mg, 1.1 mmol), 3-cyanobenzoyl chloride (202 mg, 1.22 mmol)
and Et3N (1.0 mL, 7.2 mmol) in CHCl3 (20 mL) at RT for 2 h. Flash
column chromatography (hexane/EtOAc 2:1 to 1:2) afforded com-
pound 14c as a white powder (325 mg, 74%), mp: 156–1578C.
1H NMR (270 MHz, CDCl3): d=2.70–2.87 (2H, br), 3.52–3.57 and
3.91–3.95 (2H, br), 3.79 and 3.97 (3H, s), 4.46 and 4.80 (2H, br),
5.12 (2H, s), 6.40, 6.65 and 6.68 (2H, br), 7.27–7.45 (5H, m), 7.52–
7.58 (1H, m), 7.66–7.75 ppm (3H, m); LC–MS (ES+): m/z 421.54
[M+Na]+.
1
solid (30 mg, 56%), mp: 177–1808C. H NMR (400 MHz, [D6]DMSO):
d=3.09 (2H, t, J=6.0 Hz), 3.79 (3H, s), 3.86 (3H, s), 4.17 (2H, t, J=
6.2 Hz), 7.12–7.16 (2H, m), 7.34 (1H, s), 7.46 (1H, s), 7.94–7.97 (2H,
m), 8.13 ppm (2H, s, br); LC–MS (ESꢁ): m/z 441.31 [MꢁH]ꢁ; HRMS
(ES+): m/z found 465.0392; C17H18N2O8S2Na+ [M+Na]+ requires
465.0402.
2-((3-Chlorophenyl)sulfonyl)-7-methoxy-6-(sulfamoyloxy)-3,4-di-
hydroisoquinolin-1(2H)-one (12d): Method as for 9a using com-
pound 11 d (121 mg, 0.33 mmol) and sulfamoyl chloride
(0.66 mmol) in anhydrous DMA (1.0 mL) at RT for 22 h. Flash
column chromatography (hexane to EtOAc) afforded compound
6-Benzyloxy-2-(4-methoxybenzoyl)-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (14d): Method as for 14a using compound 13
(406 mg, 1.5 mmol), 4-methoxybenzoyl chloride (318 mg,
1.8 mmol) and Et3N (0.42 mL, 3.0 mmol) in CHCl3 (30 mL) at RT for
18 h. The reaction mixture was diluted with EtOAc (80 mL) and
washed with H2O and brine, dried (MgSO4), filtered and concentrat-
ed in vacuo. Flash column chromatography (hexane/EtOAc 10:1 to
1:1) afforded compound 14d as a white powder (520 mg, 85%),
mp: 126–1278C. 1H NMR (270 MHz, CDCl3): d=2.77 (2H, br), 3.67
(2H, br), 3.83 (6H, s), 4.73 (2H, br), 5.11 (2H, s), 6.46 and 6.69 (1H,
br), 6.65 (1H, s), 6.92 (2H, dt, J=8.6, 2.3 Hz), 7.26–7.45 ppm (7H,
m); LC–MS (APCI+): m/z 404.53 [M+H]+; HRMS (ES+): m/z found
1
12d as a colourless solid (132 mg, 90%), mp: 170–1738C. H NMR
(270 MHz, [D6]DMSO): d=3.14 (2H, t, J=6.2 Hz), 3.79 (3H, s), 4.24
(2H, t, J=6.2 Hz), 7.37 (1H, s), 7.48 (1H, s), 7.68 (1H, t, J=8.0 Hz),
7.82–7.85 (1H, m), 8.00 (1H, d, J=8.2 Hz), 8.06 (1H, t, J=1.8 Hz),
8.17 ppm (2H, s); LC–MS (ESꢁ): m/z 445.30 [MꢁH]ꢁ; HRMS (ES+):
m/z found 468.9894; C16H15ClN2O7S2Na+ [M+Na]+ requires
468.9901.
Methyl 2-((7-methoxy-1-oxo-6-(sulfamoyloxy)-3,4-dihydroisoqui-
nolin-2(1H)-yl)sulfonyl)benzoate (12e): Method as for 9a using
compound 11 e (68 mg, 0.17 mmol) and sulfamoyl chloride
(0.52 mmol) in anhydrous DMA (1.0 mL) at RT for 20 h. Flash
column chromatography (hexane to EtOAc) afforded compound
+
404.1858; C25H26NO4 [M+H]+ requires 404.1856.
6-Benzyloxy-2-(3,4-dimethoxybenzoyl)-7-methoxy-1,2,3,4-tetra-
hydroisoquinoline (14e): Method as for 14a using compound 13
(300 mg, 1.1 mmol), 3,4-dimethoxybenzoyl chloride (240 mg,
1.2 mmol) and Et3N (0.5 mL, 3.6 mmol) in CHCl3 (20 mL) at RT for
18 h. Flash column chromatography (hexane/EtOAc 2:1 to 1:3) af-
forded compound 14e as a white powder (370 mg, 77%), mp:
126–1278C. 1H NMR (270 MHz, CDCl3): d=2.77 (2H, br), 3.83 (2H,
br), 3.88 (3H, s), 3.89 (3H, s), 3.90 (3H, s), 4.61 and 4.74 (2H, br),
5.11 (2H, s), 6.65 (1H, s), 6.86 (1H, d, J=8.9 Hz), 7.01 (1H, s), 7.03
(1H, dd, J=8.9, 2.0 Hz), 7.23–7.46 ppm (6H, m); LC–MS (APCI+):
m/z 432.48 (M+-H), m/z 434.50 [M+H]+; HRMS (ES+): m/z found
1
12e as a colourless powder (49 mg, 60%), mp: 181–1868C. H NMR
(270 MHz, [D6]DMSO): d=3.14 (2H, t, J=5.8 Hz), 3.80 (3H, s), 3.88
(3H, s), 4.13 (2H, t, J=5.8 Hz), 7.37 (1H, s), 7.49 (1H, s), 7.72–7.87
(3H, m), 8.16 (2H, s, br), 8.32–8.35 ppm (1H, m); LC–MS (APCI-): m/
z
390.02 [MꢁSO2NH2]ꢁ; HRMS (ES+): m/z found 493.0343;
C18H18N2O9S2Na+ [M+Na]+ requires 493.0346.
6-Benzyloxy-2-(2-methoxybenzoyl)-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (14a): Compound 13 (325 mg, 1.2 mmol) was dis-
solved in CHCl3 (20 mL) and Et3N (1.0 mL, 7.2 mmol). 2-Methoxy-
benzoyl chloride (239 mg, 1.4 mmol) was added portionwise. The
reaction mixture was stirred at RT for 16 h and washed with H2O
and brine, dried (MgSO4), filtered and concentrated in vacuo. Flash
column chromatography (hexane/EtOAc 3:1 to 2:3) afforded com-
pound 14a as a white powder (405 mg, 84%), mp: 92–938C.
1H NMR (270 MHz, CDCl3): d=2.58–2.70 and 2.76–2.86 (2H, m),
3.38–3.48 and 3.74–3.94 (2H, m), 3.72, 3.76, 3.81 and 3.88 (6H, s),
434.1966; C26H28NO5 [M+H]+ requires 434.1962.
+
6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-1,2,3,4-tetra-
hydroisoquinoline (14 f): Method as for 14a using compound 13
(404 mg, 1.5 mmol), 3,5-dimethoxybenzoyl chloride (331 mg,
1.65 mmol) and Et3N (0.42 mL, 3.0 mmol) in CHCl3 (20 mL) at RT for
18 h. The reaction mixture was diluted with EtOAc (80 mL) and
washed with H2O and brine, dried (MgSO4), filtered and concentrat-
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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CHEMMEDCHEM
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ed in vacuo. Flash column chromatography (hexane/EtOAc 10:1 to
6-Benzyloxy-2-(4-methoxybenzoyl)-7-methoxy-3,4-dihydroiso-
quinolin-1(2H)-one (15d): Method as for 15a using compound
14d (403 mg, 1.0 mmol), KMnO4 (0.79 g, 5.0 mmol) and 18-crown-6
(53 mg, 0.2 mmol) in dichloromethane (50 mL) at RT for 16 h. Flash
column chromatography (hexane/EtOAc 4:1 to 1:1 to EtOAc) af-
forded compound 15d as a white powder (188 mg, 45%), mp:
151–1528C. 1H NMR (270 MHz, CDCl3): d=3.02 (2H, t, J=6.1 Hz),
3.83 (3H, s), 3.86 (3H, s), 4.04 (2H, t, J=6.1 Hz), 5.23 (2H, s), 6.73
(1H, s), 6.88 (2H, d, J=8.7 Hz), 7.30–7.46 (5H, m), 7.58 (1H, s),
7.62 ppm (2H, d, J=8.7 Hz); HRMS (ES+): m/z found 418.1651;
1:1) afforded compound 14 f as a white powder (520 mg, 85%),
1
mp: 171–1728C. H NMR (270 MHz, CDCl3): d=2.70 and 2.81 (2H,
br), 3.58 and 3.92 (2H, br), 3.83 (9H, s), 4.49 and 4.78 (2H, br), 5.11
(2H, s), 6.42, 6.63, 6.66 and 6.68 (2H, br), 6.50 (1H, t, J=2.2 Hz),
6.55 (2H, d, J=2.2 Hz), 7.26–7.45 ppm (5H, m); LC–MS (APCI+): m/
z 434.43 [M+H]+; HRMS (ES+): m/z found 434.1962; C26H28NO5
[M+H]+ requires 434.1962.
+
6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tet-
rahydroisoquinoline (14g): Method as for 14a using compound
13 (808 mg, 3.0 mmol), 3,4,5-trimethoxybenzoyl chloride (765 mg,
3.3 mmol) and Et3N (2.0 mL, 14.4 mmol) in CHCl3 (20 mL) at RT for
18 h. The reaction mixture was diluted with CHCl3 (80 mL) and
washed with H2O and brine, dried (MgSO4), filtered and concentrat-
ed in vacuo. Flash column chromatography (hexane/EtOAc 3:1 to
1:2) afforded compound 14g as a white powder (1.10 g, 79%),
C25H24NO5 [M+H]+ requires 418.1649.
+
6-Benzyloxy-2-(3,4-dimethoxybenzoyl)-7-methoxy-3,4-dihydroi-
soquinolin-1(2H)-one (15e): Method as for 15a using compound
14e (450 mg, 1.04 mmol), KMnO4 (0.82 g, 5.2 mmol) and 18-crown-
6 (50 mg, 0.19 mmol) in dichloromethane (50 mL) at RT for 8 h.
Flash column chromatography (hexane/EtOAc 3:1) afforded com-
pound 15e as a white powder (170 mg, 37%), mp: 200–2018C.
1H NMR (270 MHz, CDCl3): d=3.04 (2H, t, J=6.2 Hz), 3.87 (3H, s),
3.90 (6H, s), 4.04 (2H, t, J=6.2 Hz), 5.23 (2H, s), 6.74 (1H, s), 6.81
(1H, d, J=8.4 Hz), 7.20 (1H, dd, J=8.4, 2.0 Hz), 7.26 (1H, d, J=
2.0 Hz), 7.28–7.46 (5H, m), 7.58 ppm (1H, s); LC–MS (ES+): m/z
470.52 [M+Na]+; LC–MS (ESꢁ): m/z 446.47 [MꢁH]ꢁ.
1
mp: 63–648C. H NMR (270 MHz, CDCl3): d=2.80 (2H, br), 3.60 and
3.80 (2H, br), 3.85 (6H, s), 3.86 (6H, s), 4.50 and 4.77 (2H, br), 5.12
(2H, s), 6.44 and 6.65 (4H, br), 7.25–7.44 ppm (5H, m); LC–MS
(ES+): m/z 496.26 ([M+Na]+, 100%), 464.28 [M+H]+; HRMS
+
(ES+): m/z found 464.2060; C27H30NO6
[M+H]+ requires
464.2068.
6-Benzyloxy-2-(2-methoxybenzoyl)-7-methoxy-3,4-dihydroiso-
quinolin-1(2H)-one (15a): Compound 14a (400 mg, 1.0 mmol),
KMnO4 (0.79 g, 5.0 mmol) and 18-crown-6 (50 mg, 0.19 mmol) were
mixed in dichloromethane (50 mL) and the reaction mixture was
stirred at RT for 8 h. The reaction mixture was diluted with CHCl3
and sodium metabisulfite (sat.) was added. The mixture was
washed with H2O and brine, dried with MgSO4, filtered and con-
centrated in vacuo. Flash column chromatography (hexane/EtOAc
3:1) afforded compound 15a as a white powder (170 mg, 40%),
mp: 163–1648C. 1H NMR (270 MHz, CDCl3): d=2.98 (2H, t, J=
6.2 Hz), 3.63 (3H, s), 3.83 (3H, s), 4.19 (2H, t, J=6.2 Hz), 5.22 (2H,
s), 6.72 (1H, s), 6.86 (1H, d, J=8.4 Hz), 7.01 (1H, dt, J=8.4, 0.8 Hz),
7.28–7.46 (7H, m), 7.56 ppm (1H, s); LC–MS (ES+): m/z 440.49 [M+
Na]+; LC–MS (ESꢁ): m/z 416.44 [MꢁH]ꢁ; HRMS (ES+): m/z found
6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroi-
soquinolin-1(2H)-one (15 f): Method as for 15a using compound
14 f (433 mg, 1.0 mmol), KMnO4 (0.79 g, 5.0 mmol) and 18-crown-6
(53 mg, 0.2 mmol) in dichloromethane (50 mL) at RT for 16 h. Flash
column chromatography (hexane/EtOAc 10:1 to 4:1) afforded com-
pound 15 f as a white powder (193 mg, 43%), mp: 180–1818C.
1H NMR (270 MHz, CDCl3): d=3.02 (2H, t, J=6.2 Hz), 3.78 (6H, s),
3.85 (3H, s), 4.06 (2H, t, J=6.2 Hz), 5.23 (2H, s), 6.56 (1H, t, J=
2.2 Hz), 6.70 (2H, d, J=2.2 Hz), 6.73 (1H, s), 7.29–7.46 (5H, m),
7.56 ppm (1H, s); LC–MS (APCI+): m/z 448.54 [M+H]+; HRMS
+
(ES+): m/z found 448.1756; C26H26NO6
[M+H]+ requires
448.1755.
6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihy-
droisoquinolin-1(2H)-one (15g): Method as for 15a using com-
pound 14g (0.85 g, 1.83 mmol) and 18-crown-6 (48 mg,
0.18 mmol) in CHCl3 (30 mL) at 08C for 2 h then at RT 16 h. The re-
action mixture was diluted with CHCl3 and sodium bisulfite (sat.)
and HCl (2m, 1.0 mL, 2.0 mmol) were added. The mixture was
washed with H2O and brine, dried with MgSO4, filtered and con-
centrated in vacuo. Flash column chromatography (hexane/EtOAc
3:1 to 1:1) afforded compound 15g as a white powder (220 mg,
25%), mp: 195–1968C. 1H NMR (270 MHz, CDCl3): d=3.05 (2H, t,
J=6.2 Hz), 3.83 (6H, s), 3.87 (3H, s), 3.87 (3H, s), 4.05 (2H, t, J=
6.2 Hz), 5.23 (2H, s), 6.75 (1H, s), 6.84 (2H, s), 7.29–7.46 (5H, m),
7.56 ppm (1H, s); LC–MS (ES+): m/z 500.18 ([M+Na]+, 100%),
418.1635; C25H24NO5 [M+H]+ requires 418.1649.
+
6-Benzyloxy-7-methoxy-2-(3-methoxybenzoyl)-3,4-dihydroiso-
quinolin-1(2H)-one (15b): Method as for 15a using compound
14b (560 mg, 1.38 mmol), KMnO4 (1.1 g, 6.9 mmol) and 18-crown-6
(70 mg, 0.26 mmol) in dichloromethane (50 mL) at RT for 16 h.
Flash column chromatography (hexane/EtOAc 3:1) afforded com-
pound 15b as a white powder (235 mg, 41%), mp: 141–1438C.
1H NMR (270 MHz, CDCl3): d=3.03 (2H, t, J=6.2 Hz), 3.81 (3H, s),
3.85 (3H, s), 4.08 (2H, t, J=6.2 Hz), 5.23 (2H, s), 6.73 (1H, s), 7.01
(1H, ddd, J=8.2, 2.7, 1.2 Hz), 7.11–7.15 (2H, m), 7.26–7.45 (6H, m),
7.56 ppm (1H, s); LC–MS (ES+): m/z 440.43 [M+Na]+; LC–MS
(ESꢁ): m/z 416.38 [MꢁH]ꢁ; HRMS (ES+): m/z found 418.1636;
478.20 [M+H]+; HRMS (ES+): m/z found 478.1844; C27H28NO7
[M+H]+ requires 478.1860.
+
+
C25H24NO5 [M+H]+ requires 418.1649.
6-Benzyloxy-2-(3-cyanobenzoyl)-7-methoxy-3,4-dihydroisoquino-
lin-1(2H)-one (15c): Method as for 15a using compound 14c
(315 mg, 0.79 mmol), KMnO4 (0.62 g, 3.8 mmol) and 18-crown-6
(40 mg, 0.15 mmol) in dichloromethane (40 mL) at RT for 16 h.
Flash column chromatography (hexane/EtOAc 3:2) afforded com-
pound 15c as a white powder (100 mg, 31%), mp: 195–1968C.
1H NMR (270 MHz, CDCl3): d=3.05 (2H, t, J=6.2 Hz), 3.82 (3H, s),
3.86 (2H, t, J=6.2 Hz), 5.24 (2H, s), 6.74 (1H, s, 7.30–7.45 (5H, m),
7.49–7.55 (2H, m), 7.74 (1H, ddd, J=7.9, 1.7, 1.5 Hz), 7.79 (1H, ddd,
J=7.9, 1.7, 1.2 Hz), 7.82 ppm (1H, d, J=1.5, 1.2 Hz); LC–MS (ES+):
m/z 435.58 [M+Na]+; HRMS (ES+): m/z found 413.1496;
6-Hydroxy-2-(2-methoxybenzoyl)-7-methoxy-3,4-dihydroisoqui-
nolin-1(2H)-one (16a): Method as for 8a using compound 15a
(145 mg, 0.35 mmol) and Pd/C (10%, 20 mg) in THF (10 mL) and
MeOH (10 mL) under hydrogen at RT for 2 h. The residue was
stirred in EtOAc (5 mL), filtered and dried in vacuo to afford com-
pound 16a as a white powder (105 mg, 92%), mp: 199–2008C.
1H NMR (270 MHz, [D6]DMSO): d=2.94 (2H, t, J=6.2 Hz), 3.57 (3H,
s), 3.74 (3H, s), 4.05 (2H, t, J=6.2 Hz), 6.76 (1H, s), 6.93–7.00 (2H,
m), 7.27 (1H, dd, J=7.4, 1.7 Hz), 7.32 (1H, s), 7.34–7.41 (1H, m),
10.21 ppm (1H, s); LC–MS (ESꢁ): m/z 326.51 [MꢁH]ꢁ; HRMS (ES+):
m/z found 328.1167; C18H18NO5 [M+H]+ requires 328.1179.
+
C25H21N2O4 [M+H]+ requires 413.1496.
+
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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CHEMMEDCHEM
FULL PAPERS
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6-Hydroxy-2-(3-methoxybenzoyl)-7-methoxy-3,4-dihydroisoqui-
nolin-1(2H)-one (16b): Method as for 8a using compound 15b
(200 mg, 0.48 mmol) and Pd/C (10%, 25 mg) in THF (10 mL) and
MeOH (10 mL) under hydrogen at RT for 1 h. The residue was
stirred in EtOAc (5 mL), filtered and dried in vacuo to afford com-
pound 16b as a white powder (125 mg, 80%), mp: 198–1998C.
1H NMR (270 MHz, [D6]DMSO): d=3.03 (2H, t, J=5.9 Hz), 3.75 (3H,
s), 3.76 (3H, s), 3.95 (2H, t, J=5.9 Hz), 6.77 (1H, s), 7.05–7.10 (3H,
m), 7.32 (1H, dt, J=6.7, 1.0 Hz), 7.34 (1H, s), 10.21 ppm (1H, s);
LC–MS (ESꢁ): m/z 326.58 [MꢁH]ꢁ; HRMS (ES+): m/z found
afford compound 16g as a white powder (140 mg, 96%), mp:
175–1768C. 1H NMR (270 MHz, CDCl3): d=3.07 (2H, t, J=6.4 Hz),
3.83 (6H, s), 3.88 (3H, s), 3.89 (3H, s), 4.06 (2H, t, J=6.4 Hz), 6.18
(1H, s), 6.80 (1H, s), 6.85 (2H, s), 7.55 ppm (1H, s); HRMS (ES+): m/
z found 388.1380; C20H22NO7 [M+H]+ requires 388.1391; LC–MS
+
(ESꢁ): m/z 386.24 [MꢁH]ꢁ.
2-(2-Methoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroi-
soquinolin-1(2H)-one (17a): Method as for 9a using compound
16a (70 mg, 0.21 mmol) and sulfamoyl chloride (0.43 mmol) in
DMA (1.0 mL) at RT for 16 h. The residue was stirred in Et2O
(30 mL), filtered and dried in vacuo to afford compound 17a as
328.1168; C18H18NO5 [M+H]+ requires 328.1179.
+
1
2-(3-Cyanobenzoyl)-6-hydroxy-7-methoxy-3,4-dihydroisoquino-
lin-1(2H)-one (16c): Method as for 8a using compound 15c
(155 mg, 0.38 mmol) and Pd/C (10%, 20 mg) in THF (10 mL) and
MeOH (10 mL) under hydrogen at RT for 1 h. The residue was dis-
solved in hot EtOAc (5 mL), filtered and concentrated then stirred
in Et2O (20 mL), filtered and dried in vacuo to afford compound
16c as a white powder (71 mg, 59%), mp: 197–1988C. 1H NMR
(270 MHz, [D6]acetone): d=3.14 (2H, t, J=6.2 Hz), 3.85 (3H, s), 4.08
(2H, t, J=6.2 Hz), 6.83 (1H, s), 7.42 (1H, s), 7.65 (1H, dd, J=8.2,
7.6 Hz), 7.86–7.91 (2H, m), 8.00–8.06 (1H, m), 8.71 ppm (1H, s, br);
LC–MS (ESꢁ): m/z 321.47 (M+-H); HRMS (ES+): m/z found
a white powder (65 mg, 75%), mp: 165–1668C. H NMR (400 MHz,
[D6]DMSO): d=3.05 (2H, t, J=6.2 Hz), 3.60 (3H, s), 3.80 (3H, s), 4.11
(2H, t, J=6.2 Hz), 6.96–7.03 (2H, m), 7.31 (1H, dd, J=7.7, 1.7 Hz),
7.39 (1H, s), 7.41 (1H, dt, J=8.4, 1.7 Hz), 7.53 (1H, s), 8.18 ppm
(2H, s, br); LC–MS (ESꢁ): m/z 405.50 [MꢁH]ꢁ; HRMS (ES+): m/z
found 407.0898; C18H19N2O7S+ [M+H]+ requires 407.0907.
2-(3-Methoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroi-
soquinolin-1(2H)-one (17b): Method as for 9a using compound
16b (80 mg, 0.24 mmol) and sulfamoyl chloride (0.48 mmol) in
DMA (1.0 mL) at RT for 16 h. The residue was stirred in Et2O
(30 mL), filtered and dried in vacuo to afford compound 17b as
323.1012; C18H15N2O4 [M+H]+ requires 323.1026.
+
1
a white powder (75 mg, 77%), mp: 173–1748C. H NMR (400 MHz,
6-Hydroxy-2-(4-methoxybenzoyl)-7-methoxy-3,4-dihydroisoqui-
nolin-1(2H)-one (16d): Method as for 8a using compound 15d
(96 mg, 0.23 mmol) and Pd/C (10%, 20 mg) in THF (10 mL) and
EtOH (10 mL) under hydrogen at RT for 0.5 h. The residue was
stirred in EtOAc (10 mL) and hexane (2 mL), filtered and dried in
vacuo to afford compound 16d as a white powder (72 mg, 96%),
[D6]DMSO): d=3.15 (2H, t, J=5.9 Hz), 3.77 (3H, s), 3.81 (3H, s),
4.01 (2H, t, J=5.9 Hz), 7.08–7.18 (3H, m), 7.31–7.36 (1H, m), 7.41
(1H, s), 7.57 (1H, s), 8.18 ppm (2H, s, br); LC–MS (ESꢁ): m/z 405.43
[MꢁH]ꢁ; HRMS (ES+): m/z found 407.0895; C18H19N2O7S+ [M+H]+
requires 407.0907.
2-(3-Cyanobenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroiso-
quinolin-1(2H)-one (17c): Method as for 9a using compound 16c
(50 mg, 0.16 mmol) and sulfamoyl chloride (0.40 mmol) in DMA
(0.5 mL) at RT for 16 h. Crystallisation from EtOAc afforded com-
pound 17c as a white powder (45 mg, 70%), mp: 171–1728C.
1H NMR (270 MHz, [D6]acetone): d=3.23 (2H, t, J=6.2 Hz), 3.88
(3H, s), 4.14 (2H, t, J=6.2 Hz), 7.24 (2H, s, br), 7.40 (1H, s), 7.58
(1H, s), 7.69 (1H, dt, J=7.9, 0.8 Hz), 7.91–7.98 (2H, m), 8.06 ppm
(1H, dt, J=1.8, 0.8 Hz); LC–MS (ESꢁ): m/z 400.53 [MꢁH]ꢁ; HRMS
(ES+): m/z found 402.0739; C18H16N3O6S+ [M+H]+ requires
402.0754.
1
mp: 224–2258C. H NMR (270 MHz, [D6]DMSO): d=3.01 (2H, t, J=
5.7 Hz), 3.77 (3H, s), 3.82 (3H, s), 3.90 (2H, t, J=5.7 Hz), 6.77 (1H,
s), 6.95 (2H, d, J=8.6 Hz), 7.36 (1H, s), 7.55 (2H, d, J=8.6 Hz),
10.19 ppm (1H, s, br); LC–MS (APCI+): m/z 328.46 [M+H]+; HRMS
(ES+): m/z found 328.1181; C18H18NO5 [M+H]+ requires 328.1179.
+
6-Hydroxy-2-(3,4-dimethoxybenzoyl)-7-methoxy-3,4-dihydroiso-
quinolin-1(2H)-one (16e): Method as for 8a using compound 15e
(165 mg, 0.37 mmol) and Pd/C (10%, 20 mg) in THF (150 mL)
under hydrogen at RT for 2 h. Crystallisation from EtOAc (5 mL) af-
forded compound 16e as a white powder (115 mg, 87%), mp:
199–2008C. 1H NMR (400 MHz, [D6]DMSO): d=3.02 (2H, t, J=
5.9 Hz), 3.75 (3H, s), 3.76 (3H, s), 3.81 (3H, s), 3.90 (2H, t, J=
5.9 Hz), 6.77 (1H, s), 6.96 (1H, d, J=9.2 Hz), 7.15–7.18 (2H, m), 7.36
(1H, s), 10.20 ppm (1H, s, br); LC–MS (ESꢁ): m/z 356.60 [MꢁH]ꢁ;
2-(4-Methoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroi-
soquinolin-1(2H)-one (17d): Method as for 9a using compound
16d (90 mg, 0.28 mmol) and sulfamoyl chloride (0.55 mmol) in
DMA (1.0 mL) at RT for 18 h. Flash column chromatography
(hexane/EtOAc 10:1 to 4:1) afforded compound 17d as a white
powder (80 mg, 71%), mp: 171–1728C. 1H NMR (270 MHz, CDCl3/
[D4]MeOH 5:1): d=3.08 (2H, s, br), 3.10 (2H, t, J=6.4 Hz), 3.83 (3H,
s), 3.85 (3H, s), 4.03 (2H, t, J=6.4 Hz), 6.88 (2H, dt, J=8.9, 2.5 Hz),
7.31 (1H, s), 7.61 (2H, dt, J=8.9, 2.5 Hz), 7.67 ppm (1H, s); LC–MS
(APCI+): m/z 407.42 [M+H]+; HRMS (ES+): m/z found 407.0904;
C18H19N2O7S+ [M+H]+ requires 407.0907.
HRMS (ES+): m/z found 358.1273; C19H20NO6 [M+H]+ requires
+
358.1285.
6-Hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroiso-
quinolin-1(2H)-one (16 f): Method as for 8a using compound 15 f
(200 mg, 0.45 mmol) and Pd/C (10%, 30 mg) in THF (15 mL) and
MeOH (15 mL) under hydrogen at RT for 3 h. The residue was
stirred in Et2O, filtered and dried in vacuo to afford compound 16 f
as a white powder (130 mg, 81%), mp: 198–1998C. 1H NMR
(270 MHz, CDCl3): d=3.05 (2H, t, J=6.2 Hz), 3.78 (6H, s), 3.86 (3H,
s), 4.07 (2H, t, J=6.2 Hz), 6.16 (1H, s), 6.56 (1H, t, J=2.2 Hz), 6.71
(2H, d, J=2.2 Hz), 6.79 (1H, s), 7.54 ppm (1H, s); LC–MS (APCI+):
2-(3,4-Dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihy-
droisoquinolin-1(2H)-one (17e): Method as for 9a using com-
pound 16e (71 mg, 0.20 mmol) and sulfamoyl chloride (0.40 mmol)
in DMA (1.0 mL) at RT for 16 h. After addition of H2O (5 mL) the re-
action mixture was extracted into EtOAc (2ꢁ50 mL), the organic
layers washed with H2O and brine, then dried (MgSO4) and evapo-
rated. The residue was stirred in EtOAc (5 mL), filtered and dried in
vacuo to afford compound 17e as a white powder (55 mg, 77%),
mp: 180–1818C. 1H NMR (270 MHz, ([D6]acetone): d=3.19 (2H, t,
J=6.2 Hz), 3.81 (3H, s), 3.87 (3H, s), 3.88 (3H, s), 4.03 (2H, t, J=
6.2 Hz), 6.96 (1H, d, J=8.9 Hz), 7.21 (2H, s, br), 7.28 (1H, s), 7.30
m/z 358.25 [M+H]+; HRMS (ES+): m/z found 358.1285; C19H20NO6
[M+H]+ requires 358.1285.
+
6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroi-
soquinolin-1(2H)-one (16g): Method as for 8a using compound
15g (180 mg, 0.38 mmol) and Pd/C (10%, 40 mg) in THF (20 mL)
and MeOH (20 mL) under hydrogen at RT for 24 h. The residue was
stirred in Et2O, filtered, washed with Et2O and dried in vacuo to
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(1H, d, J=8.9 Hz), 7.39 (1H, s), 7.62 ppm (1H, s); LC–MS (ESꢁ): m/z
435.44 [MꢁH]ꢁ; HRMS (ES+): m/z found 437.1011; C19H21N2O8S+
[M+H]+ requires 437.1013.
(ES+): m/z found 423.1220; C19H23N2O7S+ [M+H]+ requires
423.1220.
2-(3,5-Dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tet-
rahydroisoquinoline (19b): Method as for 9a using 18b (75 mg,
0.24 mmol) and sulfamoyl chloride (0.48 mmol) in anhydrous DMA
(1.0 mL) at RT for 24 h. The residue was stirred in Et2O, filtered and
dried in vacuo to afford compound 19b as a white powder
2-(3,5-Dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihy-
droisoquinolin-1(2H)-one (17 f): Method as for 9a using com-
pound 16 f (80 mg, 0.22 mmol) and sulfamoyl chloride (0.45 mmol)
in DMA (1.0 mL) at RT for 18 h. The residue was stirred in Et2O, fil-
tered and dried in vacuo to afford compound 17 f as a white
1
(80 mg, 85%), mp: 170–1718C. H NMR (270 MHz, CDCl3/[D4]MeOH
1
powder (76 mg, 78%), mp: 169–1708C. H NMR (270 MHz, (CDCl3/
5:1): d=2.70 and 2.80 (2H, t, J=5.3 Hz), 3.55 and 3.82 (2H, t, J=
5.3 Hz), 3.63 (2H, s), 3.71 (9H, s), 4.46 and 4.72 (2H, br), 6.44 (2H,
s), 6.46 and 6.74 (1H, br), 7.05 ppm (1H, br); LC–MS (APCI+): m/z
423.35 [M+H]+; HRMS (ES+): m/z found 423.1224; C19H23N2O7S+
[M+H]+ requires 423.1220.
[D4]MeOH 10:1): d=2.46 (2H, s, br), 3.08 (2H, t, J=6.2 Hz), 3.75
(6H, s), 3.82 (3H, s), 4.05 (2H, t, J=6.2 Hz), 6.56 (1H, t, J=2.3 Hz),
6.68 (2H, d, J=2.3 Hz), 7.29 (1H, s), 7.65 ppm (1H, s); LC–MS
(APCI+): m/z 437.39 [M+H]+; HRMS (ES+) m/z found 437.1011;
C19H21N2O8S+ [M+H]+ requires 437.1013.
7-Methoxy-2-(3,4,5-trimethoxybenzoyl)-6-sulfamoyloxy-3,4-dihy-
droisoquinolin-1(2H)-one (17g): Method as for 9a using com-
pound 16g (80 mg, 0.21 mmol) and sulfamoyl chloride (0.6 mmol)
in DMA (1.0 mL) at RT for 24 h. H2O (20 mL) was added and the
mixture extracted with EtOAc (50 mL) and THF (50 mL). The organ-
ic layer was washed with H2O and brine, dried (MgSO4), filtered
and concentrated in vacuo. The residue was stirred in Et2O (5 mL)
and EtOAc (5 mL), filtered and dried to afford compound 17g as
Acknowledgements
We thank Ms. Alison Smith for technical support and the NCI
DTP for providing in vitro screening resources. This work was
supported by Sterix Ltd., a member of the IPSEN Group, and in
part by the Wellcome Trust (Program Grant 082837 to B.V.L.P.).
B.V.L.P. is a Wellcome Trust Senior Investigator (Grant 101010).
1
a white powder (80 mg, 82%), mp: 196–1978C. H NMR (270 MHz,
[D6]DMSO): d=3.16 (2H, t, J=5.7 Hz), 3.72 (3H, s), 3.75 (6H, s),
3.81 (3H, s), 3.98 (2H, t, J=5.7 Hz), 6.90 (2H, s), 7.40 (1H, s), 7.57
(1H, s), 8.18 ppm (2H, s, br); LC–MS (ESꢁ): m/z 465.22 [MꢁH]ꢁ;
HRMS (ES+): m/z found 467.1109; C20H23N2O9S+ [M+H]+ requires
467.1119.
Keywords: colchicine · dihydroisoquinolinones · electrostatic
repulsion · microtubules · tubulin
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2-(3,4-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (18a): Method as for 8a using 14e (403 mg,
0.93 mmol) and Pd/C (10%, 40 mg) in THF (15 mL) and MeOH
(15 mL) under hydrogen at RT for 1.5 h. The resulting solid was
stirred in Et2O, filtered and dried in vacuo to afford compound 18a
1
as a white solid (300 mg, 94%), mp: 132–1338C. H NMR (270 MHz,
CDCl3): d=2.80 (2H, br), 3.83 (2H, br), 3.88 (3H, s), 3.90 (6H, s),
4.61 and 4.72 (2H, br), 5.62 (1H, s), 6.60 (1H, br), 6.69 (1H, br), 6.86
(1H, d, J=8.9 Hz), 7.02 (1H, s), 7.03 (1H, d, J=8.9 Hz), 8.84 ppm
(1H, s); LC–MS (APCI+): m/z 344.27 [M+H]+; HRMS (ES+): m/z
found 344.1493; C19H22NO5 [M+H]+ requires 344.1492.
+
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2-(3,5-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahy-
droisoquinoline (18b): Method as for 8a using 14 f (390 mg,
0.90 mmol) and Pd/C (10%, 40 mg) in THF (15 mL) and MeOH
(15 mL) under hydrogen at RT for 2 h. The resulting solid was
stirred in Et2O, filtered and dried in vacuo to afford compound
18b as a white solid (290 mg, 94%), mp: 136–1378C. 1H NMR
(270 MHz, CDCl3): d=2.73 and 2.84 (2H, br), 3.59 and 3.93 (2H, br),
3.79 (9H, s), 4.48 and 4.77 (2H, br), 5.58 (1H, s), 6.38 and 6.64 (1H,
br), 6.50 (1H, t, J=2.2 Hz), 6.55 (2H, d, J=2.2 Hz), 6.68 ppm (1H,
br); LC–MS (APCI+): m/z 344.33 [M+H]+; HRMS (ES+): m/z found
344.1493; C19H22NO5 [M+H]+ requires 344.1492.
+
2-(3,4-Dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tet-
rahydroisoquinoline (19a): Method as for 9a using 18a (75 mg,
0.24 mmol) and sulfamoyl chloride (0.48 mmol) in anhydrous DMA
(1.0 mL) at RT for 24 h. The residue was stirred in Et2O, filtered and
dried in vacuo to afford compound 19a as a white powder
1
(80 mg, 85%), mp: 155–1568C. H NMR (270 MHz, CDCl3/[D4]MeOH
5:1): d=2.73 (2H, br), 3.59 and 3.72 (2H, br), 3.77 (3H, s), 3.79 (6H,
s), 4.52 and 4.65 (2H, br), 6.61 and 6.70 (1H, br), 6.80 (1H, d, J=
8.2 Hz), 6.87 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=8.2, 2.0 Hz),
7.03 ppm (1H, s); LC–MS (APCI+): m/z 423.42 [M+H]+; HRMS
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[15] Crystal Data for 17 f: C19H20N2O8S, Mr =436.43 Da, l=0.71073 ꢂ, mono-
clinic, space group P21/c, a=9.8720(3), b=12.2900(4), c=15.9220(6) ꢂ,
[18] P. Verdier-Pinard, J. Y. Lai, H. D. Yoo, J. Yu, B. Marquez, D. G. Nagle, M.
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finement, University of Gçttingen (Germany), 1997.
b=97.321(1)8, U=1916.02(11) ꢂ3, Z=4, 1calcd =1.513 gcmꢁ3
,
m=
0.222 mmꢁ1, F(000)=912, crystal size 0.30ꢁ0.07ꢁ0.07 mm, unique re-
flections=4376 [Rint =0.0994], observed I>2sI=2503, data/restraints/
parameters=4376/2/283, obsd. data R1=0.0558 wR2=0.1238; all data
R1=0.1226 wR2=0.1458; max peak/hole 0.381 and ꢁ0.508 eꢂꢁ3
.
CCDC 874341 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_
request/cif.
Received: January 6, 2014
Published online on March 5, 2014
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ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 798 – 812 812