Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine derivatives as CDK inhibitors and cytotoxic agents

Article abstract of DOI:10.1016/j.bmc.2008.03.034

We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitutions o

Full text of DOI:10.1016/j.bmc.2008.03.034

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 4932–4953
Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]-
pyridine derivatives as CDK inhibitors and cytotoxic agents
a
b
b
b,
c
´
´
´
Ulrich Jacquemard, Nathalie Dias, Amelie Lansiaux, Christian Bailly, Cedric Loge,
Jean-Michel Robert,c Olivier Lozach,d Laurent Meijer,d
a
a,
*
´
Jean-Yves Merour and Sylvain Routier
aInstitut de Chimie Organique et Analytique, (1) Universite´ d’Orle´ans, (2) CNRS UMR 6005, Rue de Chartres,
BP 6759, 45067 Orle´ans Cedex 2, France
bINSERM U-837, IRCL, Place de Verdun, 59045 Lille, France
cUniversite´ de Nantes, Nantes Atlantique Universite´s, Biomole´cules et Cibles The´rapeutiques, De´partement de Pharmacochimie,
BioCiT-EA 1155, UFR Sciences Pharmaceutiques, 1 rue Gaston Veil, Nantes F-44000, France
dCNRS, Amyloids & Cell Division Cycle Group, 29680 Roscoff, France
Received 15 January 2008; revised 6 March 2008; accepted 14 March 2008
Available online 17 March 2008
Abstract—We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyr-
idine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitu-
tions of the pyridine. The resulting skeletons were successively exploited to introduce various dimethylaminoalkyl side chains by
Williamson type reactions. The synthesis includes Stille or Suzuki type reactions, which were realized on the 3,5-dibromopyridine.
The preparation and the use of stannylindoles in mono or bis cross-coupling reactions were also described and each step was
optimized and detailed. Kinase assays were realized and shown that nude compounds 7, 18, and 25 inhibited CDK1 in the 0.3–
0.7 micromolar range with a good selectivity over GSK-3. Cytotoxicity against CEM human leukemia cells was evaluated with
IC50 values in the 5–15 micromolar range. Precise structure–activity relationships were delineated. Molecular modeling and docking
solutions were proposed to complete the studies and to explain the observed SAR in the CDK assays.
ꢀ 2008 Published by Elsevier Ltd.
1. Introduction
Aspergillus terreus, which both possess a bis indolic
structure, spaced by a piperidinone or a quinonic sys-
tem.3 Structure of these cytotoxic natural products can
also be compared to some extent to synthetic 3-substi-
tuted indole derivatives of type I (Fig. 1) acting as
anti-angiogenic inhibitors of the KDR kinase.4
Numerous marine indole alkaloids have been isolated
and among them certain bis(indole) secondary metabo-
lites containing an imidazole- or a piperazine-derived
spacer unit1 exhibit a broad spectrum of biological activ-
ities, with potent cytotoxic effects toward cancer cells in
some cases. As an example, dragmacidin D (Fig. 1),2 ex-
tracted from deep-water sponges, was described as a po-
tent inhibitor of serine/threonine protein phosphatases.
In this case, a piperazinone ring separates the two in-
doles units. This compound shows a structural analogy
with hamacanthin A and asterriquinone, isolated from
These indole structures provide an interesting frame-
work for the design of novel targeted anticancer agents.
Mixing the structure of the related compound in Figure
1, suggested also that a pyridine heterocycle substituted
with one or two indoles units apparently should repre-
sent a suitable core to interact with the ATP-binding
sites of enzymes.5
Keywords: Indole; Pyridine; CDK inhibitors; Cytotoxicity; Anticancer
agent.
In an ongoing program devoted to the design of DNA-
binding anticancer agents we have developed non-fused
tris-aromatic compounds containing either a carbazole
II6,7 or pyridine III8 or pyrazine IV9 central ring. All
of them were disubstituted in positions 3 and 5 by aryl
groups. SAR studies showed that in the three series
*
Corresponding author. Tel.: +33 2 38 49 48 53; fax: +33 2 38 41 72
81; e-mail: sylvain.routier@univ-orleans.fr
´
Present address: Centre de Recherche en Oncologie Experimentale,
Institut de Recherche Pierre Fabre, 3 rue des satellites, 31140
Toulouse, France.
0968-0896/$ - see front matter ꢀ 2008 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2008.03.034

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4933
H
H
N
N
N
N
Br
H2N
N
Br
H
N
S
H
N
N
N
O
O
O
N
N
OH
H
N
HO
N
O
N
H
Br
I : KDR 16nM
N
H
OH
N
Hamacanthin A
Dragmacidin D
OR
Asterriquinone
1
RO
1
OR
R2
R O
OR
X
N
RO
OR
N
N
N
R
R
R
III
X = CH
IV X = N
N
N
R
II
N
V
VI
R or R1 = H, alkylamino side chains
R2 = H, OR1
Figure 1. 3-Substituted indolic structures and general structures of synthesized compounds.
the introduction of lateral basic side chains led to strong
DNA binders whereas the absence of side chains gener-
ally reduced or abolished the DNA sequence recognition
property. A few compounds in those series also revealed
modest kinase inhibitory activities. First molecular
modeling studies indicated that the absence of a crucial
donor acceptor hydrogen bond system in the medium
size of the tricyclic structure was for us the major reason
to explain this result.10 As we were interested in the de-
sign of new CDK inhibitors, we focused our new effort
on V-shaped pyridinyl derivatives bearing as substitu-
ents one or two indole rings. The lack of one of the
two indoles was corrected by the introduction of a phe-
nol. These compounds (types V and VI), could be con-
sidered as mimics of the related compounds in Figure
1 and were certainly able to promote binding to the
ATP sites by a supplementary hydrogen bond. 2-Substi-
tuted indoles close to the pyridinyl hydrogen acceptor
atom should achieve this donor/acceptor strategy. In
addition, based on our previous experiences with mole-
cules of types II–IV, we used the free OH to introduce
alkyl basic side chains to enhance solubility, and to
introduce molecular diversity in order to verify our
hypothesis (Fig. 1).
choose a one pot double Stille procedure in the case of
V and a Stille/Suzuki tandem cross-coupling strategy
for VI. In both cases, the starting material was the 3,5-
dibromopyridine 1.
2.1. Synthesis of symmetrical compounds type V
5-Benzyloxyindole 2 was protected with a phenylsulfo-
nyl group to give 3 (95% yield), which then was treated
with LDA (1.5 equiv) in THF at ꢀ20 ꢁC for 30 min
(Scheme 1). Tributylstannyl chloride was added at
ꢀ78 ꢁC to rt to give the stannyl derivative 4 in a good
yield (78%). The synthetic sequence was completed with
a Stille reaction involving 4 in a slight excess (2.3 equiv)
and 3,5-dibromopyridine 1 in the presence of Pd(PPh3)4
BnO
BnO
a
R
N
N
H
SO2Ph
3 R = H
4 R = SnBu3
2
b
OR2
R2
g
O
c
BnO
X
R
Bis-indoles linked by position-2 to a spacer such as in
compound of type V are scarcely described.11 Most of
them have been developed as polyaza cavity-shaped
molecules.12–15 A reported synthesis of unsubstituted
compounds of type V is the result of a double Fischer
reaction on 3,5-diacetylpyridine.16 A different strategy
was applied in the present case.
N
N
N
R1
R1
CO2H
R = H
10 R = Sn(Bu)3
N
9
5 R1 = SO2Ph, R2 = Bn
6 R1 = H, R2 = Bn
d
f
e
7 R1 = R2 = H
R1 = SO C H ,
2 = H
8
R
5
2
6
Scheme 1. Reagents and conditions: (a) NaH (2.3 equiv), PhSO2Cl
(2.0 equiv), THF, 0 ꢁC to rt, 4 h, 95%; (b) LDA (1.5 equiv), THF,
ꢀ20 ꢁC, 30 min then Bu3SnCl (1.7 equiv), ꢀ78 ꢁC to rt, 2 h, 78%; (c)
2. Chemistry
3,5-dibromopyridine 1,
4 (2.3 equiv), Pd(PPh3)4 (0.1 equiv), CuI
(0.2 equiv), THF, 8 h, reflux, 89%; (d) Bu4NF (5 equiv), THF, reflux,
2.5 h, 74%; (e) BBr3 (2.1 equiv), CH2Cl2, rt, 3 h, 33%; (f) BBr3
(7 equiv), idem, 68%. (g) i—CO2, BuLi, THF, ꢀ78 ꢁC; ii—t-BuLi,
Bu3SnCl (1.2 equiv), ꢀ78 ꢁC, 1 h 30.
In order to produce symmetrical and unsymmetrical
aromatic heterocyclic structures of types V and VI, we
performed a retrosynthetic analysis, which led us to

4934
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
Br
rectly from 2, we next prepared the 5-benzyloxy-1-car-
R
R
boxy-2-stannylindole 10 (obtained by reacting Bu3SnCl
on the dilithium salt of 5-benzyloxy-1-carboxyindole 9)
which was used in a Stille reaction with 3,5-dibromo-
pyridine 1 but we were unable to isolate the desired com-
pound and only the 5-benzyloxyindole 2 was recovered
in a quantitative manner.
b
a
SnBu3
SO2Ph
N
N
N
SO2Ph
11 R = H
4 R = OBn
12 R = H
13 R = OBn
OMe
OMe
2.2. Synthesis of dissymmetrical structure type VI
R
d
R
The second framework was the disubstituted pyridine in
positions 3 and 5, respectively, with an indole and a 4-
hydroxyphenyl ring. We used a similar approach to that
described for 5 (Scheme 1), starting from the stannyl
derivatives 4 and 11.
N
N
N
N
SO2Ph
R'
14 R = H
15 R = OBn
16 R = R' = H
17 R= OBn R' = H
c
from 14
OH
e
from 14
OH
The mono Stille coupling of 4 and 11 with 3,5-dibromo-
pyridine 1 was carefully controlled using only stoichiom-
etric amount of stannylated derivatives. In this case only
5% of catalyst was necessary to isolate compounds 12
and 13 in 88% and 78% yields from 11 and 4, respec-
tively (see Scheme 2).
N
N
N
H
N
SO2Ph
18
19
Then the second aryl unit was introduced by a Suzuki
reaction on 12 and 13 with the commercially available
4-methoxyphenylboronic acid to afford 14 and 15 in
97% and 81% yield, respectively. The experimental con-
ditions required Pd(PPh3)4 as catalyst and aqueous
NaHCO3 in a refluxing mixture of toluene and ethanol.
Deprotection of the phenylsulfonyl group of 14 and 15
was achieved with Bu4NF in THF at room temperature
and afforded 16 in 83% yield and 17 quantitatively. The
methoxy group of 16 was then removed with HBr in ace-
tic acid leading to 18 in an 83% yield. In addition, start-
ing from compound 14, the ether deprotection occurred,
using BBr3, to give 19 in a 77% yield. At this stage, it
must be pointed out that the cleavage of the ethers of
15 and 17 was unproductive. So we envisaged another
way and began by the Suzuki palladium catalyzed reac-
tion involving the 3,5-dibromopyridine 1 and a slight de-
fault of 4-methoxyphenylboronic acid (Scheme 3). Thus,
compound 20 was isolated after 18 h in a 77% yield.
After a quantitative demethylation leading to 21, the
Stille reaction with indole 4 led to 23 in only 33% yield.
Scheme 2. Reagents and conditions: (a) 3,5-dibromopyridine 1,
Pd(PPh3)4 (0.05 equiv) CuI (0.1 equiv), THF, reflux, from 11, 4 h,
12, 88%; from 4, 8 h, 13 78%; (b) 4-methoxyboronic acid (1.2 equiv),
toluene/ethanol 5/3, aq. satd. NaHCO3, reflux, 18 h, from 12,
Pd(PPh3)4 (0.1 equiv), 14 97%; from 13, Pd(PPh3)4 (0.05 eq), 15 81%;
(c) BBr3 (4.1 equiv), CH2Cl2, 0 ꢁC to rt, 3 h, from14, 19 77%; (d)
Bu4NF (3.5 equiv), THF, reflux, 2 h, from 14, 16 83%; from 15, 17
quant.; (e) HBr 47%, AcOH, reflux, 5 h, from 16, 18 83%.
(10 %) and CuI (20%) in refluxing THF. The two simul-
taneous coupling procedures led after 8 h to the bis ind-
olic compound
5 in an 89% yield. A selective
deprotection of the protecting groups was next success-
fully realized. The phenylsulfonyl group of 5 was re-
moved using Bu4NF (5 equiv) in refluxing THF to
afford 6 (74% yield). The cleavage of the benzyl groups
occurred by treating 5 or 6 at room temperature with
an excess of BBr3. A satisfactory yield of 8 was obtained
(68%) from 5, whereas similar conditions led to 7 in only
33% yield from 6. In order to synthesize compound 7 di-
OR
Br
Br
d
Br
b
a
from 21
N
N
1
20 R = CH3
21 R = H
22 R = (CH2)2N(CH3)2
c
BnO
HO
OH
OH
f
N
R
from 24
N
H
N
N
23 R = SO2C6H5
24 R = H
e
25
Scheme 3. Reagents and conditions: (a) 4-methoxyphenylboronic acid (0.95 equiv), Pd(PPh3)4,(0.1 equiv), toluene/ethanol 5/1, aq. satd. NaHCO3,
reflux, 18 h, 77%; (b) BBr3, CH2Cl2, 0 ꢁC to rt, 3 h, quant; (c) Cs2CO3, 26, DMF, 100 ꢁC, 8 h, 57%; (d) 4 (1.1 equiv), Pd(PPh3)4 (0.05 equiv), CuI
(0.1 equiv), THF, reflux, 4 h, 33%; (e) Bu4NF (5 equiv), THF, reflux, 1h, 80%; (f) BBr3 (1.2 equiv), CH2Cl2, 0 ꢁC to rt, 3 h, 52%.

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4935
Table 1. Conditions for the synthesis of 28–35
Entry Starting material Conditions
Compound R1
R2
Yielda (%)
1
6
(a) NaH (8 equiv), 26 (2.25 equiv),
DMF, 0 ꢁC to 100 ꢁC, 2 h
Idem (a) with 27 (2.5 equiv)
(b) Idem, NaH (2.5 equiv), 26 (1.2 equiv)
Idem (b) with 27
28
(CH2)2N(CH3)2 (CH2)2N(CH3)2 55
2
3
4
5
6
7
8
6
6
29
30
31
(CH2)3N(CH3)2 (CH2)3N(CH3)2 52
(CH2)2N(CH3)2
(CH2)3N(CH3)2
H
H
58
60
6
28
29
30
31
(c) BBr3, (1.25 equiv), CH2Cl2, 0 ꢁC to rt, 2 h 32
(CH2)2N(CH3)2 (CH2)2N(CH3)2 49
(CH2)3N(CH3)2 (CH2)3N(CH3)2 47
Idem (c) with 29
Idem (c) with and BBr3 (2eq)
Idem (c) with 31
33
34
35
(CH2)2N(CH3)2
(CH2)3N(CH3)2
H
H
52
48
SM, starting material.
a Yields in purified products.
Step by step deprotection afforded first 24 in an 83%
yield and then 25 in a 52% yield.
dimethylaminoethyl side chain at the beginning of the
synthesis.
2.3. Synthesis of symmetrical alkylated compounds of
type V
The 5-[2-dimethylamino(ethoxy)]indole 36 was prepared
in a global yield of 54% from 3 by (i) a cleavage of the
benzyl group with BBr3 (ii) an alkylation using 26 and
Cs2CO3 as base (Scheme 5).
Direct alkylation of symmetrical compounds of type V
was performed under Williamson type alkylations
involving the 2-chloroethyl or 3-chloropropyl dimeth-
ylamine hydrochloride salts 26 and 27. In order to di-
rect successfully all the reactions on the two nitrogen
indolic atoms, compound 6 was treated with an excess
of NaH at 0 ꢁC. After 30 min, hydrochlorides 26/27
were added and the temperature adjusted to 100 ꢁC
for the desired time. All results are indicated in Table
1 and Scheme 4. Using a large excess of 26 or 27,
disubstituted compounds 28 and 29were obtained
whereas in the presence of 1.0 equiv of the same re-
agents only mono alkylated products 30 and 31 were
isolated. Cleavages of the residual ether groups were
carried out with BBr3 at room temperature. All alkyl-
ation and deprotection steps were quantitative on
TLC but numerous difficulties appeared during aque-
ous treatment and chromatographic purification,
decreasing also the yields in isolated compounds 28–
35.
The best conditions for obtaining the stannyl derivative
37 were the use of LDA (3 equiv) at ꢀ20 ꢁC followed by
the addition of Bu3SnCl (3.4 equiv) at ꢀ78 ꢁC to rt (60%
yield). A large excess of LDA (4.5 equiv) gave a lower
yield (50%). In spite of our numerous efforts, the Stille
coupling of 37 with 3,5-dibromopyridine gave unfortu-
nately only traces (<4%) of the targeted bis-indole 38.
2.4. Synthesis of disymmetrical alkylated compounds of
type VI
Having in our hands the two main frameworks 24 and
25, the introduction of the 2-dimethylaminoethyl and
3-dimethylaminopropyl residues was tentatively per-
formed on the nitrogen and oxygen atoms simulta-
neously with the corresponding chlorides 26 and 27.
However, despite numerous efforts, all attempts failed.
In contrast, alkylations of the phenol group of the par-
tially protected compounds 19 and 23 were successfully
performed (Scheme 6, Table 2 entries 1–4).
All our efforts concerning the use of fully unprotected
compound 7 in such alkylation reactions or Mitsunobu
reaction using the corresponding alcohol failed. To cir-
cumvent this problem, we decided to introduce the
BnO
O
a
N
R
N
SO2Ph
N
SO2Ph
OBn
BnO
3
36 R = H
37 R = SnBu3
b
N
N
a or b
6
O
O
N
R2
N
R1
c
37
N
28-31
Traces
N
N
OH
HO
PhO2S
SO2Ph
c
N
38
N
N
R 2
Scheme 5. Reagents and conditions: (a) i—BBr3 (1.2 equiv), CH2Cl2,
0 ꢁC to rt, 2 h, 80%; ii—26 (1.2 equiv), Cs2CO3 (2.7 equiv), DMF, rt to
100 ꢁC, 3.5 h, 67%; (b) i—LDA (3 equiv), THF, ꢀ20 ꢁC, 30 min then
Bu3SnCl (3.4 equiv), ꢀ78 ꢁC to rt, 18 h, 60%; (c) Pd(PPh3)4 (0.1 equiv),
CuI (0.2 equiv), THF, reflux, 24 h, traces.
1
R
N
32-35
Scheme 4. Reagents and conditions: see also Table 1.

4936
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
R1
R1
OR2
OH
a or b
N
N
PhO2S
PhO2S
N
39-42
N
19 R1 = H
23 R1 = OBn
)
R2 = (CH2 nN(CH3)2
n =2,3
R1
c
HO
OR2
OR2
d
N
N
H
H
N
N
43-46
47, 48
R1
HO
e
OR2
OR2
f
N
N
R3
R3
N
N
57-60
49-56
Scheme 6. Reagents and conditions: For details see also Table 2.
Table 2. Synthesis of compounds 39–60
Entry Starting material Conditions
Compound R1
R2
R3
—
Yielda (%)
77
1
2
19
19
(a) 26 (1.5 equiv), Cs2CO3 (2.9 equiv), 39
DMF, rt, 2 h
H
H
(CH2)2N(CH3)2
(b) 27 (1.5 equiv), Cs2CO3 (2.9 equiv), 40
DMF, rt, 2 h
(CH2)3N(CH3)2
—
80
3
4
23
23
39
40
41
42
45
46
43
Idem (a) with Cs2CO3 (2.7 equiv), 4 h
Idem (b) with Cs2CO3 (2.7 equiv), 4 h 42
41
OBn (CH2)2N(CH3)2
OBn (CH2)3N(CH3)2
—
—
—
—
—
—
—
—
69
72
64
87
84
85
60
54
5
(c) Bu4NF (1.5 equiv), THF, rflx, 3 h
Idem
43
44
45
46
47
48
49
H
H
(CH2)2N(CH3)2
(CH2)3N(CH3)2
6
7
Idem
Idem
OBn (CH2)2N(CH3)2
OBn (CH2)3N(CH3)2
8
9
(d) BBr3 (1.1 equiv), CH2Cl2, rt, 2 h
Idem
(e) 26 (1.5 equiv), NaH (4 equiv),
OH
OH
H
(CH2)2N(CH3)2
(CH2)3N(CH3)2
10
11
(CH2)2N(CH3)2 (CH2)2N(CH3)2 83
DMF, 100 ꢁC
Idem
Idem
12
13
14
15
16
17
18
19
20
21
22
27
44
44
45
45
46
46
53
54
55
56
50
51
52
53
54
55
56
57
58
59
60
H
H
H
(CH2)2N(CH3)2 (CH2)3N(CH3)2 81
(CH2)3N(CH3)2 (CH2)2N(CH3)2 53
(CH2)3N(CH3)2 (CH2)3N(CH3)2 45
Idem (e) with 27
Idem (e) with 26
Idem (e) with 27
Idem (e) with 26
Idem (e) with 27
(f) BBr3 (1.1 equiv), CH2Cl2, rt, 2 h
Idem
OBn (CH2)2N(CH3)2 (CH2)2N(CH3)2 53
OBn (CH2)2N(CH3)2 (CH2)3N(CH3)2 69
OBn (CH2)3N(CH3)2 (CH2)2N(CH3)2 70
OBn (CH2)3N(CH3)2 (CH2)3N(CH3)2 67
—
—
—
—
(CH2)2N(CH3)2 (CH2)2N(CH3)2 55
(CH2)2N(CH3)2 (CH2)3N(CH3)2 50
(CH2)3N(CH3)2 (CH2)2N(CH3)2 52
(CH2)3N(CH3)2 (CH2)3N(CH3)2 49
Idem
Idem
SM, starting material.
a Yields in purified products.
Mono O-alkylation of 19 or 23 being the only pos-
sibility, we used an excess of the electrophile 26 and
27, in the presence of Cs2CO3 as base to afford 39–
42 in 69–80% yields. The indolic nitrogen atom was
first deprotected using Bu4NF for 2 h in refluxing
THF giving access to 43–46 in fairly good yields
(entries 5–8). As a last step, cleavage of the benzyl
ether groups of 45 and 46 with BBr3 (2.1 equiv)
led to compounds 47 and 48 (entries 9–10). Here
again, all reactions appeared as quantitative on
TLC.
Following a similar strategy, the indolic nitrogen atom
of 43–46 was reacted with the corresponding chlorides
26 and 27 and an excess of NaH in DMF at rt. Com-
pounds 49–56 were thus obtained in 45–83% yields
(entries 11–18). As a final reaction, the O-benzyl
group of 53–56 was cleaved with BBr3 in dichloro-

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4937
methane to afford compounds 57–60in 49–55% yields
(entries 19–22).
In the second mono indolyl series, the size of one of the
pyridine satellites was reduced to a 4-hydroxyphenyl
moiety (entries 6–19). As attempted all the unsubstituted
NH indolic compounds exhibited quantifiable inhibition
of the enzyme (18, 43, 44, 25, 47, and 48, IC50 < 10 lM).
The best activity was found with the unsubstituted com-
pound 25 (IC50 = 0.31 lM, entry 13). Suppression of the
hydroxyl group on the indole ring decreases the activity
(18, entry 6), suggesting that this OH function is essen-
tial for enzyme binding through hydrogen-bonding,
leading to inhibition. The same behavior was observed
by alkylation of the phenol by a hydrophilic chain.
Activities of compounds 43 and (47, 48) were signifi-
cantly reduced by a factor of 5- to 10-fold compared
to 18 and 25, respectively. There is no doubt that the do-
nor/acceptor hydrogen bond system (NH of indole/N of
pyridine) and the two OH groups are key elements for
the kinase inhibition.
3. Results and discussion
Several compounds were evaluated for inhibition of pro-
tein kinases. Cytotoxicity and cell cycle analyses were
also performed. In addition, a molecular modeling study
was performed to support the experimental results of the
best compounds. Kinases activities assays were per-
formed according to our previously published method-
ology (all experimental details were indicated).9
Compounds with two indole rings and N-aminoalkyl
side chains (32–35), which were certainly charged at
physiologic pHs, have no effect on the tested kinases,
whatever the length of the side chain (2 or 3 carbons).
The same is true for the monoindolic compounds
substituted on the indole NH and bearing a phenol
function (49–52, 57–60). In the bis indolic series, the
best activities appeared when all the O- and N- hetero-
atoms were unsubstituted, indicating also the crucial
role of donor/acceptor hydrogen bonds to generate
the CDK binding. Nevertheless compound 7 exhibits
a moderate inhibition of CDK1 with an IC50 of
0.54 lM (Table 3, entry 1). The two indoles should
be also too bulky to give full inhibition of the enzyme
at low concentration. This hypothesis was confirmed
with compounds 34 and 35 bearing an indolic side
chain, which certainly modified the conformation of
the molecule and dramatically decreased the activities
(entries 4–5).
Preliminary information about kinase selectivity was ob-
tained by testing the compounds for inhibition of two
related kinases, CDK5 and GSK-3. Interestingly, the
three most potent molecules 7, 18, and 25 were also
slightly less active toward CDK5. In addition, these
compounds were 30- to 100-fold more active toward
CDK1 versus GSK-3. This excellent selectivity could
be explained by the substitution of the phenol. Addition
of an hydrophilic side chain (i) decreased the inhibition
of CDK1, (ii) enhanced the inhibition of GSK-3, and
(iii) decreased also the selectivity [(43, 44), and (47, 48)
compared to 18 and 25, respectively]. The aminoalkyl
chain should interfere with an hydrophilic pocket in
the ATP site of GSK-3. The observed selectivity of
Table 3. Biological activities
Entry Formula
Compound R1
R2
H
R3
H
CEM CDK1 CDK5 GSK-3 a/
IC50
IC50
IC50
b IC50
R1
R1
1
7
32
33
34
OH
7.99
0.54
1.2
30
2
OH (CH2)2N(CH3)2 (CH2)2N(CH3)2 14.8
OH (CH2)3N(CH3)2 (CH2)3N(CH3)2 11.1
>10
>10
ND
ND
ND
ND
>10
>10
>10
3
N
R3
N
R2
4
OH (CH2)2N(CH3)2
H
5.76 >10
N
7, 32-35
5
6
7
8
35
18
43
44
49
50
51
52
25
47
48
57
58
59
60
OH (CH2)3N(CH3)2
H
H
H
H
H
14.21 >10
>10
>100
4.8
H
4.67
9.02
5.4
0.7
2.5
0.9
H
(CH2)2N(CH3)2
(CH2)3N(CH3)2
3.1
1
H
0.9
31
9
H
(CH2)2N(CH3)2 (CH2)2N(CH3)2
(CH2)2N(CH3)2 (CH2)3N(CH3)2
(CH2)3N(CH3)2 (CH2)2N(CH3)2
(CH2)3N(CH3)2 (CH2)3N(CH3)2
7.97 >10
3.72 >10
4.13 >10
4.19 >10
ND
>10
>10
>10
>10
40
R 1
10
11
12
H
ND
ND
ND
OR2
H
H
OH
N
R3
13
14
15
16
17
18
19
H
H
H
H
14.45
12.33
5.35
0.31
1.5
OH (CH2)2N(CH3)2
OH (CH2)3N(CH3)2
3.6
1.9
6.7
5
4.6
3.8
N
18, 25, 43, 44, 47-52, 57-60
OH (CH2)2N(CH3)2 (CH2)2N(CH3)2 31.94 >10
OH (CH2)2N(CH3)2 (CH2)3N(CH3)2 59.26 >10
OH (CH2)3N(CH3)2 (CH2)2N(CH3)2 20.76 >10
OH (CH2)3N(CH3)2 (CH2)3N(CH3)2 12.67 >10
ND
>10
>10
>10
>10
ND
ND
ND
ND, not determined. All IC50 were expressed in lM and were linked to cytotoxicity for CEM and to kinase inhibition for CDK 1, 5 and GSK-3. IC50
values are averaged from two experiments.

4938
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
our compounds prompted us to investigate further their
binding to the enzyme using molecular modeling.
the ATP pocket of our homology model of human
CDK1 are shown in Figure 3. These compounds have
a similar docking mode and make two key hydrogen-
bonding interactions with the backbone of the kinase
at the hinge region; the NH group of Leu83 donates a
hydrogen bond to the pyridine nitrogen, the carbonyl
oxygen of Leu83 acts as a hydrogen bond acceptor to
the indole nitrogen NH of the inhibitors. This typical
pattern of hydrogen-bonding has previously been ob-
served in the complexes of CDK2 with several inhibi-
tors.19,20 Moreover, the para-phenol moiety is involved
in a hydrogen-bonding interaction with the terminal
amino group of Lys33 and exploit an aromatic stacking
interaction at residue Phe80, located at the bottom of
the pocket. Interestingly, compound 25, which has a hy-
droxyl moiety at the C-5 position of the indole, is more
potent than the parent indole analogue 18. The hydroxyl
group of compound 25 forms three additional hydrogen
bonds with the Asp86 backbone NH and its carboxylic
side chain and with the side chain NH of Lys89, similar
to those observed in other series of CDK inhibitors sug-
gesting an importance of those interactions in binding
affinity (Fig. 3).20–24
3.1. Cytotoxicity
The compounds were evaluated for cytotoxicity using
CEM human leukemia cells. In parallel, we measured
the DNA binding (data not shown) but no strict corre-
lation could be established with the cytotoxicity. IC50
values in the 3–5 lM range were obtained for the best
compounds. A marked cytotoxic effect was also mea-
sured with the CDK1 inhibitor 18, which is more cyto-
toxic than
7 and much more potent than 25.
Nevertheless the inhibition of the tumor cell prolifera-
tion and the cytotoxicity are limited to the micromolar
range. This result is also in agreement with the other
published results,17 which indicate that potent inhibition
of the CDKs led rarely to strong cytotoxic agents.
3.2. Molecular modeling
Several forms of CDK2 have been crystallized in the last
years. In sharp contrast, the 3D structure of CDK1 has
not been reported. As our compounds were evaluated
for biochemical activity against CDK1-cyclin B, we
decided to create a homology model of human CDK1-
cyclin B from the crystal structure of human CDK2-cy-
clin A in complex with indirubin-5-sulfonate.18 Our goal
was to obtain a working model of CDK1 able to illus-
trate some features of the binding of a new class of
inhibitors into the ATP-binding site cavity. Indeed,
molecular modeling studies of the compounds shown
in Table 3 were conducted a posteriori to understand
the observed structure–activity relationships. Sequence
alignment was performed as described in Section 5,
and the results are shown in Figure 2. Sequence identity
between CDK1 and CDK2 is about 65% and reaches
90% within the ATP-binding site.
Replacement of the para-hydroxyl moiety by amin-
oalkyloxy analogues 43, 47, and 48 seems to be detri-
mental for high potency (Table 3). Inspection of the
CDK1/compound 25 complex model can provide an
explanation. The para-phenol moiety is positioned in a
small cavity due to the bulkiness of the Phe80 side chain.
As this part of the binding site appears to be compatible
only with small substituents, sterically encumbering
compounds would be expected to encounter unfavorable
steric interactions with the enzyme. Therefore, the dock-
ing studies suggest a change in binding conformation
compared to compounds 18 and 25 leading to a lack
of a key hydrogen-bonding interaction with the back-
bone carbonyl of Leu83 (Fig. 4). The indole nitrogen
NH is directed toward the backbone carbonyl of residue
Glu81 of the hinge region but the distance is too large
The binding poses found by the docking program
GOLD for the most active compounds 18 and 25 into
˚
(higher than 4 A) to allow the formation of an appropri-
Figure 2. Sequence alignment of human CDK2 and CDK1. Asterisks indicate residues, which are completely conserved in the two sequences.
Residues corresponding to the ATP-binding site are marked in bold red type.

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4939
Figure 3. Docking solutions of compounds 18 and 25 in the ATP-
binding site of the homology model of human CDK1. The hydrogen
bonds are indicated as yellow dotted lines.
Figure 5. Docking solution of compound 7 in the ATP-binding site of
the homology model of human CDK1.
indole ring is involved in a hydrogen bond with the ter-
minal carboxylate group of Asp86 (Fig. 5). The loss of
the interaction with Lys89 could explain the slight de-
crease of the inhibition of CDK1 of 7.
Of particular interest are indoles bearing N-aminoalkyl
groups, which were completely inactive against CDK1
(compounds 49–52, 57–60, and 32–35; Table 3). The
dimension of the pocket in this area constituted of
Phe80, Glu81, and Leu83 (Figs. 4 and 5) is not suitable
to accept bulky substituents, leading to a steric clash.
The result of this steric hindrance is probably the loss of
any hydrogen-bonding interactions at the hinge region
crucial for a good inhibitory activity.
The properties and activities of our compounds have
been characterized in more detail. Inhibitors 18, 25,
and 7 show selectivity for CDK1 over GSK-3 (Table
3). As mentioned before, several potent CDK inhibitors
also inhibit GSK-3, due mainly to the high degree of
homology (ꢁ86%) between the ATP-binding site of the
two kinases.25 Nevertheless, other papers have shown
that specificity among kinases can be achieved utilizing
structural differences of the ATP-binding sites even if
competition with ATP does not seem to be favorable
for high selectivity.26–31 In such case, the gain in selectiv-
ity can be associated with the main differences in the
ATP pocket between the enzymes. Phe80 in CDK1,
the so-called gatekeeper residue, is replaced by Leu132
in GSK-3. Moreover, the negative-charged side chain
of Asp86 is replaced by Thr138 and the positive-charged
side chain of Lys89 by Arg141. Interactions with these
residues have already been mentioned in some papers
and seem to be especially relevant for the binding affin-
ity and selectivity of the ligands.20,32,33 However, only
optimization of this series including further pharmaco-
logical evaluation of selected compounds against a large
panel of functionally diverse kinases are necessary to
confirm this hypothesis.
Figure 4. Docking solutions of compounds 43, 47, and 48 in the ATP-
binding site of the homology model of human CDK1.
ate hydrogen bond (Fig. 4). The reported weak activities
for these compounds are consistent with that
expectation.
As evocated in the kinase inhibition part, we showed
that the bis-indole product 7 was less efficient as its phe-
nol analogue 25, suggesting that the two indoles moie-
ties modified mainly the approach of the inhibitor in
the active site. Modeling of 7 suggests also interactions
analogous to hydrogen bonds between compound 25
and CDK1 (Fig. 5). Precisely, key interactions with
the hinge segment are remarkably conserved by two di-
rect hydrogen bonds with Leu83. Perhaps more impor-
tantly, the hydroxyl group at C-5 position of the

4940
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4. Conclusion
5.1.1. 1-Phenylsulfonyl-5-benzyloxy-2-tributylstannyl-1H-
indole (4). To a solution of 1-phenylsulfonyl-5-benzyloxy-
1H-indole34 3 (1.62 g, 4.48 mmol) in dry THF (25 mL)
under argon at ꢀ20 ꢁC was added dropwise an LDA
solution in hexane (2 M, 3.36 mL, 6.72 mmol). After
30 min stirring at ꢀ20 ꢁC, the resulting red solution was
cooled to ꢀ78 ꢁC and treated with Bu3SnCl (2.06 mL,
7.61 mmol). The mixture was warmed to room tempera-
ture within 2 h under stirring and then hydrolyzed with
water (50 mL). The mixture was extracted with ethyl
acetate (3· 100 mL), the combined organic layers were
successively washed with a saturated solution of KF
(100 mL), water (100 mL) then dried over MgSO4, and fil-
tered. The solvents were removed under reduced pressure
and the crude material was purified by flash chromatogra-
phy (petroleum ether/ethyl acetate 9:1) to afford
compound 4 as a white solid (2.26 g, 78%). Mp:
67–69 ꢁC; Rf (petroleum ether/ethyl acetate 94:6) : 0.68;
IR (KBr, cmꢀ1) m 2955, 2923, 2850, 1605, 1503, 1446,
1365, 1233, 1147, 843, 725; 1H NMR (CDCl3,
250 MHz): d 0.89 (t, 9H, J = 7.1 Hz, 3· CH3), 1.15–1.20
(m, 5H, CH2), 1.25–1.41 (m, 7H, CH2), 1.49–1.59 (m,
6H, CH2), 5.05 (s, 2H, OCH2), 6.73 (s, 1H, H3), 6.88
(dd, 1H, J = 2.4 Hz, J = 8.9 Hz, H6), 7.02 (d, 1H,
J = 2.4 Hz, H4), 7.30–7.60 (m, 8H, Harom), 7.59–7.62
(m, 3H, Harom), 7.72 (d, 1H, J = 8.9 Hz, H7); 13C NMR
(CDCl3, 62.5 MHz): d 11.9 (3· CH2), 13.8 (3· CH3),
27.5 (3· CH2), 29.1 (3· CH2), 70.6 (CH2), 103.9
(CH), 113.8 (CH), 114.5 (CH), 120.7 (CH), 126.3 (2·
CH), 127.6 (2· CH), 128.0 (CH), 128.7 (2· CH), 129.1
(2· CH), 133.0 (Cq), 133.4 (CH), 133.5 (Cq), 137.3
(Cq), 139.5 (Cq), 144.7 (Cq), 155.5 (Cq); MS (IS): 654
(M+1)+.
We have synthesized a novel series of mono- and bis-in-
dole-pyridine derivatives via an efficient widely, applica-
ble chemical procedure. Concerning their mechanism of
action, two major conclusions can be drawn from this
study. First, a number of DNA-binding ligands were
identified, in particular those bearing one or two cat-
ionic side chains. In terms of DNA recognition, the most
interesting molecule is compound 33, which behaves as a
conventional DNA minor groove binder. Indeed, circu-
lar dichroism experiments revealed that this molecule
exhibits a positive CD at 345 nm upon complex forma-
tion with DNA and footprinting studies indicated pref-
erential binding to some AT-rich sequences. A binding
affinity of 6.8 · 105 Mꢀ1 was measured with this com-
pound (data not shown) but it showed only a modest
cytotoxic effect and did not affect the cell cycle of
CEM leukemia cells. Second, we have identified and
characterized three CDK1 inhibitors: 7, 18, and 25,
which exhibit selectivity over GSK-3. A docking study
performed with a homology model for human CDK1
strongly suggests that these compounds can fit into the
ATP pocket of the enzyme. Several potential hydrogen
bonds have been identified. This study may be very help-
ful to guide the rational design of more potent CDK1
targeted therapeutic agents. For example, based on the
suggested binding mode of these compounds, structural
modifications could be carried out toward the surface-
exposed front area or the ribose pocket.
5. Experimental
5.1. Chemistry
5.1.2. 3,5-Bis(1-phenylsulfonyl-5-benzyloxy-1H-indole) pyr-
A solution of compound 4 (730 mg,
idine (5).
1H and 13C NMR spectra were recorded on a Bruker
250 Avance instrument using CDCl3 or DMSO-d6.
Chemical shifts are reported in ppm (d scale) and all J
values are in Hz. The following abbreviations are used:
singlet (s), doublet (d), doubled doublet (dd), triplet (t),
quintuplet (qt), multiplet (m), quaternary carbon (Cq).
Melting points are uncorrected. IR absorptions were re-
corded on a Perkin Elmer PARAGON 1000 PC or on
Avatar 320 using an ATR (Ge) technique and values
were reported in cmꢀ1. MS spectra (Ion Spray) were per-
formed on a Perkin Elmer Sciex PI 300. Monitoring of
the reactions was performed using silica gel TLC plates
(silica Merck 60 F254). Spots were visualized by UV light
at 254 and 356 nm. Flash chromatography columns
were performed using silica gel 60 (0.063–0.200 mm,
Merck) (Scheme 7).
1.12 mmol), 3,5-dibromopyridine (115 mg, 0.49 mmol)
and CuI (19 mg, 0.097 mmol) in dry THF (15 mL)
was degassed by argon bubbling for 30 min Pd(PPh3)4
(10% mol, 56 mg, 0.049 mmol) was then added and the
mixture was immediately transferred to a pre-heated oil
bath and was refluxed for 8 h. After hydrolysis
(20 mL), the mixture was extracted with ethyl acetate
(3 · 20 mL), washed with brine (20 mL) then dried over
MgSO4, and filtered. The solvents were removed under
reduced pressure and the crude material was purified
by flash chromatography (petroleum ether/ethyl acetate
7:3) to afford compound 5 as a red solid (346 mg,
89%). Mp: 211–213 ꢁC; Rf (petroleum ether/ethyl
acetate 1:1): 0.62; IR (KBr, cmꢀ1) m 3444, 2370, 1609,
1
1448, 1368, 1177, 1147, 1023, 686; H NMR (CDCl3,
250 MHz): d 5.08 (s, 4H, 2· OCH2), 6.67 (s, 2H, H3),
7.00 (d, 2H, J = 2.4 Hz, H4), 7.09 (dd, 2H,
J = 2.4 Hz, J = 9.1 Hz, H6), 7.27–7.47 (m, 2H, Harom),
8.19 (s, 1H, H4 ), 8.22 (d, 2H, J = 9.1 Hz, H7); 13C
0
R'
3"
NMR (CDCl3, 62.5 MHz): d 70.6 (2· CH2), 104.9
(2· CH), 115.4 (CH), 117.8 (2· CH), 126.0 (2· CH),
126.9 (2· CH), 127.6 (8· CH), 128.2 (2· CH), 128.8
(8· CH), 129.1 (2· CH), 131.7 (2· Cq), 133.4 (2·
Cq), 134.0 (2· CH), 136.7 (2· Cq), 136.9 (4· Cq),
156.6 (4· Cq); MS (IS): 802 (M+1)+; Anal. Calcd for
C47H35N3O6S2: C 70.39, H 4.40, N 5.24. Found: C
70.73, H 4.56, N 5.12.
3"
2"
2"
4
4'
3
5
2 '
6
1 N
N
6'
7
R
Scheme 7. Atom labeling scheme for NMR spectra.

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4941
0
0
0
5.1.3. 3,5-Bis(5-benzyloxy-1H-indole)pyridine (6). To a
solution of compound 5 (400 mg, 0.50 mmol) in dry
THF (20 mL), a solution of Bu4NF in dry THF (1 M,
2.50 mL, 2.50 mmol) was added. The solution was stir-
red to reflux for 2.5 h and the reaction mixture was con-
centrated under reduced pressure. After hydrolysis
(20 mL), the mixture was extracted with ethyl acetate
(3 · 20 mL), washed with brine (20 mL) then dried over
MgSO4, and filtered. The solvents were removed under
reduced pressure and the crude material was purified
by flash chromatography (petroleum ether/ethyl acetate
2:8) to afford compound 6 as a yellow solid (230 mg,
74%). Mp: 209–211 ꢁC; Rf (petroleum ether/ethyl acetate
1:1): 0.17; IR (KBr, cmꢀ1) m 3444, 2904, 1619, 1578,
H4 ), 8.81 (s, 2H, H2 , H6 ), 9.51 (s large, 2H, 2· OH);
13C NMR (CDCl3, 62.5 MHz): d 106.0 (2· CH), 114.7
(2· CH), 116.4 (2· CH), 117.2 (2· CH), 126.4 (4·
CH), 127.3 (2· Cq), 129.3 (4· CH), 131.3 (2· Cq),
131.8 (2· Cq), 134.4 (2· CH), 135.4 (2· Cq), 137.3
(CH), 138.4 (2· Cq), 149.0 (2· CH), 155.0 (2· Cq);
MS (IS): 622 (M+1)+; Anal. Calcd for C33H23N3O6S2:
C 63.76, H 3.73, N 6.76. Found: C 64.02, H 3.58, N 6.89.
5.1.6. 1-Phenylsulfonyl-2-tributylstannyl-1H-indole (11).
To a solution of 1-phenylsulfonyl-1H-indole (5 g,
19.43 mmol) in dry THF (70 mL) under argon at
ꢀ20 ꢁC was added dropwise a solution of LDA in dry
THF (2 M, 14.6 mL, 29.15 mmol). After 30 min at
ꢀ20 ꢁC, the resulting red solution was cooled to ꢀ78 ꢁC
and treated with Bu3SnCl (8.97 mL, 33.07 mmol). The
mixture was warmed up to room temperature within 2 h
and then hydrolyzed with cold water (100 mL). The mix-
ture was extracted with ethyl acetate (3· 100 mL), the
combined organic layers were successively washed with
a saturated solution of KF (100 mL), water (100 mL) then
dried over MgSO4, and filtered. The solvents were re-
moved under reduced pressure and the crude material
was purified by flash chromatography (petroleum ether/
ethyl acetate 9:1) to afford compound 11 as a pale brown
oil (9.00 g, 85%), which was conserved by freezing under
argon and rapidly used. Rf (ether petroleum/ethyl acetate
9:1): 0.68; IR (NaCl, cmꢀ1) m 2962, 2923, 2853, 1465, 1361,
1228, 1169, 1129, 1092, 747, 727; 1H NMR (CDCl3,
250 MHz): d 0.89 (t, 9H, J = 7.0 Hz, 3· CH3), 1.16–1.20
(m, 5H, CH2), 1.25–1.43 (m, 7H, CH2), 1.50–1.66 (m,
6H, CH2), 6.82 (s, 1H, H3), 7.17 (m, 2H, Harom), 7.38
(m, 2H, Harom), 7.45–7.51 (m, 2H, Harom), 7.63 (m, 2H,
Harom), 7.80–7.83 (m, 1H, Harom); 13C NMR (CDCl3,
62.5 MHz): d 11.9 (3· CH2), 13.8 (3· CH3), 27.4 (3·
CH2), 29.1 (3· CH2), 113.7 (CH), 120.4 (CH), 120.7
(CH), 123.1 (CH), 124.0 (CH), 126.3 (2· CH), 129.1 (2·
CH), 133.2 (Cq), 133.4 (CH), 138.5 (Cq), 139.4 (Cq),
143.6 (Cq); MS (IS): 546 (M+1)+.
1
1483, 1451, 1295, 1206, 1135, 1015, 845, 794; H NMR
(CDCl3, 250 MHz): d 5.09 (s, 4H, 2· OCH2), 6.79 (s,
2H, H3), 6.97 (dd, 2H, J = 1.6 Hz, J = 8.3 Hz, H6),
7.14 (d, 2H, J = 1.6 Hz, H4), 7.29–7.49 (m, 13H, Harom),
8.04 (s, 1H, H4 ), 8.71 (br s, 3H); 13C NMR (CDCl3,
0
62.5 MHz): d 70.9 (2· CH2), 101.5 (2· CH), 104.0 (2·
CH), 112.2 (2· CH), 114.5 (2· CH), 126.0 (2· CH),
127.7 (4· CH), 128.0 (2· CH), 128.7 (4· CH), 128.8
(2· Cq), 129.5 (2· Cq), 132.9 (2· Cq), 134.9 (2· Cq),
137.6 (2· Cq), 144.6 (CH), 154.0 (2· Cq); MS (IS):
522 (M+1)+; Anal. Calcd for C35H27N3O2: C 80.59, H
5.22, N 8.06. Found: C 80.18, H 5.13, N 8.19.
5.1.4. 3,5-Bis(5-hydroxy-1H-indol)pyridine (7). To a
solution of compound 6 (230 mg, 0.44 mmol) in CH2Cl2
(15 mL) at 0 ꢁC, a solution of BBr3 in CH2Cl2 (1 M,
0.92 mL, 0.92 mmol) was added dropwise. After 3 h at
room temperature, the reaction mixture was poured into
ice (50 g), extracted with ethyl acetate (2· 50 mL) then
dried over MgSO4 and filtered. The solvents were re-
moved under reduced pressure and the crude material
was purified by flash chromatography (dichlorometh-
ane/methanol 9:1) to afford compound 7 as a yellow so-
lid (50 mg, 33%). Mp: 150–152 ꢁC; Rf (dichloromethane/
methanol 9:1): 0.30; IR (KBr, cmꢀ1) m 3422, 3270, 2955,
1636, 1625, 1560, 1458, 1372, 1200, 783; 1H NMR
(DMSO-d6, 250 MHz): d 6.69 (dd, 2H, J = 2.2 Hz,
J = 8.5 Hz, H6), 6.89 (d, 2H, J = 2.2 Hz, H4), 6.95 (d,
2H, J = 1.4 Hz, H3), 7.25 (d, 2H, J = 8.7 Hz, H7), 8.58
5.1.7. 1-Phenylsulfonyl-2-(5-bromopyridin-3-yl)-1H-indole
(12). Same procedure as described for compound 5 start-
ing from compound 11 and 3,5-dibromopyridine
(1.05 equiv). Compound 12 was purified by flash chro-
matography (petroleum ether/ethyl acetate 7:3) and
isolated as an orange solid (88%). Mp: 153–155 ꢁC; Rf
(petroleum ether/ethyl acetate 7:3): 0.36; IR (KBr,
cmꢀ1) m 1561, 1448, 1373, 1172, 1059, 987, 835, 724;
1H NMR (CDCl3, 250 MHz): d 5.97 (s, 1H, H3), 7.31–
0
(s, 1H, H4 ), 8.75 (s, 2H, 2· OH), 8.92 (d, 2H,
J = 2.0 Hz, H2 , H6 ), 11.41 (s, 2H, 2· NH); 13C NMR
(DMSO-d6, 62.5 MHz): d 99.5 (2· CH), 103.4 (2·
CH), 111.8 (2· CH), 112.8 (2· CH), 128.3 (2· Cq),
129.2 (2· CH), 132.0 (2· Cq), 134.6 (2· Cq), 139.2 (2·
Cq), 144.1 (CH), 151.1 (2· Cq); MS (IS): 342 (M+1)+;
Anal. Calcd for C21H15N3O2: C 73.89, H 4.43, N
12.31. Found: C 74.07, H 4.52, N 12.18.
0
0
0
7.51 (m, 8H, Harom), 8.01 (t, 1H, J = 1.8 Hz, H4 ), 8.32
0
(d, 1H, J = 8.3 Hz, H7), 8.57 (d, 1H, J = 1.8 Hz, H2 ),
0
8.73 (d, 1H, J = 2.1 Hz, H6 ); 13C NMR (CDCl3,
5.1.5. 3,5-Bis(1-phenylsulfonyl-5-hydroxy-1H-indol) pyri-
dine (8). Same procedure as described for compound 7
starting from compound 5 and BBr3 (7 equiv). Com-
pound 8 was purified by flash chromatography (dichlo-
romethane/methanol 9:1) and isolated as a white solid
(68%). Mp: 164–166 ꢁC; Rf (ethyl acetate/petroleum
ether 1:1): 0.10; IR (KBr, cmꢀ1) m 3388, 1611, 1448,
1366, 1371, 1207, 1175, 1089, 723, 685; 1H NMR
(CDCl3, 250 MHz): d 6.87–6.91 (m, 4H, Harom), 6.99
(s, 2H, H3), 7.43–7.45 (m, 8H, Harom), 7.57–7.62 (m,
2H, Harom), 7.96 (d, 2H, J = 8.5 Hz, H7), 8.15 (s, 1H,
62.5 MHz): d 115.6 (CH), 116.6 (CH), 119.7 (Cq),
121.4 (CH), 124.9 (CH), 125.9 (CH), 126.6 (2· CH),
129.0 (2· CH), 130.1 (2· Cq), 134.1 (CH), 136.4 (Cq),
137.3 (Cq), 138.5 (Cq), 140.3 (CH), 147.9 (CH), 150.7
(CH); MS (IS): 413 (M+1, 79Br)+ and 415 (M+1,
81Br)+; Anal. Calcd for C19H13BrN2O2S: C 55.22, H
3.17, N 6.78. Found: C 55.57, H 3.03, N 6.63.
5.1.8. 1-Phenylsulfonyl-5-benzyloxy-2-(5-bromopyridin-
3-yl)-1H-indole (13). Same procedure as described for
compound 5 starting from compound 4 and 3,5-dib-

4942
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
romopyridine (1.05 equiv). Compound 13 was purified
by flash chromatography (petroleum ether/ethyl acetate
7:3) and isolated as a yellow solid (78%). Mp: 84–86 ꢁC;
Rf (petroleum ether/ethyl acetate 1:1): 0.72; IR (KBr,
cmꢀ1) m 3416, 1609, 1473, 1447, 1371, 1207, 1184,
(m, 4H, Harom), 7.29–7.45 (m, 12H, Harom), 7.61 (d,
00
2H, J = 8.5 Hz, H2 ), 8.03 (t, 1H, J = 2.1 Hz, H4 ), 8.24
0
0
(d, 1H, J = 8.9 Hz, H7), 8.51 (d, 1H, J = 1.8 Hz, H6 ),
0
8.85 (d, 1H, J = 2.1 Hz, H2 ); 13C NMR (CDCl3,
62.5 MHz): d 55.4 (CH3), 70.5 (CH2), 104.7 (CH),
114.7 (2· CH), 114.9 (CH), 115.0 (CH), 117.7 (CH),
126.6 (2· CH), 127.5 (2· CH), 128.1 (CH), 128.3 (Cq),
128.4 (2· CH), 128.6 (2· CH), 128.8 (2· CH), 129.7
(Cq), 131.4 (Cq), 133.2 (Cq), 133.8 (CH), 134.9 (Cq).
(Cq), 136.3 (CH), 136.9 (Cq), 137.1 (Cq), 139.1 (Cq),
147.4 (CH), 147.8 (CH), 156.5 (Cq), 160.1 (Cq); MS
(IS): 547 (M+1)+; Anal. Calcd for C33H26N2O4S: C
72.51; H 4.79, N 5.12. Found: C 72.83, H 4.62, N 5.30.
1
1089, 1019, 869, 723; H NMR (CDCl3, 250 MHz): d
5.06 (s, 2H, 2· OH), 6.54 (s, 1H, H3), 6.97 (d, 1H,
J = 2.3 Hz, H4), 7.09 (dd, 1H, J = 2.6 Hz, J = 9.1 Hz,
H6), 7.24–7.48 (m, 10H, Harom), 7.99 (t, 1H,
J = 2.1 Hz, H4), 8.19 (d, 1H, J = 9.1 Hz, H7), 8.57 (d,
1H, J = 1.8 Hz, H2 ), 8.70 (d, 1H, J = 2.1 Hz, H6 ); 13C
NMR (CDCl3, 62.5 MHz): d 70.6 (CH2), 104.8 (CH),
115.5 (CH), 115.9 (CH), 117.7 (CH), 126.6 (2· CH),
127.6 (2· CH), 128.2 (CH), 128.7 (2· CH), 129.0 (2·
CH), 131.2 (2· Cq), 133.2 (Cq), 134.0 (CH), 136.8 (2·
Cq), 137.0 (Cq), 137.3 (Cq), 140.3 (CH), 147.8 (CH),
150.7 (CH), 156.6 (Cq); MS (IS): 519 [M+1, 79Br] and
521 [M+1, 81Br]; Anal. Calcd for C26H19BrN2O3S: C
60.12, H 3.69, N 5.39. Found: C 59.75, H 3.87, N 5.54.
0
0
5.1.11. 2-[5-(4-Methoxyphenyl)-pyridin-3-yl]-1H-indole (16).
Same procedure as described for compound 6starting
from compound 14 (1.22 g, 2.78 mmol) and Bu4NF
(3.5 equiv). The mixture was refluxed for 2 h. Compound
16 was purified by flash chromatography (petroleum
ether/ethyl acetate 4:6) and isolated as a white solid
(83%). Mp: 209–211 ꢁC; Rf (petroleum ether/ethyl acetate
6:4): 0.46; IR (KBr, cmꢀ1) m 3418, 1596, 1515, 1455, 1249,
1184, 1027, 837, 803; 1H NMR (DMSO-d6, 250 MHz): d
3.83 (s, 3H, CH3), 7.00–7.18 (m, 5H, Harom), 7.45 (d,
1H, J = 7.8 Hz, H4), 7.58 (d, 1H, J = 7.8 Hz, H7), 7.81
5.1.9. 1-Phenylsulfonyl-2-[5-(4-methoxyphenyl)-pyridin-
3-yl]-1H-indole (14). A solution of compound 12 (2 g,
4.84 mmol) and 4-methoxyphenylboronic acid (888 mg,
5.81 mmol) in a mixture of toluene (80 mL), ethanol
(48 mL), and aqueous saturated NaHCO3 solution
(32 mL) was degassed by argon bubbling for 30 min
Pd(PPh3)4 (10% mol, 0.48 mmol) was added and the
mixture was immediately transferred to a pre-heated
oil bath and was refluxed for 18 h. After hydrolysis
(150 mL), the mixture was extracted with ethyl acetate
(2· 150 mL), washed with brine (150 mL) then dried
over MgSO4, and filtered. The solvents were removed
under reduced pressure and the crude material was puri-
fied by flash chromatography (petroleum ether/ethyl
acetate 1:1) to afford compound 14 as a white solid
(1.45 g, 97%). Mp: 161–163 ꢁC; Rf (ether petroleum/
ethyl acetate 1:1): 0.59; IR (KBr, cmꢀ1) m 1608, 1515,
00
(d, 2H, J = 8.5 Hz, H2 ), 8.47 (t, 1H, J = 1.9 H, H4 ),
0
0
8.78 (d, 1H, J = 1.9 Hz, H6 ), 9.05 (d, 1H, J = 1.9 Hz,
0
H2 ), 11.74 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz): d 55.3 (CH3), 100.1 (CH), 111.4 (CH), 114.6
(2· CH), 119.6 (CH), 120.3 (CH), 122.2 (CH), 128.1
(Cq), 128.2 (2· CH), 128.5 (Cq), 129.0 (Cq), 129.1
(CH), 134.5 (Cq), 135.2 (Cq), 137.3 (Cq), 144.6 (CH),
145.6 (CH), 159.6 (Cq); MS (IS): 301 (M+1)+; Anal. Calcd
for C20H16N2O: C 79.98; H 5.37, N 9.33. Found: C 80.24,
H 5.25, N 9.18.
5.1.12. 5-Benzyloxy-2-[5-(4-methoxyphenyl)pyridin-3-yl]-
1H-indole (17). Same procedure as described for com-
pound 6 starting from compound 15 and Bu4NF
(1.5 equiv). The mixture was refluxed for 2 h. Com-
pound 17 was purified by flash chromatography (petro-
leum ether/ethyl acetate 1:1) and isolated as a white solid
(99%). Mp: 164–166 ꢁC; Rf (petroleum ether/ethyl ace-
tate 1:1): 0.54; IR (KBr, cmꢀ1) m 3450, 2942, 1608,
1515, 1455, 1284, 1241, 1184, 1060, 801; 1H NMR
(CDCl3, 250 MHz): d 3.86 (s, 3H, CH3), 5.12 (s, 2H,
OCH2), 6.85 (s, 1H, H3), 6.95–7.04 (m, 3H, Harom),
7.18 (d, 1H, J = 1.8 Hz, H4), 7.31–7.57 (m, 8H, Harom),
1
1430, 1369, 1250, 1172, 1025, 825; H NMR (CDCl3,
250 MHz): d 3.86 (s, 3H, CH3), 6.67 (s, 1H, H3), 7.03
00
(d, 2H, J = 8.8 Hz, H3 ), 7.22–7.50 (m, 8H, Harom),
0
7.60 (d, 2H, J = 8.6 Hz, H2 ), 8.06 (t, 1H, J = 2.1 Hz,
0
0
H4 ), 8.34 (d, 1H, J = 8.3 Hz, H7), 8.53 (s, 1H, H6 ),
0
8.86 (s, 1H, H2 ); 13C NMR (CDCl3, 62.5 MHz): d
55.4 (CH3), 114.7 (CH), 114.8 (CH), 116.6 (CH), 121.2
(CH), 124.7 (CH), 125.5 (Cq), 125.9 (2· CH), 126.6
(2· CH), 128.5 (2· CH), 128.9 (2· CH), 129.7 (Cq),
130.3 (Cq), 133.9 (CH), 135.0 (Cq), 136.5 (CH), 137.4
(Cq), 138.2 (Cq), 138.5 (Cq), 147.5 (CH), 147.8 (CH),
160.0 (Cq); MS (IS): 441 (M+1)+; Anal. Calcd for
C26H20N2O3S: C 70.89, H 4.58, N 6.36. Found: C
70.54, H 4.73, N 6.54.
0
8.04 (t, 1H, J = 2.1 Hz, H4 ), 8.71 (d, 1H, J = 1.8 Hz,
0
H6 ), 8.80 (s large, 1H, NH), 8.86 (d, 1H, J = 1.8 Hz,
0
H2 ); 13C NMR (CDCl3, 62.5 MHz): d 55.5 (CH3),
71.0 (CH2), 101.4 (CH), 104.0 (CH), 112.0 (CH), 114.3
(CH), 114.8 (2· CH), 126.0 (CH), 127.7 (2· CH),
128.0 (Cq), 128.4 (2· CH), 128.7 (2· CH), 129.6 (Cq),
129.9 (Cq), 130.3 (CH), 132.8 (Cq), 135.3 (Cq), 136.7
(Cq), 137.7 (Cq), 144.4 (CH), 146.7 (CH), 154.0 (Cq),
160.1 (Cq); MS (IS): 407 (M+1)+; Anal. Calcd for
C27H22N2O2: C 79.78, H 5.46, N 6.89. Found: C
80.05, H 5.33, N 6.98.
5.1.10. 1-Phenylsulfonyl-5-benzyloxy-2-[5-(4-methoxy phe-
nyl)-pyridin-3-yl]-1H-indole (15). Same procedure as de-
scribed for compound 14 starting from compound 13
and 4-methoxyphenylboronic acid (1.2 equiv). Com-
pound 15 was purified by flash chromatography (petro-
leum ether/ethyl acetate 1:1 to 7:3) and isolated as a
white solid (81%). Mp: 184–186 ꢁC; Rf (ether petro-
leum/ethyl acetate 6:4): 0.19; IR (KBr, cmꢀ1) m 3430,
1609, 1515, 1448, 1371, 1251, 1181, 1089, 1025, 831,
725; 1H NMR (CDCl3, 250 MHz): d 3.87 (s, 3H,
CH3), 5.08 (s, 2H, OCH2), 6.59 (s, 1H, H3), 6.99–7.11
5.1.13. 5-(1H-Indol-2-yl)pyridin-3-yl]phenol (18). A solu-
tion of compound 16 (200 mg, 0.67 mmol) in HBr
(10 mL, 47% in acetic acid) was refluxed for 5 h. The

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4943
reaction mixture was cooled to room temperature, neu-
tralized with an aqueous saturated NaHCO3 solution,
and extracted with ethyl acetate (3 · 20 mL) then dried
over MgSO4, and filtered. The solvents were removed
under reduced pressure and the crude material was puri-
fied by flash chromatography (ethyl acetate/petroleum
ether 1:1) to afford compound 18 as a white solid
(191 mg, 83%). Mp: >250 ꢁC; Rf (ethyl acetate/petro-
leum ether 6:4): 0.45; IR (KBr, cmꢀ1) m 3390, 3367,
2576, 1597, 1518, 1445, 1269, 837, 803; 1H NMR
5.1.16. 4-(5-Bromopyridin-3-yl)phenol (21). Same proce-
dure as described for compound 7 starting from com-
pound 20 (1.10 g, 4.16 mmol) and BBr3 (3.2 equiv).
Compound 21 was purified by flash chromatography
(petroleum ether/ethyl acetate 7:3) and isolated as a
white solid (99%). Mp: >250 ꢁC; Rf (petroleum ether/
ethyl acetate 7:3): 0.27; IR (KBr, cmꢀ1) m 3514, 3089,
1607, 1553, 1442, 1273, 1182, 1067, 836; 1H NMR
0
(DMSO-d6, 250 MHz): d 6.97 (d, 2H, J = 8.5 Hz, H3 ),
0
7.70 (d, 2H, J = 8.7 Hz, H2 ), 9.09 (s, 1H, H4), 9.35 (s,
(DMSO-d6, 250 MHz): d 6.93 (d, 2H, J = 8.6 Hz, H3 ),
1H, H6), 9.46 (s, 1H, H2), 10.16 (s large, 1H, OH); 13C
NMR (DMSO-d6, 62.5 MHz): d 116.6 (2· CH), 122.9
(Cq), 129.1 (2· CH), 140.0 (CH), 140.9 (Cq), 142.8
(CH), 144.5 (CH), 159.8 (2· Cq); MS (IS): 250 (M+1,
79Br) and 252 (M+1, 81Br); Anal. Calcd for
C11H8BrNO: C 52.83, H 3.22, N 5.60. Found: C
52.48, H 3.40, N 5.46.
00
7.00–7.17 (m, 4H, Harom), 7.44 (d, 1H, J = 7.9 Hz, H4),
7.57 (d, 1H, J = 7.6 Hz, H7), 7.68 (d, 2H, J = 8.4 Hz,
00
0
0
H2 ), 8.43 (s, 1H, H4 ), 8.73 (s, 1H, H6 ), 9.00 (s, 1H,
0
H2 ), 11.75 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz): d 100.0 (CH), 111.4 (CH), 116.0 (2· CH),
119.6 (CH), 120.3 (CH), 122.1 (CH), 127.4 (Cq), 128.0
(Cq), 128.2 (2· CH), 128.5 (Cq), 128.8 (CH), 134.6
(Cq), 135.6 (Cq), 137.3 (Cq), 144.3 (CH), 145.5 (CH),
157.9 (Cq); MS (IS): 287 (M+1)+; Anal. Calcd for
C19H14N2O: C 79.70, H 4.93, N 9.78. Found: C 79.43,
H 4.86, N 9.93.
5.1.17. {2-[4-(5-Bromopyridin-3-yl)phenoxy]-ethyl}dimethyl-
amine (22). To a solution of 4-(5-bromo-pyridin-3-
yl)-phenol21 in dry DMF (30 mL), Cs2CO3 (1.72 g,
5.28 mmol) was added under argon at room temperature.
At the same time, a solution of 2-chloroethyldimethyl-
amine hydrochloride 26 (950 mg, 6.60 mmol) in DMF
(30 mL) was stirred in the presence of Cs2CO3 (2.44 g,
7.48 mmol). After 30 min, this solution was added to
the solution containing the 4-(5-bromo-pyridin-3-yl)-
phenol 21. The mixture was heated to 100 ꢁC for 8 h. After
cooling to room temperature, hydrolysis was performed
with water (100 mL) and the reaction mixture was
extracted with ethyl acetate (3· 100 mL) then dried
over MgSO4, and filtered. The solvents were removed
under reduced pressure and the crude material was
purified by flash chromatography (dichloromethane/
methanol/triethylamine 9:1:0.01) to afford compound
22 as a white solid (800 mg, 57%). Mp: 97–99 ꢁC; Rf
5.1.14. 4-[5-(1-Phenylsulfonyl-1H-indol-2-yl)pyridin-3-yl]phe-
nol (19). Same procedure as described for compound 7
starting from compound 14 (1.44 g, 3.28 mmol) and
BBr3 (4.2 equiv). Compound 19 was purified by flash
chromatography (ethyl acetate/petroleum ether 1:1)
and isolated as a white solid (77%). Mp: 119–121 ꢁC;
Rf (ethyl acetate/petroleum ether 1:1): 0.64; IR (KBr,
cmꢀ1) m 3054, 1610, 1517, 1447, 1371, 1175, 1270,
1
831; H NMR (CDCl3, 250 MHz): d 4.41 (s, 1H, OH),
00
6.88 (s, 1H, H3), 7.07 (d, 2H, J = 8.5 Hz, H3 ),
7.33–7.63 (m, 9H, Harom), 8.37 (d, 2H, J = 8.5 Hz,
00
0
0
H2 ), 8.63 (s, 1H, H4 ), 9.32 (s, 1H, H2 ), 9.75 (s, 1H,
0
H6 ); 13C NMR (CDCl3, 62.5 MHz): d 114.8 (CH),
114.9 (CH), 116.6 (CH), 116.7 (CH), 121.2
(CH), 124.8 (CH), 125.7 (CH), 126.7 (2· CH), 128.6
(CH), 128.7 (CH), 129.0 (2· CH), 129.6 (Cq), 130.3
(2· Cq), 134.0 (CH), 136.9 (CH), 137.5 (Cq), 138.1
(Cq), 138.6 (Cq), 147.1 (CH), 147.5 (CH), 157.8 (Cq),
160.2 (Cq); MS (IS): 427 (M+1)+; Anal. Calcd for
C25H18N2O3S: C 70.41, H 4.25, N 6.57. Found: C
70.02, H 4.37, N 6.46.
(dichloromethane/methanol/triethylamine
9:1:0.01):
0.40; IR (KBr, cmꢀ1) m 3444, 2940, 2766, 2366, 1607,
1509, 1436, 1234, 1192, 1044, 1002, 837; 1H NMR
(CDCl3, 250 MHz): d 2.91 (s, 6H, 2· CH3), 3.47 (t,
2H, J = 4.2 Hz, CH2), 4.56 (t, 2H, J = 4.5 Hz, CH2),
0
7.04 (d, 2H, J = 8.7 Hz, H3 ), 7.51 (d, 2H, J = 8.7 Hz,
0
H2 ), 7.97 (s, 1H, H4), 8.62 (s, 1H, H6), 8.70 (s, 1H, H2);
13C NMR (CDCl3, 62.5 MHz): d 45.6 (2· CH3),
57.9 (CH2), 65.7 (CH2), 115.2 (2· CH), 120.8 (Cq),
128.2 (2· CH), 128.6 (Cq), 136.2 (CH), 137.8 (Cq),
145.8 (CH), 148.5 (CH), 159.2 (Cq); MS (IS): 321 (M+1,
79Br) and 323 (M+1, 81Br); Anal. Calcd for
C15H17BrN2O: C 56.09, H 5.33, N 8.72. Found: C
56.32, H 5.18, N 8.65.
5.1.15. 3-Bromo-5-(4-methoxyphenyl)pyridine (20).35
Same procedure as described for compound 14 starting
from 3,5-dibromopyridine 1 (3 g, 12.66 mmol) and 4-
methoxyphenylboronic acid (0.95 equiv). Compound
20 was purified by flash chromatography (petroleum
ether/ethyl acetate 7:3) and isolated as a white solid
(77%). Mp: 119–121 ꢁC Rf (petroleum ether/ethyl ace-
tate 7/ 3): 0.49; IR (KBr, cmꢀ1) m 3021, 1608, 1510,
5.1.18. 4-[5-(1-Phenylsulfonyl-5-benzyloxy-1H-indol-2-
yl)pyridin-3-yl]phenol (23). Same procedure as described
for compound 5 starting from 4-(5-bromo-pyridin-3-yl)-
phenol 21 (1 g, 4.00 mmol) and compound 4 (1.5 equiv).
The reaction mixture was refluxed for 4 h. Compound
23 was purified by flash chromatography (petroleum
ether/ethyl acetate 7:3) and isolated as a white solid
(33%). Mp: 143–145 ꢁC; Rf (petroleum ether/ethyl ace-
tate 7:3): 0.43; IR (KBr, cmꢀ1) m 3440, 3090, 1609,
1518, 1448, 1371, 1247, 1182, 1152, 1090, 1039, 831,
1
1428, 1248, 1184, 1024, 1015, 840; H NMR (CDCl3,
0
250 MHz): d 7.01 (dd, 2H, J = 2.2 Hz, J = 6.5 Hz, H3 ),
0
7.50 (dd, 2H, J = 2.2 Hz, J = 6.7 Hz, H2 ), 7.97 (t, 1H,
J = 2.2 Hz, H4), 8.60 (d, 1H, J = 2.2 Hz, H6), 8.72 (d,
1H, J = 1.8 Hz, H2); 13C NMR (CDCl3, 62.5 MHz): d
55.3 (CH3), 114.6 (2· CH), 120.8 (Cq), 120.8 (2· CH),
128.4 (Cq), 136.1 (CH), 137.7 (Cq), 145.9 (CH), 148.6
(CH), 160.1 (Cq); MS (IS): 264 (M+1, 79Br) and 266
(M+1, 81Br); Anal. Calcd for C12H10BrNO: C 54.57,
H 3.82, N 5.30. Found: C 54.13, H 3.98, N 5.17.
1
799, 729; H NMR (CDCl3, 250 MHz): d 5.05 (s, 2H,
CH2), 6.47 (s, 1H, H3), 6.92–7.08 (m, 4H, Harom),

4944
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
00
7.26–7.43 (m, 11H, Harom), 7.59 (d, 2H, J = 8.3 Hz, H2 ),
C19H14N2O2: C 75.48, H 4.67, N 9.27. Found: C
75.16, H 4.53, N 9.40.
0
8.03 (s, 1H, H4 ), 8.21 (d, 1H, J = 8.8 Hz, H7), 8.49 (d,
13
0
0
1H, J = 1.7 Hz, H2 ), 8.81 (d, 1H, J = 1.8 Hz, H6 ); C
NMR (CDCl3, 62.5 MHz): d 70.2 (CH2), 103.9 (CH),
113.9 (2· CH), 114.2 (CH), 115.1 (CH), 117.1 (CH),
125.9 (2· CH), 126.9 (2· CH), 128.5 (CH), 128.7 (Cq),
128.9 (2· CH), 129.1 (2· CH), 129.4 (2· CH), 129.7
(Cq), 131.2 (Cq), 133.2 (Cq), 133.6 (CH), 134.2 (Cq),
136.7 (CH), 136.9 (Cq), 137.6 (Cq), 140.2 (Cq), 147.5
(CH), 147.8 (CH), 155.4 (Cq), 159.8 (Cq); MS (IS):
533 (M+1)+; Anal. Calcd for C32H24N2O4S: C 72.16,
H 4.54, N 5.26. Found: C 72.53, H 4.39, N 5.41.
5.1.21. [2-(5-Benzyloxy-2-{5-[5-benzyloxy-1-(2-dimethyl ami-
noethyl)-1H-indol-2-yl]pyridin-3-yl}indol-1-yl) ethyl]dimeth-
ylamine (28). A solution of 3,5-bis-(5-benzyloxy-1H-
indole)-pyridine
6 (162 mg, 0.31 mmol) in DMF
(10 mL) was cooled to 0 ꢁC, under argon, then NaH
(60% dispersion in oil, 100 mg, 2.48 mmol) was portion
wise added and the solution was stirred for 30 min. 2-
Chloroethyldimethylamine hydrochloride 26 (112 mg,
0.77 mmol) was added and the resulting mixture was
heated for 2 h at 100 ꢁC. Water (10 mL) was added,
the mixture was extracted with dichloromethane (3·
20 mL), the combined organic layers were dried over
MgSO4 and filtered. The solvents were removed under
reduced pressure and the crude material was purified
by flash chromatography (dichloromethane/methanol/
triethylamine 9:1:0.01) to afford compound 28 as a
yellow oil (113 mg, 55%). Rf (dichloromethane/metha-
nol/triethylamine 9:1:0.01): 0.67; IR (NaCl, cmꢀ1) m
2953, 2825, 2777, 2249, 1620, 1479, 1454, 1292, 1197,
1023, 909, 734; 1H NMR (CDCl3, 250 MHz): d 2.13
(s, 12H, 4· CH3), 2.58 (t, 4H, J = 7.1 Hz, 2· CH2),
4.24 (t, 4H, J = 7.1 Hz, 2· CH2), 5.11 (s, 4H, 2·
CH2), 6.56 (s, 2H, H3), 7.02 (dd, 2H, J = 2.2 Hz,
J = 8.8 Hz, H6), 7.19 (d, 2H, J = 2.4 Hz, H4), 7.31–
5.1.19. 4-[5-(5-Benzyloxy-1H-indol-2-yl)pyridin-3-yl] phe-
nol (24). To a solution of compound 23 (100 mg,
0.19 mmol) in dry THF (10 mL), Bu4NF (0.94 mL,
1 M in THF, 0.94 mmol) was added. The solution was
stirred to reflux for 1 h. The reaction mixture was con-
centrated under reduced pressure. After hydrolysis
(20 mL), the mixture was extracted with ethyl acetate
(3· 20 mL), washed with brine (20 mL) then dried over
MgSO4, and filtered. The solvents were removed under
reduced pressure and the crude material was purified by
flash chromatography (ethyl acetate/petroleum ether
6:4) to afford compound 24 as a yellow solid (60 mg,
80%). Mp: 165–167 ꢁC; Rf (ethyl acetate/petroleum
ether 1:1): 0.23; IR (NaCl, cmꢀ1) m 3322, 2965, 1611,
1595, 1518, 1467, 1265, 1221, 1175, 1124, 1018, 738;
1H NMR (CDCl3, 250 MHz): d 5.08 (s, 2H, OCH2),
6.81 (s, 1H, H3), 6.85 (dd, 1H, J = 2.4, 8.9 Hz, H6),
7.49 (m, 14H, Harom), 8.80 (s, 1H, H4 ); 13C NMR
0
(CDCl3, 62.5 MHz): d 43.0 (2· CH2), 45.8 (4· CH3),
58.7 (2· CH2), 70.9 (2· CH2), 103.6 (2· CH), 104.1
(2· CH), 110.9 (2· CH), 113.6 (2· CH), 127.6 (2·
CH), 127.9 (2· CH), 128.5 (2· Cq), 128.6 (4· CH),
128.9 (2· Cq), 133.4 (2· Cq), 136.8 (2· CH), 137.6
(2· Cq), 137.7 (2· Cq), 148.9 (CH), 153.8 (2·
Cq); MS (IS): 665 (M+1)+; Anal. Calcd for
C43H45N5O2: C 77.80, H 6.83, N 10.55. Found: C
78.17, H 6.91, N 10.40.
00
7.03 (d, 2H, J = 8.5 Hz, H3 ), 7.11 (d, 1H, J = 2.4 Hz,
0
H4), 7.27–7.56 (m, 9H, Harom), 8.37 (s, 1H, H4 ), 8.60
(s, 1H, H2 ), 8.92 (s, 1H, H6 ), 11.11 (s, 1H, NH); 13C
NMR (CDCl3, 62.5 MHz): d 70.9 (CH2), 99.7 (CH),
103.3 (CH), 113.3 (CH), 116.6 (CH), 126.0 (CH),
126.1 (2· CH), 127.6 (CH), 127.8 (CH), 127.9 (Cq),
128.0 (2· CH), 128.3 (CH), 128.6 (CH), 129.2 (Cq),
129.3 (CH), 130.1 (Cq), 133.5 (Cq), 135.6 (Cq), 137.8
(Cq), 145.2 (2· CH), 146.9 (Cq), 153.5 (Cq), 158.4
(Cq); MS (IS): 393 (M+1)+; Anal. Calcd for
C26H20N2O2: C, H, N. Found: C, 79.57; H, 5.14; N,
7.14. Found C 79.57, H 5.14, N 7.14. Found C 79.21,
H 5.25, N 7.02.
0
0
5.1.22. [3-(5-Benzyloxy-2-{5-[5-benzyloxy-1-(3-dimethyl
aminopropyl)-1H-indol-2-yl]pyridin-3-yl}indol-1-yl)pro-
pyl]dimethylamine (29). Same procedure as described
for compound 28 starting from compound 6 and 3-chlo-
ropropyldimethylamine hydrochloride 27 (2.5 equiv).
Compound 29 was purified by flash chromatography
(dichloromethane/methanol/triethylamine 9:1:0.01) and
isolated as a pale yellow oil (52%). Rf (dichlorometh-
ane/methanol/triethylamine 9:1:0.01) : 0. 32; IR (NaCl,
cmꢀ1) m 2934, 2857, 2251, 2218, 1620, 1478, 1455,
1379, 1195, 1025, 909, 733; 1H NMR (CDCl3,
250 MHz): d 1.79–1.90 (m, 4H, 2· CH2), 2.11 (s, 12H,
4· CH3), 2.17 (t, 4H, J = 6.9 Hz, 2· CH2), 4.26 (t, 4H,
J = 7.5 Hz, 2· CH2), 5.13 (s, 4H, 2· OCH2), 6.57 (s,
2H, H3), 7.02 (dd, 2H, J = 2.4 Hz, J = 8.9 Hz, H6),
7.19 (d, 2H, J = 2.4 Hz, H4), 7.31–7.50 (m, 14H, Harom),
5.1.20. 2-[5-(4-Hydroxyphenyl) pyridin-3-yl]-5-hydroxy-
1H-indole (25). Same procedure as described for com-
pound 7 starting from compound 24 and BBr3
(1.2 equiv). Compound 25 was purified by flash chroma-
tography
(dichloromethane/methanol/triethylamine
9:1:0.01) and isolated as a pale brown solid (52%).
Mp: 112–115 ꢁC; Rf (dichloromethane/methanol/trieth-
ylamine 9:1:0.01): 0.42; IR (NaCl, cmꢀ1) m 3514, 3089,
1607, 1553, 1442, 1273, 1182, 1067, 836; 1H NMR
00
(DMSO-d6, 250 MHz): d 6.91 (d, 2H, J = 8.4 Hz, H3 ),
6.99–7.14 (m, 4H, Harom), 7.42 (d, 1H, J = 7.8 Hz, H6),
8.77 (s, 1H, H4 ); 13C NMR (CDCl3, 62.5 MHz): d 28.1
0
7.53 (d, 1H, J = 7.8 Hz, H7), 7.59 (d, 2H, J = 8.1 Hz,
00
(2· CH2), 42.3 (2· CH2), 45.1 (4· CH3), 56.4 (2· CH2),
70.8 (2· CH2), 103.7 (2· CH), 103.9 (2· CH), 111.1 (2·
CH), 113.6 (2· CH), 127.5 (4· CH), 127.8 (2· CH),
128.4 (2· Cq), 128.5 (4· CH), 129.1 (2· Cq), 133.5 (2·
Cq), 136.3 (2· CH), 137.3 (2· Cq), 137.6 (2· Cq),
148.7 (CH), 153.7 (2· Cq); MS (IS): 693 (M+1)+; Anal.
Calcd for C45H49N5O2: C 78.12, H 7.14, N 10.12.
Found: C 77.70, H 7.33, N 10.27.
0
0
H2 ), 8.41 (s, 1H, H4 ), 8.71 (s, 1H, H6 ), 8.97 (s, 1H,
0
H2 ), 11.72 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz): d 100.0 (CH), 111.4 (CH), 116.0 (2· CH),
119.6 (CH), 120.3 (CH), 127.4 (Cq), 128.0 (Cq), 128.2
(2· CH), 128.5 (Cq), 128.8 (CH), 134.6 (Cq), 135.6
(Cq), 137.3 (Cq), 138.9 (Cq), 144.3 (CH), 145.5 (CH),
157.9 (Cq); MS (IS): 303 (M+1)+; Anal. Calcd for

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4945
0
0
5.1.23.
(2-{5-Benzyloxy-2-[5-(5-benzyloxy-1H-indol-2-
OH), 8.79 (s, 2H, H2 , H6 ); 13C NMR (CDCl3,
62.5 MHz): d 42.4 (2· CH2), 45.4 (4· CH3), 58.1 (2·
CH2), 102.8 (2· CH), 105.0 (2· CH), 110.2 (2· CH),
112.8 (2· CH), 127.9 (2· CH), 128.7 (2· Cq), 132.6
(2· Cq), 137.1 (2· Cq), 141.2 (2· Cq), 148.2 (CH),
151.1 (2· Cq); MS (IS): 484 (M+1)+; Anal. Calcd for
C29H33N5O2: C 72.02, H 6.88, N 14.48. Found: C
72.31, H 6.70, N 14.35.
yl)pyridin-3-yl]indol-1-yl}ethyl)dimethylamine (30). Same
procedure as described for compound 28 starting from
compound 6 and 2-chloroethyldimethylamine hydro-
chloride 26 (1.2 equiv). Compound 30 was purified by
flash chromatography (dichloromethane/methanol/tri-
ethylamine 9:1:0.01) and isolated as a pale brown oil
(58%). Rf (dichloromethane/methanol/triethylamine
9:1:0.01): 0.32; IR (NaCl, cmꢀ1) m 3398, 2867, 2424,
1
1601, 1485, 1392, 1227, 1007, 727; H NMR (CDCl3,
2.10–2.13 (m, 8H), 4.24 (t, 2H,
5.1.26.
3,5-Bis-(1-(3-dimethylaminopropyl)-5-hydroxy-
250 MHz):
d
1H-indol)pyridine (33). Same procedure as described
for compound 32 starting from 29. Compound 33 was
isolated as a pale brown oil ( 47%). Rf (dichlorometh-
ane/methanol/triethylamine 9:1:0.01): 0.20; IR (NaCl,
cmꢀ1) m 3276, 3225, 2823, 2810, 1617, 1498, 1454,
J = 7.1 Hz, 2· CH2), 5.12 (s, 4H, 2· OCH2), 6.56 (s,
2H, H3), 7.02 (dd, 2H, J = 2.2 Hz, J = 8.8 Hz, H6),
7.19 (d, 2H, J = 2.4 Hz, H4), 7.25–7.49 (m, 14H, Harom),
8.04 (d, 1H, J = 20.8 Hz), 8,80 (s, 1H, NH); 13C NMR
(CDCl3, 62.5 MHz): d 42.5 (CH2), 46.4 (2· CH3), 58.9
(CH2), 70.9 (2· CH2), 102.4 (2· CH), 103.0 (2· CH),
109.7 (2· CH), 112.5 (2· CH), 126.5 (4· CH), 126.8
(2· CH), 127.3 (2· Cq), 127.6 (4· CH), 127.9 (2· Cq),
132.1 (2· Cq), 135.6 (2· CH), 136.6 (2· Cq), 136.9 (2·
Cq), 147.6 (CH), 152.9 (2· Cq); MS (IS): 593 (M+1)+;
Anal. Calcd for C39H36N4O2: C 79.03, H, 6.12, N
9.45. Found: C 78.76, H 6.30, N 9.32.
1
1227, 1086, 829, 756; H NMR (CDCl3, 250 MHz): d
1.78–1.92 (m, 4H), 2.12 (s, 12H, 4· CH3), 2.21 (t, 4H,
J = 7.0 Hz, 2· CH2), 4.19 (t, 4H, J = 7.1 Hz, 2· CH2),
6.47 (s, 2H, H3), 6.70 (dd, 2H, J = 2.0 Hz, J = 8.5 Hz,
H6), 6.96 (d, 2H, J = 2.0 Hz, H4), 7.15 (d, 2H,
0
J = 9.1 Hz, H7), 7.90 (s, 1H, H4 ), 8.62 (s large, 2H, 2·
OH), 8.74 (s, 2H, H2 , H6 ); 13C NMR (CDCl3,
62.5 MHz): d 28.2 (2· CH2), 42.5 (2· CH2), 45.2 (4·
CH3), 56.6 (2· CH2), 103.4 (2· CH), 105.3 (2· CH),
111.0 (2· CH), 113.2 (2· CH), 128.6 (2· Cq), 129.5
(2· Cq), 133.2 (2· CH), 136.6 (2· Cq), 137.3 (2· Cq),
148.5 (CH), 153.2 (2· Cq); MS (IS): 512 (M+1)+; Anal.
Calcd for C31H37N5O2: C 72.77, H 7.29, N 13.69.
Found: C 73.06, H 7.12, N 13.75.
0
0
5.1.24. (3-{5-Benzyloxy-2-[5-(5-benzyloxy-1H-indol-
2-yl)pyridin-3-yl]indol-1-yl}propyl)dimethylamine (31).
Same procedure as described for compound 30 starting
from compound 6 and 3-chloropropyldimethylamine
hydrochloride 27 (1.2 equiv). Compound 31 was purified
by flash chromatography (dichloromethane/methanol/
triethylamine 9:1:0.01) and isolated as a pale brown oil
(60%). Rf (dichloromethane/methanol/triethylamine
9:1:0.01): 0.33; IR (NaCl, cmꢀ1) m 3408, 2873, 2436,
5.1.27. 1-(2-Dimethylaminoethyl)-2-[5-(5-hydroxy-1H-indol-
2yl)pyridin-3-yl]-5-hydroxy-1H-indole (34). Same proce-
dure as described for 32 starting from 30 and BBr3
(2.0 equiv). Compound 34 was isolated as a pale brown
oil (52%). Rf (dichloromethane/methanol/triethylamine
9:1:0.01): 0.35; IR (NaCl, cmꢀ1) m 3289, 3238, 2877,
2834, 2665, 2101, 1623, 1502, 1423, 1201, 1098, 887,
714; H NMR (DMSO-d6, 250 MHz): d 2.09–2.12 (m,
8H), 4.15 (t, 2H, J = 6.9 Hz, CH2), 6.58 (dd, 2H,
J = 1.9 Hz, J = 8.1 Hz, H6), 6.87 (m, 4H, Harom), 7.12
1
1607, 1498, 1460, 1235, 1019, 743; H NMR (CDCl3,
250 MHz): d 1.78 (m, 2H, CH2), 2.10–2.13 (m, 8H),
4.24 (t, 2H, J = 7.1 Hz, 2· CH2), 5.12 (s, 4H, 2· CH2),
6.56 (s, 2H, H3), 7.02 (dd, 2H, J = 2.2, 8.8 Hz, H6),
7.19 (d, 2H, J = 2.4 Hz, H4), 7.25–7.49 (m, 14H, Harom),
8.04 (d, 1H, J = 20.8 Hz), 8.80 (s, 1H, NH); 13C NMR
(CDCl3, 62.5 MHz): d 27.4 (CH2), 42.2 (CH2), 46.7 (2·
CH3), 58.2 (CH2), 70.3 (2· CH2), 102.2 (2· CH), 103.3
(2· CH), 109.5 (2· CH), 112.8 (2· CH), 126.2 (4·
CH), 126.6 (2· CH), 127.7 (2· Cq), 127.9 (4· CH),
128.1 (2· Cq), 132.6 (2· Cq), 135.9 (2· CH), 136.8 (2·
Cq), 137.3 (2· Cq), 147.9 (CH), 153.4 (2· Cq); MS
(IS): 607 (M+1)+; Anal. Calcd for C40H38N4O2: C
79.18; H, 6.31, N 9.23. Found: C 79.44, H 6.12, N 9.07.
1
0
(d, 2H, J = 8.2 Hz, H7), 8.16 (s, 1H, H4 ), 8.68 (s, 2H,
0
0
2· OH), 8.74 (d, 2H, J = 1.7 Hz, H2 , H6 ), 11.32 (s,
1H, NH); 13C NMR (DMSO-d6, 62.5 MHz): d 41.3
(CH2), 45.2 (2· CH3), 57.6 (CH2), 100.1 (2· CH),
102.8 (2· CH), 111.6 (2· CH), 112.2 (2· CH), 127.8
(2· Cq), 128.7 (2· CH), 132.3 (2· Cq), 134.5 (2· Cq),
139.2 (2· Cq), 144.7 (CH), 150.8 (2· Cq); MS (IS):
413 (M+1)+; Anal. Calcd for C25H24N4O2: C 72.80, H
5.86, N 13.58. Found: C 72.41, H 5.99, N 13.41.
5.1.25. 3,5-Bis-(1-(2-dimethylaminoethyl)-5-hydroxy-1H-
indol)pyridine (32). Same procedure as described for
compound 7 starting from compound 28 and BBr3
(1.25 equiv). The reaction mixture was stirred at room
temperature for 2 h. Compound 32 was purified by flash
chromatography (dichloromethane/methanol/triethyl-
amine 9:1:0.01) and isolated as a colorless oil (49%).
Rf dichloromethane/methanol/triethylamine 9:1:0.01):
0.40; IR (NaCl, cmꢀ1) m 3254, 3214, 2795, 2822, 1634,
1495, 1427, 1212, 1054, 815, 747; 1H NMR (CDCl3,
250 MHz): d 2.12 (s, 12H, 4· CH3), 2.59 (t, 4H,
J = 6.8 Hz, 2· CH2), 4.24 (t, 4H, J = 7.0 Hz, 2· CH2),
6.48 (s, 2H, H3), 6.95 (dd, 2H, J = 2.0 Hz, J = 8.7 Hz,
H6), 7.02 (d, 2H, J = 2.2 Hz, H4), 7.27 (d, 2H,
5.1.28. 1-(3-Dimethylaminopropyl)-2-[5-(5-hydroxy-1H-
indol-2-yl)pyridin-3-yl]-5-hydroxy-1H-indole (35). Same
procedure as described for compound 32 starting from
31. Compound 35 was isolated as a pale brown oil
(48%) Rf (dichloromethane/methanol/triethylamine
9:1:0.01): 0.39; IR (NaCl, cmꢀ1) m 3312, 3267, 2948,
2817, 2657, 2058, 1617, 1487, 1432, 1205, 1023, 901,
1
726; H NMR (DMSO-d6, 250 MHz): d 1.67 (m, 2H,
CH2), 2.07–2.11 (m, 8H), 4.15 (t, 2H, J = 7.1 Hz, CH2),
6.59 (dd, 2H, J = 1.8 Hz, J = 8.4 Hz, H6), 6.88 (dd, 4H,
J = 1.5 Hz, J = 12.7 Hz), 7.24 (d, 2H, J = 8.6 Hz, H7),
0
8.14 (s, 1H, H4 ), 8.69 (s, 2H, 2· OH), 8.76 (d, 2H,
J = 1.9 Hz, H2 , H6 ), 11.36 (s, 1H, NH);; 13C NMR
0
0
0
J = 8.9 Hz, H7), 8.06 (s, 1H, H4 ), 8.62 (s large, 2H, 2·

4946
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
(DMSO-d6, 62.5 MHz): d 39.6 (CH2), 42.9 (2· CH3), 45.9
(CH2), 54.8 (CH2), 103.8 (CH), 104.4 (CH), 111.3 (CH),
112.7 (CH), 125.4 (CH), 127.4 (2· Cq), 128.0 (2· CH),
128.5 (2· CH), 132.1 (2· Cq), 134.3 (2· Cq), 136.1
(CH), 139.7 (2· Cq), 148.4 (CH), 150.4 (2· Cq); MS
(IS): 427 (M+1)+; Anal. Calcd for C26H26N4O2: C
73.22, H 6.14, N 13.14. Found: C 73.58, H 6.01, N 13.03.
CH2), 1.49–1.59 (m, 6H, CH2), 2.37 (s, 6H, 2· CH3),
2.78 (t, 2H, J = 5.7 Hz, CH2), 4.09 (t, 2H, J = 5.7 Hz,
CH2), 6.73 (s, 1H, H3), 6.83 (dd, 1H, J = 2.6 Hz,
J = 9.1 Hz, H6), 6.96 (d, 1H, J = 2.3 Hz, H4), 7.34–7.62
(m, 5H, Harom), 7.70 (d, 1H, J = 9.1 Hz, H7).
5.1.31. [2-(1-Benzenesulfonyl-2-{5-[1-benzenesulfonyl-5-(2-
dimethylaminoethoxy)-1H-indol-2-yl]pyridin-3-yl}-1H-indol-
5-yloxy)ethyl]dimethylamine (38). Same procedure as
described for compound 5 starting from compound 37
(110 mg, 0.17 mmol) and 3,5-dibromopyridine (18 mg,
0.07 mmol). The mixture was refluxed for 18 h. Com-
pound 38 was purified by flash chromatography (dichlo-
romethane/methanol 9:1) and isolated as a colorless oil
(2 mg, 4%). Rf (dichloromethane/methanol 9:1): 0.17;
IR (NaCl, cmꢀ1) m 3431, 2370, 2332, 1802, 1652, 1450,
5.1.29. [2-(1-Phenylsulfonyl-1H-indol-5-yloxy)ethyl]di-
methylamine (36). Same procedure as described for com-
pound 7 starting from 1-phenylsulfonyl-5-benzyloxy-
1H-indole 3(500 Hz, 1.38 mmol) and BBr3 (1.2 equiv).
The mixture was stirred for 2 h at room temperature.
1-Phenylsulfonyl-5-hydroxy-1H-indole was purified by
flash chromatography (ethyl acetate/petroleum ether
3:7 to 1:1) and isolated as a white solid (80%). Rf (ethyl
acetate/petroleum ether 3:7): 0.31; IR (KBr, cmꢀ1) m
1
1375, 1219, 1166, 1092; H NMR (CDCl3, 250 MHz):
1
3494, 2366, 1589, 1449, 1350, 1221, 1143, 997, 807; H
d 2.39 (s, 6H, 2· CH3); 2.40 (s, 6H, 2· CH3), 2.81 (t,
4H, J = 5.5 Hz, 2· CH2), 4.12 (t, 4H, J = 4.2 Hz, 2·
CH2), 6.58 (d, 2H, J = 2.8 Hz, 2· CH), 6.92–6.99 (m,
4H), 7.05 (dd, 1H, J = 2.6 Hz, J = 8.9 Hz, CH), 7.27–
7.52 (m, 7H), 7.82–7.89 (m, 3H), 8.01 (t, 1H,
J = 1.8 Hz, CH), 8.19 (d, 1H, J = 9.1 Hz, CH), 8.56 (d,
1H, J = 1.4 Hz, CH), 8.72 (d, 1H, J = 2.0 Hz, CH);
13C NMR (CDCl3, 62.5 MHz): d 45,6 (2· CH3); 45.8
(2· CH3), 58.1 (2· CH2), 58.2 (2· CH2), 66.0 (2·
CH2), 66.1 (2· CH2), 104.4 (CH), 104.8 (CH), 114.4
(CH), 114.5 (CH), 115.3 (CH), 115.9 (CH), 117.7
(CH),119.7 (Cq), 126.0 (Cq), 126.6 (2· CH), 126.8 (2·
CH), 127.2 (CH), 129.0 (2· CH), 129.3 (2· CH), 129.8
(Cq), 130.0 (Cq), 131.3 (Cq), 131.8 (Cq), 133.2 (Cq),
133.9 (CH), 134.1 (CH), 137.0 (Cq), 137.4 (Cq), 138.3
(Cq), 140.2 (CH), 147.8 (CH), 150.7 (CH), 155.5 (Cq),
156.5 (Cq).
NMR (CDCl3, 250 MHz): d 5.44 (s, 1H, OH), 6.52 (d,
1H, J = 3.6 Hz, H3), 6.84 (dd, 1H, J = 2.6 Hz,
J = 8.8 Hz, H6), 6.92 (d, 1H, J = 2.3 Hz, H4), 7.36–7.50
(m, 4H, Harom), 7.80–7.84 (m, 3H, Harom); 13C NMR
(CDCl3, 62.5 MHz): d 106.5 (CH), 109.3 (CH), 113.8
(CH), 114.5 (CH), 126.8 (2· CH), 127.4 (CH), 129.3
(2· CH), 129.7 (Cq), 132.1 (Cq), 133.9 (CH), 138.1
(Cq), 152.4 (Cq). MS (IS): 274 (M+1)+; the previously
obtained 1-phenylsulfonyl-5-hydroxy-1H-indole was then
used following the same procedure as described for com-
pound 22 and 2-chloroethyldimethylamine hydrochlo-
ride 26 (1.2 equiv). The reaction was heated at 100 ꢁC
for 3.5 h. Compound 36 was purified by flash chroma-
tography
(dichloromethane/methanol/triethylamine
8:2:0.01) and isolated as a colorless hygroscopic solid
(250 m 67%). Rf (dichloromethane/methanol/triethyl-
amine 8:2:0.01): 0.43; IR (NaCl, cmꢀ1) m 2952, 2660,
1
1485, 1396, 1205, 1161, 1036, 786; H NMR (CDCl3,
5.1.32. (2-{4-[5-(1-Phenylsulfonyl-1H-indol-2-yl)pyridin-
3-yl] phenoxy}ethyl)dimethylamine (39). Same procedure
as described for compound 22 starting from com-
pounds 19 and 26. Compound 39 was purified by flash
chromatography (dichloromethane/methanol/triethyl-
amine 9:1:0.01) and isolated as a white solid (77%).
Mp: 134–136 ꢁC; Rf (dichloromethane/methanol 9:1):
0.33; IR (KBr, cmꢀ1) m 3770, 1605, 1517, 1369, 1186,
250 MHz): d 2.32 (s, 6H, 2· CH3), 2.72 (t, 2H,
J = 5.7 Hz, CH2), 4.05 (t, 2H, J = 5.7 Hz, CH2), 6.57
(d, 1H, J = 3.6 Hz, H3), 6.94–6.97 (m, 3H, Harom),
7.36–7.51 (m, 4H, Harom), 7.81–7.89 (m, 3H, Harom);
13C NMR (CDCl3, 62.5 MHz): d 45.8 (2· CH3), 58.2
(CH2), 66.3 (CH2), 104.5 (CH), 109.4 (CH), 114.3 (2·
CH), 126.5 (2· CH), 127.0 (CH), 129.1 (2· CH), 129.5
(Cq), 131.7 (Cq), 133.7 (CH), 138.0 (Cq), 155.6 (Cq);
MS (IS): 345 (M+1)+; Anal. Calcd for C18H20N2O3S:
C 62.77, H 5.85, N 8.13. Found: C 63.13, H 5.69, N 7.99.
1
1035, 843; H NMR (CDCl3, 250 MHz): d 2.37 (s, 6H,
2· CH3), 2.78 (t, 2H, J = 5.6 Hz, CH2), 4.14 (t, 2H,
J = 5.6 Hz, CH2), 6.68 (s, 1H, H3), 7.06 (d, 2H,
00
J = 8.5 Hz, H3 ), 7.24–7.51 (m, 8H, Harom), 7.60
00
0
5.1.30. [2-(1-Phenylsulfonyl-2-tributylstannyl-1H-indol-5-
yloxy)ethyl]dimethylamine (37). An LDA solution
(0.44 mL, 0.87 mmol, 2 M in THF) was added dropwise
to compound 36 (100 mg, 0.29 mmol) in THF (10 mL),
at ꢀ20 ꢁC and stirred 30 min. Then, a solution of tribu-
tylstannyl chloride (0.27 mL, 0.99 mmol) in THF (1 mL)
was added dropwise at ꢀ78 ꢁC and stirred for 2 h at
room temperature. Water (20 mL) was added and the
mixture was extracted with ethyl acetate (3· 50 mL).
The combined organic layers were washed with a satu-
rated solution of KF (3· 50 mL) and dried over MgSO4.
After evaporation the residue was purified by flash chro-
matography (dichloromethane/methanol 9:1) to afford
(d, 2H, J = 8.3 Hz, H2 ), 8.06 (t, 1H, J = 2.0 Hz, H4 ),
8.35 (d, 1H, J = 8.3 Hz, H7), 8.52 (d, 1H, J = 1.6 Hz,
H2 ), 8.85 (d, 1H, J = 1.6 Hz, H6 ); 13C NMR (CDCl3,
0
0
62.5 MHz):
d 46.0 (2· CH3), 58.4 (CH2), 66.2
(CH2), 114.8 (CH), 115.4 (2· CH), 116.7 (CH), 121.2
(CH), 124.8 (CH), 125.6 (CH), 126.7 (2· CH), 128.4
(Cq), 128.5 (2· CH), 128.9 (2· CH), 129.9 (Cq), 130.3
(Cq), 134.0 (CH), 135.0 (Cq), 136.5 (CH), 137.5 (Cq),
138.3 (Cq), 138.6 (Cq), 147.6 (CH), 147.9 (CH), 159.3
(Cq); MS (IS): 498 (M+H)+; Anal. Calcd for
C29H27N3O3S: C 70.00, H 5.47, N 8.44. Found: C
69.67, H 5.62, N 8.58.
1
compound 37 as a pale brown oil (110 mg, 67%). H
NMR (CDCl3, 250 MHz) d: 0.89 (t, 9H, J = 7.1 Hz, 3·
CH3), 1.15–1.20 (m, 5H, CH2), 1.25–1.41 (m, 7H,
5.1.33. (3-{4-[5-(1-Phenylsulfonyl-1H-indol-2-yl)pyridin-
3-yl]phenoxy}propyl)dimethylamine (40). Same proce-
dure as described for 22 starting from compounds 19

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4947
0
and 27. Compound 40 was purified by flash chromatogra-
phy (dichloromethane/methanol/triethylamine 9:1:0.01)
and isolated as a white solid (80%). Mp: 131–133 ꢁC;
Rf (dichloromethane/methanol/triethylamine 9:1:0.01):
0.43; IR (KBr, cmꢀ1) m 3408, 2758, 1605, 1515, 1433,
1368, 1250, 1186, 1171, 834, 760; 1H NMR (CDCl3,
250 MHz): d 2.02–2.07 (m, 2H, CH2), 2.34 (s, 6H, 2·
CH3), 2.58 (t, 2H, J = 7.2 Hz, CH2), 4.09 (t, 2H,
J = 6.4 Hz, CH2), 6.67 (s, 1H, H3), 7.03 (d, 2H,
J = 9.1 Hz, H7), 8.51 (s, 1H, H2 ), 8.85 (d, 1H,
0
J = 1,8 Hz, H6 ); 13C NMR (CDCl3, 62.5 MHz): d 27.5
(CH2), 45.5 (2· CH3), 56.4 (CH2), 66.4 (CH2), 70.5
(CH2), 104.7 (CH), 115.0 (CH), 115.1 (CH), 115.2 (2·
CH), 117.7 (CH), 126.6 (2· CH), 127.6 (2· CH), 128.1
(CH), 128.3 (Cq), 128.4 (2· CH), 128.7 (2· CH), 128.9
(2· CH), 129.6 (Cq), 131.5 (Cq), 133.2 (Cq), 133.9
(CH), 135.0 (Cq), 136.3 (CH), 136.9 (Cq), 137.1 (Cq),
139.1 (Cq), 147.3 (CH), 147.8 (CH), 156.5 (Cq), 159.4
(Cq); MS (IS): 618 (M+H)+; Anal. Calcd for
C37H35N3O4S: C 71.94, H 5.71, N 6.80. Found: C
71.63, H 5.83, N 6.94.
00
J = 8.8 Hz, H3 ), 7.23–7.51 (m, 8H, Harom), 7.59 (d,
00
0
2H,J = 8.7 Hz, H2 ), 8.05 (t, 1H, J = 2 Hz, H4 ), 8.35
0
(d, 1H, J = 8.3 Hz, H7), 8.52 (d, 1H, J = 1.8 Hz, H2 ),
0
8.85 (d, 1H, J = 2 Hz, H6 ); 13C NMR (CDCl3,
62.5 MHz): d 27.3 (CH2), 45.3 (2· CH3), 56.4 (CH2),
66.3 (CH2), 114.8 (CH), 115.3 (2· CH), 116.6 (CH),
121.2 (CH), 124.8 (CH), 125.6 (CH), 126.7 (2· CH),
128.9 (Cq), 128.5 (2· CH), 128.9 (2· CH), 129.8 (Cq),
130.3 (Cq), 134.0 (CH), 135.0 (Cq), 136.5 (CH), 137.5
(Cq), 138.3 (Cq), 138.6 (Cq), 147.5 (CH), 147.9 (CH),
159.4 (Cq); MS (IS): 512 (M+H)+; Anal. Calcd for
C30H29N3O3S: C 70.43, H 5.71, N 8.21. Found: C
70.76, H 5.63, N 8.08.
5.1.36. (2-{4-[5-(1H-Indol-2-yl)pyridin-3-yl]phenoxy} ethyl)-
dimethyl-amine (43). Same procedure as described for
compound 6 starting from compound 39 and Bu4NF
(1.5 equiv) was added. The solution was stirred to reflux,
for 3 h. Compound 43 was purified by flash chromatog-
raphy (dichloromethane/methanol 9:1) and isolated as a
white solid (64%). Mp: 182–184 ꢁC; Rf (dichlorometh-
ane/methanol/triethylamine 9:1:0.01): 0.34; IR (KBr,
cmꢀ1) m 3450, 2942, 1608, 1515, 1455, 1284, 1241,
1
1184, 1060, 801; H NMR (CDCl3, 250 MHz): d 2.25
5.1.34. (2-{4-[5-(1-Phenylsulfonyl-5-benzyloxy-1H-indol-
2-yl)pyridin-3-yl]phenoxy}ethyl)dimethylamine (41).
Same procedure as described for 22 starting from com-
pounds 23 and 26. Compound 41 was purified by flash
chromatography (dichloromethane/methanol/triethyl-
amine 9:1:0.01) and isolated as a brown solid (69%).
Mp: 97 ꢁC; Rf (dichloromethane/methanol/triethylamine
9:1:0.01): 0.51; IR (KBr, cmꢀ1) m 3056, 2360, 1675, 1610,
1515, 1449, 1373, 1265, 1183, 1091, 1025; 1H NMR
(CDCl3, 250 MHz): d 2.36 (s, 6H, 2· CH3), 2.76 (t,
2H, J = 5.6 Hz, CH2), 4.12 (t, 2H, J = 5.9 Hz, CH2),
5.06 (s, 2H, CH2), 6.58 (s, 1H, H3), 6.98–7.10 (m, 5H,
Harom), 7.21–7.45 (m, 10H, Harom), 7.59 (d, 2H,
(s, 6H, 2· CH3), 2.68 (t, 2H, J = 5.7 Hz, CH2), 4.13 (t,
2H, J = 5.6 Hz, CH2), 7.03–7.15 (m, 5H, Harom), 7.46
(d, 1H, J = 8.0 Hz, H4), 7.58 (d, 1H, J = 7.8 Hz, H7),
00
0
7.81 (d, 2H, J = 8.4 Hz, H2 ), 8.51 (s, 1H, H4 ), 8.78 (s,
1H, H2 ), 9.06 (s, 1H, H6 ), 11.86 (s, 1H, NH); 13C
NMR (CDCl3, 62.5 MHz): d 45.5 (2· CH3), 57.6
(CH2), 65.8 (CH2), 100.0 (CH), 111.4 (CH), 115.1 (2·
CH), 119.6 (CH), 120.3 (CH), 122.1 (CH), 128.1 (Cq),
128.2 (2· CH), 128.4 (Cq), 129.0 (Cq), 129.1 (CH),
134.5 (Cq), 135.2 (Cq), 137.4 (Cq), 144.6 (CH), 145.5
(CH), 158.8 (Cq); MS (IS): 357 (M+1)+; Anal. Calcd
for C23H23N3O: C 77.28, H 6.49, N 11.76. Found: C
77.64, H 6.59, N 11.61.
0
0
00
J = 8.5 Hz, H2 ), 8.23 (d, 1H, J = 9.1 Hz, H7), 8.51 (d,
1H, J = 1.7 Hz, H2 ), 8.84 (d, 1H, J = 2.0 Hz, H6 ); 13C
NMR (CDCl3, 62.5 MHz): d 45.9 (2· CH3), 58.3
(CH2), 66.1 (CH2), 70.5 (CH2), 104.7 (CH), 114.9
(CH), 115.0 (CH), 115.3 (2· CH), 117.7 (CH), 126.6
(2· CH), 127.5 (2· CH), 128.0 (CH), 128.3 (Cq), 128.4
(2· CH), 128.6 (2· CH), 128.8 (2· CH), 129.7 (Cq),
131.4 (Cq), 133.2 (Cq), 133.8 (CH), 134.9 (Cq), 136.3
(CH), 136.8 (Cq), 137.1 (Cq), 139.1 (Cq), 147.3 (CH),
147.8 (CH), 156.5 (Cq), 159.2 (Cq); MS (IS): 604
(M+H)+; Anal. Calcd for C36H33N3O4S: C 71.62, H
5.51, N 6.96. Found: C 71.35, H 5.40, N 7.15.
5.1.37. (3-{4-[5-(1H-Indol-2-yl)pyridin-3-yl]phenoxy} pro-
pyl)dimethylamine (44). Same procedure as described
for compound 43 starting from compound 40. Com-
pound 44 was isolated as a white solid (87%). Mp:
178–180 ꢁC; IR (KBr, cmꢀ1) 3424, 1610, 1515, 1444,
1285, 1243, 1192, 831, 791; 1H NMR (DMSO-d6,
250 MHz): d 1.89 (qt, 2H, J = 6.0 Hz, CH2), 2.21
(s, 6H, 2· CH3), 2.45 (t, 2H, J = 7.1 Hz, CH2), 4.06
(t, 2H, J = 6.3 Hz, CH2), 7.00–7.18 (m, 5H, Harom),
7.46 (d, 1H, J = 8.1 Hz, H4), 7.58 (d, 1H, J = 7.5 Hz,
0
0
00
0
H7), 7.79 (d, 2H, J = 8.7 Hz, H2 ), 8.49 (s, 1H, H4 ),
0
8.77 (d, 1H, J = 1.8 Hz, H2 ), 9.05 (d, 1H, J = 1.8 Hz,
0
5.1.35. (3-{4-[5-(1-Phenylsulfonyl-5-benzyloxy-1H-indol-
2-yl)pyridin-3-yl]phenoxy}propyl)dimethyl-amine (42).
Same procedure as described for 22 starting from com-
pounds 23 and 27. Compound 42 was purified by flash
chromatography (dichloromethane/methanol/triethyl-
amine 9:1:0.01) and isolated as a pale brown oil (72%).
Rf (dichloromethane/methanol/triethylamine 9:1:0.01):
0.40; IR (NaCl, cmꢀ1) m 3417, 2951, 1674, 1610, 1515,
H6 ), 11.81 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz): d 26.6 (CH2), 44.9 (2· CH3), 55.5 (CH2),
65.8 (CH2), 100.0 (CH), 111.4 (CH), 115.1 (2· CH),
119.6 (CH), 120.3 (CH), 122.1 (CH), 128.1 (Cq), 128.1
(2· CH), 128.5 (Cq), 128.9 (Cq), 129.0 (CH), 134.5
(Cq), 135.2 (Cq), 137.3 (Cq), 144.6 (CH), 145.5 (CH),
159.0 (Cq); MS (IS): 372 (M+1)+; Anal. Calcd for
C24H25N3O: C 77.60, H 6.78, N 11.31. Found: C
77.28, H 6.95, N 11.17.
1
1465, 1373, 1265, 1183, 1091, 1025; H NMR (CDCl3,
250 MHz): d 2.03 (qt, 2H, J = 6.2 Hz, CH2), 2.32 (s,
6H, 2· CH3), 2.55 (t, 2H, J = 6.9 Hz, CH2), 4.09 (t,
2H, J = 6.3 Hz, CH2), 5.08 (s, 2H, CH2), 6.59 (s, 1H,
H3), 6.99–7.12 (m, 5H, Harom), 7.23–7.61 (m, 10H, Har-
5.1.38. (2-{4-[5-(5-Benzyloxy-1H-indol-2-yl)pyridin-3-yl]phen-
oxy}ethyl)dimethylamine (45). Same procedure as
described for compound 43 starting from compound 41.
Compound 45 was isolated as a pale brown oil (84%).
00
om), 8.03 (d, 2H, J = 9.1 Hz, H2 ), 8.24 (d, 1H,

4948
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
Rf (dichloromethane/methanol/triethylamine 9:1:0.01):
0.37; IR (NaCl, cmꢀ1) m 3056, 2360, 1675, 1610, 1515,
1449, 1373, 1265, 1183, 1091, 1025; H NMR (CDCl3,
(Cq); MS (IS): 374 (M+1)+; Anal. Calcd for
C23H23N3O2: C 73.97, H 6.21, N 11.25. Found: C
73.63, H 6.40, N 11.34.
1
250 MHz): d 2.40 (s, 6H, 2· CH3), 2.81 (t, 2H,
J = 5.4 Hz, CH2), 4.04 (t, 2H, J = 5.4 Hz, CH2), 5.07 (s,
2H, CH2), 6.80–6.92 (m, 5H, Harom), 7.11 (d, 1H,
J = 1.9 Hz, H4), 7.28–7.59 (m, 7H, Harom), 8.34 (s, 1H,
5.1.41. 2-{5-[4-(3-Dimethylaminopropoxy)phenyl]pyri-din-
3-yl}-5-hydroxy-1H-indole (48). Same procedure as
described for compound 7 starting from compound 46.
Compound 48 was isolated as a white solid (54%).
Mp: 199–201 ꢁC; Rf (dichloromethane/methanol/
triethylamine 9:1:0.01): 0.31; IR (KBr, cmꢀ1) m 3432,
1654, 1607, 1513, 1466, 1389, 1286, 1247, 1213, 1182,
0
0
0
H4 ), 8.61 (s, 1H, H2 ), 8.95 (s, 1H, H6 ), 11.05 (s, 1H,
NH); 13C NMR (CDCl3, 62.5 MHz): d 45.3 (2· CH3),
57.7 (CH2), 65.2 (CH2), 70.7 (CH2), 99.5 (CH), 103.2
(CH), 113.3 (CH), 113.4 (CH), 115.1 (2· CH), 127.5 (2·
CH), 127.7 (CH), 127.9 (2· CH), 128.4 (2· CH), 128.7
(Cq), 129.0 (Cq), 129.7 (Cq), 129.9 (CH), 133.4 (Cq),
135.5 (Cq), 136.0 (Cq), 137.6 (Cq), 144.6 (CH), 145.3
(CH), 153.3 (Cq), 158.7 (Cq); MS (IS): 464 (M+1)+; Anal.
Calcd for C30H29N3O2: C 77.73, H 6.31, N 9.06. Found: C
77.97, H 6.44, N 8.92.
1
835, 789; H NMR (DMSO-d6, 250 MHz): d 1.89 (qt,
2H, J = 4.3 Hz, CH2), 2.20 (s, 6H, 2· CH3), 2.43 (t,
2H, J = 7.3 Hz, CH2), 4.04 (t, 2H, J = 7.3 Hz, CH2),
6.68 (dd, 1H, J = 1.9, 8.5 Hz, H6), 6.88 (d, 1H,
J = 1.9 Hz, H4), 6.96 (s, 1H, H3), 7.09 (d,
00
2H, J = 8.8 Hz, H3 ), 7.24 (d, 1H, J = 8.5 Hz, H7), 7.78
00
(d, 2H, J = 8.5 Hz, H2 ), 8.41 (s, 1H, H4 ), 8.74 (d, 2H,
0
0
0
5.1.39. (3-{4-[5-(5-Benzyloxy-1H-indol-2-yl)pyridin-3-yl]
phenoxy}propyl)dimethylamine (46). Same procedure as
described for compound 43 starting from compound
42. Compound 46 was isolated as a pale brown oil
(85%). Rf (dichloromethane/methanol/triethylamine
9:1:0.01): 0.34; IR (NaCl, cmꢀ1) m 3417, 2951, 1674,
1610, 1515, 1465, 1373, 1265, 1183, 1091, 1025; 1H
NMR (CDCl3, 250 MHz): d 1.97 (qt, 2H, J = 4.6 Hz,
CH2), 2.36 (s, 6H, 2· CH3), 2.62 (t, 2H, J = 7.3 Hz,
CH2), 3.87 (t, 2H, J = 6.1 Hz, CH2), 5.07 (s, 2H, CH2),
6.80–6.92 (m, 5H, Harom), 7.13 (d, 1H, J = 2.2 Hz, H4),
J = 1.7 Hz, H2 , OH), 8.98 (d, 1H, J = 1.7 Hz, H6 ),
11.44 (s, 1H, NH); 13C NMR (DMSO-d6,
62.5 MHz): d 26.7 (CH2), 45.0 (2· CH3), 55.6 (CH2),
65.9 (CH2), 99.4 (CH), 103.9 (CH), 111.8 (CH), 112.7
(CH), 115.1 (2· CH), 128.1 (2· CH), 128.3 (Cq), 128.8
(CH), 129.0 (Cq), 129.2 (Cq), 132.0 (Cq), 134.7 (Cq),
135.2 (Cq), 144.4 (CH), 145.3 (CH), 151.1 (Cq), 159.0
(Cq); MS (IS): 388 (M+1)+; Anal. Calcd for
C24H25N3O2: C 74.39, H 6.50, N 10.84. Found: C
74.13, H 6.37, N 11.02.
0
7.27–7.51 (m, 7H, Harom), 8.25 (s, 1H, H4 ), 8.60 (s,
5.1.42. 2-(4-{5-[1-(2-Dimethylaminoethyl)-1H-indol-2-yl]pyri-
din-3-yl}phenoxy)ethyl]dimethylamine (49). Same procedure
as described for compound 28 starting from com-
pound 43 and 2-chloroethyldimethylamine hydrochlo-
ride 26 (1.5 equiv). Compound 49 was purified by flash
chromatography (dichloromethane/methanol/triethyl-
amine 9:1:0.01) and isolated as a pale brown oil (83%).
Rf (dichloromethane/methanol/triethylamine 9:1:0.01):
0.35; IR (NaCl, cmꢀ1) m 3418, 2934, 2366, 1610, 1514,
1H, H2 ), 8.94 (s, 1H, H6 ), 10.76 (s, 1H, NH); 13C
NMR (CDCl3, 62.5 MHz): d 44.3 (2· CH3); 45.9
(CH2), 55.9 (CH2), 58.5 (CH2), 65.5 (CH2), 100.3
(CH), 103.7 (CH), 112.5 (CH), 113.8 (CH), 115.0 (2·
CH), 127.6 (2· CH), 127.8 (CH), 128.2 (2· CH), 128.5
(2· CH), 128.8 (Cq), 129.3 (Cq), 129.7 (Cq), 130.1
(CH), 133.2 (Cq), 135.4 (Cq), 136.2 (Cq), 137.6 (Cq),
144.5 (CH), 145.7 (CH), 153.6 (Cq), 158.9 (Cq); MS
(IS): 478 (M+1)+; Anal. Calcd for C31H31N3O2: C
77.96, H 6.54, N 8.80. Found: C 78.37, H 6.61, N 8.68.
0
0
1
1460, 1249, 1037, 751; H NMR (CDCl3, 250 MHz): d
2.15 (s, 6H, 2· CH3), 2.45 (s, 6H, 2· CH3), 2.62 (t, 2H,
J = 7.6 Hz, CH2), 2.88 (t, 2H, J = 5.4 Hz, CH2), 4.19 (t,
2H, J = 5.6 Hz, CH2), 4.28 (t, 2H, J = 7.3 Hz, CH2),
00
6.64 (s, 1H, H3), 7.05 (d, 2H, J = 8.6 Hz, H3 ), 7.16 (t,
1H, J = 7.6 Hz, H5 or H6), 7.27 (t, 1H, J = 7.1 Hz, H5
ou H6), 7.43 (d, 1H, J = 8.1 Hz, H4), 7.58 (d, 2H,
5.1.40. 2-{5-[4-(2-Dimethylaminoethoxy)phenyl]pyridin-
3-yl}-5-hydroxy-1H-indole (47). Same procedure as de-
scribed for compound 7 starting from compound 45
and BBr3 (1.1 equiv). The reaction was stirred at room
temperature for 2 h. Compound 47 was purified by flash
chromatography (dichloromethane/methanol/triethyl-
amine 9:1:0.01) and isolated as a brown solid (60%).
Mp: 190–192 ꢁC; Rf (dichloromethane/methanol/trieth-
ylamine 9:1:0.01): 0.34; IR (KBr, cmꢀ1) m 3412, 1644,
1617, 1504, 1456, 1388, 1277, 1234, 1208, 1179, 789;
1H NMR (DMSO-d6, 250 MHz): d 2.37 (s, 6H, 2·
CH3), 2.85 (t, 2H, J = 5.1 Hz, CH2), 4.19 (t, 2H,
J = 5.6 Hz, CH2), 6.68 (d, 1H, J = 7.1 Hz, H6), 6.88 (s,
1H, H4), 6.96 (s, 1H, H3), 7.12 (d, 2H, J = 8.5 Hz,
00
J = 8.6 Hz, H2 ), 7.66 (d, 1 Hz J = 7.8 Hz, H7), 8.04 (t,
0
0
1H, J = 1.9 Hz, H4 ), 8.72 (d, 1H, J = 1.7 Hz, H2 ), 8.85
0
(d, 1H, J = 1.7 Hz, H6 ); 13C NMR (CDCl3, 62.5 MHz):
d 42.6 (CH2), 45.4 (2· CH3), 45.7 (2· CH3), 57.9 (CH2),
58.5 (CH2), 65.3 (CH2), 103.6 (CH), 110.1 (CH), 115.4
(2· CH), 120.4 (CH), 121.0 (CH), 122.4 (CH), 128.2
(Cq), 128.4 (2· CH), 129.0 (Cq), 130.1 (Cq), 134.5
(CH), 135.9 (Cq), 137.6 (Cq), 137.8 (Cq), 147.2 (CH),
148.1 (CH), 158.8 (Cq); MS (IS): 429 (M+1)+; Anal. Calcd
for C27H32N4O: C 75.67, H 7.53, N 13.07. Found: C 75.55,
H 7.62, N 13.15.
00
H3 ), 7.24 (d, 1H, J = 8.5 Hz, H7), 7.80 (d, 2H,
00
0
0
J = 8.5 Hz, H2 ), 8.43 (s, 1H, H4 ), 8.74 (s, 2H, H2 ,
0
OH), 8.99 (s, 1H, H6 ), 11.48 (s, 1H, NH); 13C NMR
5.1.43. [3-(2-{5-[4-(2-Dimethylaminoethoxy)-phenyl]pyri-
din-3-yl}indol-1-yl)propyl]dimethylamine (50). Same pro-
cedure as described for compound 49 starting from
compounds 43 and 27. Compound 50 was isolated as
a pale brown oil (81%). Rf (dichloromethane/metha-
nol/triethylamine 9:1:0.01): 0.33; IR (NaCl, cmꢀ1) m
(DMSO-d6, 62.5 MHz): d 45.0 (2· CH3), 57.2 (CH2),
65.2 (CH2), 99.3 (CH), 103.8 (CH), 111.8 (CH), 112.7
(CH), 115.2 (2· CH), 125.5 (Cq), 128.1 (2· CH), 128.3
(Cq), 128.8 (CH), 129.2 (Cq), 132.0 (Cq), 134.7 (Cq),
135.1 (Cq), 144.4 (CH), 145.3 (CH), 151.1 (Cq), 158.6

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4949
0
(d, 1H, J = 7.6 Hz, H7), 7.95 (t, 1H, J = 1.9 Hz, H4 ),
3430, 3053, 2934, 1610, 1520, 1464, 1265, 1181, 1038,
896; 1H NMR (CDCl3, 250 MHz): d 1.85 (qt, 2H,
J = 6.8 Hz, CH2), 2.11 (s, 6H, 2· CH3), 2.18 (t, 2H,
J = 6.8 Hz, CH2), 2.38 (s, 6H, 2· CH3), 2.79 (t, 2H,
J = 5.6 Hz, CH2), 4.14 (t, 2H, J = 5.6 Hz, CH2), 4.28
(t, 2H, J = 7.3 Hz, CH2), 6.64 (s, 1H, H3), 7.05 (d, 2H,
00
J = 8.5 Hz, H3 ), 7.15 (t, 1H, J = 7.6 Hz, H5 or H6),
7.26 (t, 1H, J = 8.1 Hz, H5 or H6), 7.45 (d, 1H,
00
J = 8.1 Hz, H4), 7.57 (d, 2H, J = 8.5 Hz, H2 ), 7.66 (d,
8.69 (s, 1H, H2 ), 8.83 (s, 1H, H6 ); 13C NMR (CDCl3,
62.5 MHz): d 26.9 (CH2), 28.0 (CH2), 42.2 (CH2), 45.0
(2· CH3), 45.1 (2· CH3), 56.2 (CH2), 56.5 (CH2), 66.1
(CH2), 103.7 (CH), 110.2 (CH), 115.3 (2· CH), 120.2
(CH), 120.9 (CH), 122.3 (CH), 128.1 (Cq), 128.2 (2·
CH), 128.4 (Cq), 129.7 (Cq), 134.3 (CH), 135.9 (Cq),
137.3 (Cq), 137.8 (Cq), 147.2 (CH), 147.8 (CH), 159.3
(Cq); MS (IS): 457 (M+1)+; Anal. Calcd for
C29H36N4O: C 76.28, H 7.95, N 12.27. Found: C
76.43, H 8.09, N 12.12.
0
0
0
1H, J = 7.8 Hz, H7), 7.95 (t, 1H, J = 1.9 Hz, H4 ), 8.69
0
0
(d, 1H, J = 1.7 Hz, H2 ), 8.84 (d, 1H, J = 2.0 Hz, H6 );
13C NMR (CDCl3, 62.5 MHz): d 28.0 (CH2), 42.1
(CH2), 45.1 (2· CH3), 45.8 (2· CH3), 56.5 (CH2), 58.2
(CH2), 66.0 (CH2), 103.6 (CH), 110.2 (CH), 115.3 (2·
CH), 120.1 (CH), 120.8 (CH), 122.2 (CH), 128.1 (Cq),
128.3 (2· CH), 129.1 (Cq), 129.7 (Cq), 134.2 (CH),
136.0 (Cq), 137.3 (Cq), 137.8 (Cq), 147.1 (CH), 147.8
(CH), 159.2 (Cq); MS (IS): 443 (M+1)+; Anal. Calcd
for C28H34N4O: C 75.98, H 7.74, N 12.66. Found: C
76.36, H 7.60, N 12.48.
5.1.46. [2-(4-{5-[5-Benzyloxy-1-(2-dimethylaminoethyl)-
1H-indol-2-yl]pyridin-3-yl}phenoxy)ethyl]dimethyl amine
(53). Same procedure as described for compound 49
from compounds 45 and 26; Compound 53 was isolated
as a pale brown oil (53%). Rf (dichloromethane/metha-
nol/triethylamine 9:1:0.01): 0.53; IR (NaCl, cmꢀ1) m
2934, 1680, 1610, 1515, 1480, 1265, 1185, 1035, 909,
1
734; H NMR (CDCl3, 250 MHz): d 2.16 (s, 6H, 2·
CH3), 2.53 (s, 6H, 2· CH3), 2.62 (t, 2H, J = 7.3 Hz,
CH2), 3.01 (t, 2H, J = 6.8 Hz, CH2), 4.20–4.24 (m,
4H), 5.12 (s, 2H, CH2), 6.55 (s, 1H, H3), 6.99–7.10 (m,
2H, Harom), 7.19 (d, 2H, J = 2.2 Hz, H4), 7.31–7.41
5.1.44. [3-(4-{5-[1-(2-Dimethylaminoethyl)-1H-indol-2-
yl]pyridin- 3-yl}phenoxy)propyl]dimethylamine (51). Same
procedure as described for compound 49 starting from
compounds 44 and 26; Compound 51 was isolated as a
pale brown oil (53%). Rf (dichloromethane/methanol/
triethylamine 9:1:0.01): 0.30; IR (NaCl, cmꢀ1) m 3396,
00
(m, 4H, Harom), 7.48 (d, 2H, J = 7.1 Hz, H3 ), 7.58 (d,
00
0
2H, J = 8.5 Hz, H2 ), 8.04 (s, 1H, H4 ), 8.69 (s, 1H,
H2 ), 8.82 (s, 1H, H6 ); 13C NMR (CDCl3, 62.5 MHz):
d 43.0 (CH2), 45.8 (2· CH3), 46.0 (2· CH3), 58.3
(CH2), 58.8 (CH2), 66.2 (CH2), 70.9 (CH2), 103.2
(CH), 104.1 (CH), 110.8 (CH), 113.4 (CH), 115.4 (2·
CH), 127.6 (2· CH), 127.8 (CH), 128.3 (2· CH), 128.5
(Cq), 128.6 (2· CH), 128.9 (Cq), 129.8 (Cq), 133.3
(Cq), 134.4 (CH), 135.9 (Cq), 137.7 (Cq), 138.3 (Cq),
147.1 (CH), 147.9 (CH), 153.8 (Cq), 159.3 (Cq); MS
(IS): 536 (M+1)+; Anal. Calcd for C34H38N4O2: C
76.37, H 7.16, N 10.48. Found: C 76.01, H 7.23, N
10.62.
0
0
1
3066, 2990, 1618, 1430, 1265, 1052, 912, 739; H NMR
(CDCl3, 250 MHz): d 1.41–1.50 (m, 2H, CH2), 1.69
(qt, 2H, J = 8.3 Hz, CH2), 2.02 (t, 2H, J = 7.8 Hz,
CH2), 2.10 (s, 6H, 2· CH3), 2.15 (s, 6H, 2· CH3), 4.09
(t, 2H, J = 6.1 Hz, CH2), 4.28 (t, 2H, J = 7.1 Hz,
00
CH2), 6.64 (s, 1H, H3), 7.03 (d, 2H, J = 8.8 Hz, H3 ),
7.16 (t, 1H, J = 7.3 Hz, H5 or H6), 7.27 (t, 1H,
J = 7.3 Hz, H5 or H6), 7.43 (d, 1H, J = 8.3 Hz, H4), 7.58
00
(d, 2H, J = 8.8 Hz, H2 ), 7.66 (d, 1H, J = 7.6 Hz, H7),
0
8.05 (t, 1H, J = 1.9 Hz, H4 ), 8.71 (d, 1H, J = 1.9 Hz,
H2 ), 8.84 (d, 1H, J = 1.9 Hz, H6 ); 13C NMR (CDCl3,
62.5 MHz): d 27.6 (CH2), 42.8 (CH2), 45.6 (2· CH3),
45.8 (2· CH3), 56.4 (CH2), 58.6 (CH2), 66.4
(CH2), 103.5 (CH), 110.0 (CH), 115.3 (2· CH), 120.3
(CH), 120.9 (CH), 122.3 (CH), 128.2 (Cq), 128.3 (2·
CH), 129.0 (Cq), 129.6 (Cq), 134.5 (CH), 135.9 (Cq),
137.7 (Cq), 137.8 (Cq), 147.2 (CH), 148.0 (CH), 159.5
(Cq); MS (IS): 443 (M+1)+; Anal. Calcd for
C28H34N4O: C 75.98, H 7.74, N 12.66. Found: C 75.62,
H 7.58, N 12.80.
0
0
5.1.47. [3-(5-Benzyloxy-2-{5-[4-(2-dimethylaminoeth-
oxy)phenyl]pyridin-3-yl}indol-1-yl)propyl-dimethyl amine
(54). Same procedure as described for compound 49
starting from 45 and 27. Compound 54 was isolated
as a pale brown oil (69%). Rf (dichloromethane/metha-
nol/triethylamine 9:1:0.01): 0.32; IR (NaCl, cmꢀ1) m
3431, 2966, 1611, 1515, 1480, 1266, 1187, 1124, 1035,
1
1088, 737; H NMR (CDCl3, 250 MHz): d 1.80–1.87
(m, 2H, CH2), 2.28 (t, 2H, J = 7.0 Hz, CH2), 2.46 (s,
6H, 2· CH3), 2.62 (t, 2H, J = 6.9 Hz, CH2), 2.72 (s,
6H, 2· CH3), 4.27–4.35 (m, 4H), 5.12 (s, 2H, OCH2),
7.00 (dd, 1H, J = 2.0, 8.9 Hz, H6), 7.06 (d, 2H,
5.1.45. [3-(4-{5-[1-(3-Dimethylaminopropyl)-1H-indol-2-
yl]pyridin-3-yl}phenoxy)propyl]dimethylamine (52). Same
procedure as described for compound 49 starting from
compounds 44 and 27; Compound 52 was isolated as
a pale brown oil (45%). Rf (dichloromethane/metha-
nol/triethylamine 9:1:0.01): 0.30; IR (NaCl, cmꢀ1) m
3438, 3066, 2996, 1654, 1515, 1422, 1265, 1058, 896,
741; 1H NMR (CDCl3, 250 MHz): d 1.85 (t, 2H,
J = 7.1 Hz, CH2), 2.05–2.12 (m, 8H), 2.19 (t, 2H,
J = 6.8 Hz, CH2), 2.41 (s, 6H, 2· CH3), 2.67 (t, 2H,
J = 7.1 Hz, CH2), 4.10 (t, 2H, J = 6.1 Hz, CH2), 4.28
(t, 2H, J = 7.3 Hz, CH2), 6.64 (s, 1H, H3), 7.02 (d, 2H,
00
J = 8.5 Hz, H3 ), 7.17 (d, 1H, J = 2.2 Hz, H4), 7.32–
0
7.60 (m, 9H, Harom), 7.92 (s, 1H, H4 ), 8.65 (s, 1H,
H2 ), 8.81 (s, 1H, H6 ); 13C NMR (CDCl3, 62.5 MHz):
d 24.0 (CH2), 42.9 (CH2), 43.6 (2· CH3), 44.5 (2·
CH3), 55.3 (CH2), 57.0 (CH2), 64.2 (CH2), 70.8 (CH2),
103.8 (CH), 104.0 (CH), 111.1 (CH), 113.6 (CH),
115.4 (2· CH), 127.5 (2· CH), 127.8 (CH), 128.4 (2·
CH), 128.7 (Cq), 129.4 (2· CH), 129.3 (Cq), 129.7
(Cq), 133.1 (Cq), 134.1 (CH), 135.7 (Cq), 135.9 (Cq),
138.2 (Cq), 147.1 (CH), 147.5 (CH), 153.7 (Cq), 158.4
(Cq); MS (IS): 550 (M+1)+; Anal. Calcd for
C35H40N4O2: C 76.61, H 7.35, N 10.21. Found: C
76.43, H 7.46, N 10.34.
0
0
00
J = 8.5 Hz, H3 ), 7.16 (td, 1H, J = 1.0, 7.8 Hz, H5 or
H6), 7.27 (td, 1H, J = 1.2, 7.1 Hz, H5 or H6), 7.45 (d,
00
1H, J = 8.1 Hz, H4), 7.56 (d, 2H, J = 8.8 Hz, H2 ), 7.66

4950
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
5.1.48. [3-(4-{5-[5-Benzyloxy-1-(2-dimethylaminoethyl)-
1H-indol-2-yl]pyridin-3-yl}phenoxy)-propyl]dimethyl
amine (55). Same procedure as described for compound
49 starting from compounds 46 and 26. Compound 55
was isolated as a pale brown oil (70%). Rf (dichloro-
methane/methanol/triethylamine 9:1:0.01): 0.61; IR
(NaCl, cmꢀ1) m 3386, 2947, 1610, 1515, 1479, 1453,
1249, 1188, 1033, 909, 831; 1H NMR (CDCl3,
250 MHz): d 1.79–1.85 (m, 2H, CH2), 2.18 (s, 6H, 2·
CH3), 2.31 (t, 2H, J = 7.1 Hz, CH2), 2.64 (t, 2H,
J = 7.0 Hz, CH2), 2.76 (s, 6H, 2· CH3), 4.15 (t, 2H,
J = 6.7 Hz, CH2), 4.28 (t, 2H, J = 7.4 Hz, CH2), 5.13
(s, 2H, OCH2), 6.56 (s, 1H, H3), 7.01–7.05 (m, 2H,
Harom), 7.19 (d, 1H, J = 2.4 Hz, H4), 7.32–7.60 (m,
CH2), 2.84 (t, 2H, J = 6.9 Hz, CH2), 4.11 (t, 2H,
J = 6.1 Hz, CH2), 4.23 (t, 2H, J = 7.9 Hz, CH2), 6.47
(s, 1H, H3), 6.97–7.07 (m, 4H, Harom), 7.16–7.45 (m,
00
3H, Harom), 7.56 (d, 2H, J = 8.1 Hz, H2 ), 8.68 (s, 1H,
H2 ), 8.89 (s, 1H, H6 ); 13C NMR (CDCl3, 62.5 MHz):
d 42.3 (CH2), 44.2 (2· CH3), 45.2 (2· CH3), 55.5
(CH2), 58.0 (CH2), 65.4 (CH2), 102.2 (CH), 104.8
(CH), 110.0 (CH), 112.4 (CH), 114.8 (2· CH), 127.7
(CH), 127.8 (CH), 128.3 (Cq), 128.6 (Cq), 129.1 (Cq),
132.3 (Cq), 133.8 (CH), 135.5 (Cq), 137.5 (Cq), 146.3
(CH), 147.1 (CH), 151.0 (Cq), 158.7 (Cq); MS (IS):
445 (M+1)+; Anal. Calcd for C27H32N4O2: C 72.95, H
7.26, N 12.60. Found: C 73.29, H 7.17, N 12.75.
0
0
0
0
9H, Harom), 8.03 (s, 1H, H4 ), 8.70 (s, 1H, H2 ), 8.83
0
5.1.51. 2-{5-[4-(2-Dimethylaminoethoxy)phenyl]pyridin-
3-yl}-1-(3-dimethylaminopropyl)-5-hydroxy-1H-indole
(58). Same procedure as described for compound 47
starting from compound 54. Compound 58 was isolated
as a pale brown oil (50%). Rf (dichloromethane/metha-
nol/triethylamine 9:1:0.01): 0.40; IR (NaCl, cmꢀ1) m
3302, 2928, 1678, 1623, 1506, 1481, 1262, 1191, 1052,
(s, 1H, H6 ); 13C NMR (CDCl3, 62.5 MHz): d 27.0
(CH2), 42.9 (CH2), 45.1 (2· CH3), 45.8 (2· CH3), 56.3
(CH2), 58.6 (CH2), 66.1 (CH2), 70.9 (CH2), 103.2
(CH), 104.0 (CH), 110.8 (CH), 113.4 (CH), 115.2
(2· CH), 127.6 (2· CH), 127.8 (CH), 128.3 (2· CH),
128.5 (Cq), 128.6 (2· CH), 129.0 (Cq), 129.7 (Cq),
133.3 (Cq), 134.4 (CH), 135.9 (Cq), 137.7 (Cq), 138.2
(Cq), 147.1 (CH), 147.9 (CH), 153.7 (Cq), 159.3
(Cq); MS (IS): 550 (M+1)+; Anal. Calcd for
C35H40N4O2: C 76.61, H 7.35, N 10.21. Found: C
76.24, H 7.51, N 10.37.
1
909, 723; H NMR (CDCl3, 250 MHz): d 1.79 (t, 2H,
J = 6.6 Hz, CH2), 2.26 (s, 6H, 2· CH3), 2.43–2.52 (m,
8H), 2.96 (t, 2H, J = 5.4 Hz, CH2), 4.19–4.23 (m, 4H,
2· CH2), 6.55 (s, 1H, H3), 6.74 (dd, 1H, J = 2.2,
8.7 Hz, H6), 6.91 (s, 1H, H4), 7.11 (d, 2H, J = 8.5 Hz,
00
H3 ), 7.40 (d, 1H, J = 9.1 Hz, H7), 7.79 (d, 2H,
00
0
0
5.1.49. [3-(4-{5-[5-Benzyloxy-1-(3-dimethylaminopro-pyl)-
1H- indol-2-yl]pyridin-3-yl}-phenoxy)propyl]di methylamine
(56). Same procedure as described for compound 49
starting from compounds 46 and 27. Compound 56
was isolated as a pale brown oil (67%). Rf (dichloro-
methane/methanol/triethylamine 9:1:0.01): 0.35; IR
(NaCl, cmꢀ1) m 3376, 2945, 1609, 1517, 1482, 1457,
1244, 1192, 1026, 904, 835; 1H NMR (CDCl3,
250 MHz): d 1.63–1.71 (m, 2H, CH2), 1.79–1.85 (m,
2H, CH2), 2.10 (s, 6H, 2· CH3), 2.17 (t, 2H,
J = 6.9 Hz, CH2), 2.39 (s, 6H, 2· CH3), 2.65 (t, 2H,
J = 7.1 Hz, CH2), 4.10 (t, 2H, J = 6.4 Hz, CH2), 4.25
(t, 2H, J = 7.5 Hz, CH2), 5.13 (s, 2H, OCH2), 6.99–
7.05 (m, 3H, Harom), 7.19 (d, 1H, J = 2.4 Hz, H4),
J = 8.7 Hz, H2 ), 8.14 (s, 1H, H4 ), 8.67 (s, 1H, H2 ),
0
8.85 (s large, 1H, OH), 8.90 (s, 1H, H6 ); 13C NMR
(CDCl3, 62.5 MHz): d 23.3 (CH2), 42.1 (CH2), 44.1 (2·
CH3), 45.4 (2· CH3), 56.5 (CH2), 57.7 (CH2), 64.5
(CH2), 102.2 (CH), 104.8 (CH), 110.1 (CH), 112.5
(CH), 115.3 (2· CH), 128.0 (2· CH), 128.5 (Cq), 128.8
(Cq), 129.6 (Cq), 132.1 (Cq), 133.2 (CH), 134.8 (Cq),
137.7 (Cq), 146.1 (CH), 147.9 (CH), 151.4 (CH), 158.1
(Cq); MS (IS): 459 (M+1)+; Anal. Calcd for
C28H34N4O2: C 73.33, H 7.47, N 12.22. Found: C
73.06, H 7.60, N 12.38.
5.1.52. 1-(2-Dimethylaminoethyl)-2-{5-[4-(3-dimethylami-
nopropoxy)phenyl]pyridin-3-yl}-5-hydroxy-1H-indole (59).
Same procedure as described for compound 47 starting
from compound 55. Compound 59 was isolated as a
pale brown oil (52%). Rf (dichloromethane/methanol/
triethylamine 9:1:0.01): 0.39; IR (NaCl, cmꢀ1) m 3322,
2923, 1656, 1617, 1509, 1476, 1298, 1187, 1045, 917,
721; 1H NMR (CDCl3, 250 MHz): d 1.81 (t, 2H,
J = 6.3 Hz, CH2), 2.24 (s, 6H, 2· CH3), 2.41–2.50 (m,
8H), 2.91 (t, 2H, J = 5.7 Hz, CH2), 4.17–4.26 (m, 4H,
2· CH2), 6.57 (s, 1H, H3), 6.71 (dd, 1H, J = 2.0,
8.7 Hz, H6), 6.90 (s, 1H, H4), 7.11 (d, 2H, J = 8.1 Hz,
0
7.32–7.58 (m, 9H, Harom), 7.94 (s, 1H, H4 ), 8.67 (s,
1H, H2 ), 9.19 (s, 1H, H6 ); 13C NMR (CDCl3,
62.5 MHz): d 27.0 (CH2), 27.9 (CH2), 42.8 (CH2), 45.1
(2· CH3), 45.7 (2· CH3), 56.4 (CH2), 58.5 (CH2), 66.2
(CH2), 70.9 (CH2), 103.2 (CH), 104.1 (CH), 110.5
(CH), 113.3 (CH), 115.2 (2· CH), 127.6 (2· CH),
127.9 (CH), 128.0 (2· CH), 128.4 (Cq), 128.8 (2· CH),
129.0 (Cq), 129.7 (Cq), 133.0 (Cq), 134.9 (CH), 135.6
(Cq), 137.5 (Cq), 138.2 (Cq), 147.1 (CH), 147.6 (CH),
153.8 (Cq), 159.3 (Cq); MS (IS): 564 (M+1)+; Anal.
Calcd for C36H42N4O2: C 76.84, H 7.52, N 9.96. Found:
C 77.18, H 7.67, N 10.06.
0
0
00
H3 ), 7.40 (d, 1H, J = 8.8 Hz, H7), 7.76 (d, 2H,
00
0
0
J = 8.4 Hz, H2 ), 8.15 (s, 1H, H4 ), 8.67 (s, 1H, H2 ),
0
8.84 (s large, 1H, OH), 8.89 (s, 1H, H6 ); 13C NMR
5.1.50. 2-{5-[4-(2-Dimethylaminoethoxy)phenyl]pyridin-
3-yl}-1-(2-dimethylaminoethyl)-5-hydroxy-1H-indole (57).
Same procedure as described for compound 47 starting
from compound 53. Compound 57 was isolated as a pale
brown oil (55%). Rf (dichloromethane/methanol/trieth-
ylamine 9:1:0.01): 0.43; IR (NaCl, cmꢀ1) m 3324, 3052,
2973, 2939, 2738, 2673, 2490, 1470, 1397, 1265, 1170,
(CDCl3, 62.5 MHz): d 23.1 (CH2), 41.9 (CH2), 44.4
(2· CH3), 45.0 (2· CH3), 56.7 (CH2), 57.7 (CH2), 64.5
(CH2), 102.3 (CH), 104.1 (CH), 110.9 (CH), 112.3
(CH), 115.3 (2· CH), 128.3 (2· CH), 128.5 (Cq),
128.6 (Cq), 129.1 (Cq), 132.3 (Cq), 133.3 (CH), 134.8
(Cq), 137.5 (Cq), 146.3 (CH), 147.4 (CH), 151.4 (Cq),
158.5 (Cq); MS (IS): 459 (M+1)+; Anal. Calcd for
C28H34N4O2: C 73.33, H 7.47, N 12.22. Found: C
73.74, H 7.35, N 12.37.
1
1035; H NMR (CDCl3, 250 MHz): d 2.16 (s, 6H, 2·
CH3), 2.53 (s, 6H, 2· CH3), 2.60 (t, 2H, J = 7.1 Hz,

U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
4951
5.1.53. 2-{5-[4-(3-Dimethylaminopropoxy) phenyl]pyridin-
3-yl}-1-(3-dimethylaminopropyl)-5-hydroxy-1H-indole (60).
Same procedure as described for compound 47 starting
from compound 56. Compound 60 was isolated as a
pale brown oil (49%). Rf (dichloromethane/methanol/
triethylamine 9:1:0.01): 0.44; IR (NaCl, cmꢀ1) m 3312,
2933, 1687, 1608, 1511, 1478, 1268, 1188, 1044, 917,
733; 1H NMR (CDCl3, 250 MHz): d 1.63–1.71 (m,
2H, CH2), 1.79–1.85 (m, 2H, CH2), 2.15 (s, 6H, 2·
CH3), 2.17 (t, 2H, J = 6.9 Hz, CH2), 2.25 (s, 6H, 2·
CH3), 2.65 (t, 2H, J = 7.1 Hz, CH2), 4.10 (t, 2H,
J = 6.0 Hz, CH2), 4.22 (t, 2H, J = 7.9 Hz, CH2), 6.46
(s, 1H, H3), 6.95–7.04 (m, 3H, Harom), 7.16–7.47 (m,
was performed using GOLD software.41 For each com-
pound, the most stable docking model was selected
according to the best scored conformation predicted
by the GoldScore41 and X-Score42 scoring functions.
The complexes were energy-minimized using the Powell
method available in Maximin2 procedure with the Tri-
pos force field and a dielectric constant of 4.0 until the
˚
gradient value reached 0.1 kcal/mol A.
5.3. Cell cultures and survival assay
CEM human leukemia cells were grown at 37 ꢁC in a
humidified atmosphere containing 5% CO2 in RPMI
1640 medium, supplemented with 10% fetal bovine ser-
um, glutamine (2 mM), penicillin (100 UI/ml), and
streptomycin (100 lg/mL). The cytotoxicity of the stud-
ied molecules was assessed using a cell proliferation as-
say developed by Promega (CellTiter 96ꢂ AQueous one
solution cell proliferation assay). Briefly, 2 · 104 expo-
nentially growing cells were seeded in 96-well microcul-
ture plates with various drug concentrations in a volume
of 100 lL. After 72 h incubation at 37 ꢁC, 20 lL of the
tetrazolium dye solution was added to each well and
the samples were incubated for a further 2 h at 37 ꢁC.
Plates were analyzed on a Labsystems Multiskan MS
(type 352) reader at 492 nm.
00
2H, Harom), 7.57 (d, 2H, J = 8.3 Hz, H2 ), 7.84 (s,
0
0
1H, H4 ), 8.67 (s, 1H, H2 ), 8.75 (s large, 1H, OH),
0
8.80 (s, 1H, H6 ); 13C NMR (CDCl3, 62.5 MHz): d
27.1 (CH2), 28.1 (CH2), 42.1 (CH2), 45.2 (2· CH3),
45.9 (2· CH3), 56.5 (CH2), 58.2 (CH2), 65.0 (CH2),
102.1 (CH), 104.7 (CH), 110.0 (CH), 112.4 (CH),
114.5 (2· CH), 127.9 (CH), 128.1 (CH), 128.3 (Cq),
128.6 (Cq), 129.6 (Cq), 132.1 (Cq), 133.5 (CH), 135.5
(Cq), 137.5 (Cq), 146.7 (CH), 147.9 (CH), 153.1 (Cq),
158.9 (Cq); MS (IS): 474 (M+1)+; Anal. Calcd for
C29H36N4O2: C 73.70, H 7.68, N 11.85. Found: C
73.44,H 7.54, N 12.02.
5.2. Computational methods
5.4. Protein kinase assays
5.2.1. Homology modeling of CDK1-cyclinB. Molecular
modeling studies were performed using Sybyl software
version 7.0 running on a Silicon Graphics Octane work-
station.36 The structure of human CDK2-cyclinA com-
5.4.1. Biochemical reagents. Sodium ortho-vanadate,
EGTA, EDTA, Mops, b-glycerophosphate, phenylphos-
phate, sodium fluoride, dithiothreitol (DTT), glutathi-
one–agarose, glutathione, bovine serum albumin (BSA),
nitrophenylphosphate, leupeptin, aprotinin, pepstatin,
soybean trypsin inhibitor, benzamidine, and histone H1
(type III-S) were obtained from Sigma Chemicals.
[c-32P]ATP (PB 168) was obtained from Amersham.
The GS-1 peptide (YRRAAVPPSPSLSRHSSPHQSpE-
DEEE) was synthesized by the Peptide Synthesis Unit,
Institute of Biomolecular Sciences, University of South-
ampton, Southampton SO16 7PX, UK.
˚
plexed with indirubin-5-sulfonate at 2.5 A resolution
(PDB code, 1E9H)37 was used as the template. The ami-
no acid sequence of human CDK1 was retrieved from
the Protein Information Resource (http://pir.george-
town.edu, Accession No. A29539) and aligned to that
of human CDK2-cyclinA using ClustalW.38 The high
degree of primary sequence identity between CDK2
and CDK1 (65%, Fig. 4) strongly indicates that CDK2
structures are good models to be used as templates for
CDK1. The 3D model of CDK1 was constructed by
the Nest program from the protein structure modeling
package JACKAL.39 The resulting model was subjected
to energy minimization using the Powell method avail-
able in Maximin2 procedure with the Tripos force field40
and a dielectric constant of 4.0 until the gradient value
5.4.2. Buffers. Homogenization buffer: 60mM b-glycero-
phosphate, 15 mM p-nitrophenylphosphate, 25 mM
Mops (pH 7.2), 15 mM EGTA, 15 mM mgCl2, 1 mM
DTT, 1 mM sodium vanadate, 1 mM NaF, 1 mM phe-
nylphosphate, 10 lg leupeptin/ml, 10 lg aprotinin/ml,
10 lg soybean trypsin inhibitor/ml, and 100 lM ben-
zamidine. Bead buffer: 50 mM Tris, pH 7.4, 5 mM
NaF, 250 mM NaCl, 5 mM EDTA, 5 mM EGTA,
0.1% Nonidet P-40, 10 lg leupeptin/ml, 10 lg aproti-
nin/ml, 10 lg soybean trypsin inhibitor/ml, and
100 lM benzamidine. Buffer A: 10 mM mgCl2, 1 mM
EGTA, 1 mM DTT, 25 mM Tris–HCl, pH 7.5, 50 lg
heparin/ml. Buffer C: homogenization buffer but 5 mM
EGTA, no NaF and no protease inhibitors. Tris-buf-
fered saline–Tween 20 (TBST): 50 mM Tris, pH 7.4,
150 mM NaCl, 0.1% Tween 20. Hypotonic lysis buffer
(HLB): 50 mM Tris–HCl, pH 7.4, 120 mM NaCl,
10% glycerol, 1% Nonidet-P40, 5 mM DTT, 1 mM
EGTA, 20 mM NaF, 1 mM orthovanadate, 5 lM micr-
ocystin, 100 lg/ml each of leupeptin, aprotinin, and
pepstatin.
˚
reached 0.1 kcal/mol A. Energy minimization was
started with the core side chains then the core main
chains. The Sybyl ProTable module checked the struc-
ture periodically. Where present, bad geometries were
manually corrected and the structure minimized again
with the above protocol.
5.2.2. Docking. Three-dimensional structures of com-
pounds were built from a standard fragments library,
and their geometry was subsequently optimized using
the Tripos force field including the electrostatic term cal-
culated from Gasteiger and Huckel atomic charges.
¨
Powell’s method available in Maximin2 procedure was
used for energy minimization until the gradient value
˚
was smaller than 0.001 kcal/mol A. Flexible docking of
compounds into the ATP-binding site of CDK1 model

4952
U. Jacquemard et al. / Bioorg. Med. Chem. 16 (2008) 4932–4953
5.4.3. Kinase preparations and assays. Kinases activities
were assayed in Buffer A or C (unless otherwise stated),
at 30 ꢁC, at a final ATP concentration of 15 lM. Blank
values were subtracted and activities calculated as pmol
of phosphate incorporated for a 10 min incubation. Con-
trols were performed with appropriate dilutions of
dimethylsulfoxide. GSK-3a/b was purified from porcine
brain.43 It was assayed, following a 1/100 dilution in
1 mg BSA/ml 10 mM DTT, with 5 ll 40 lM GS-1 peptide
as a substrate, in buffer A, in the presence of 15 lM [c-33P]
ATP (3000 Ci/mmol; 1 mCi/ml) in a final volume of 30 ll.
After 30 min incubation at 30 ꢁC, 25 ll aliquots of super-
natant were spotted onto 2.5 · 3 cm pieces of Whatman
P81 phosphocellulose paper, and, 20 s later; the filters
were washed five times (for at least 5 min each time) in a
solution of 10 mL phosphoric acid/liter of water. The
wet filters were counted in the presence of 1 mL ACS
(Amersham) scintillation fluid. CDK1-cyclin B__was ex-
tracted in homogenization buffer from M phase starfish
(Marthasterias glacialis) oocytes and purified by affinity
chromatography on p9CKShs1-sepharose beads, from
which it was eluted by free p9CKShs1 as previously de-
scribed.25,44 The kinase activity was assayed in buffer C,
with 1 mg histone H1/ml, in the presence of 15 lM
[[c-33P] ATP (3000 Ci/mmol; 1 mCi/ml) in a final volume
of 30 ll. After 10 min incubation at 30 ꢁC, 25 ll aliquots
of supernatant were spotted onto P81 phosphocellulose
papers and treated as described above. CDK5/p25 was
reconstituted by mixing equivual amounts of recombi-
nant mammalian CDK5 and p25 expressed in Escherichia
coli as GST (Glutathione-S-transferase) fusion proteins
and purified by affinity chromatography on glutathione-
agarose (vectors kindly provided by Dr. J.H. Wang)
(p25 is a truncated version of p35, the 35 kDa CDK5 acti-
vator). Its activity was assayed in buffer C as described for
CDK1-cyclin B.
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This research was supported by grants from the Can-
´
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Region Centre (S.R.), Ligue Nationale Contre le Cancer
´
´
(Comite du Nord), the Institut de Recherches sur le
Cancer de Lille (IRCL) (A.L. and fellowship to N.D.)
and a grant from the EEC (FP6–2002-Life Sciences
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The expert technical assistance of B. Baldeyrou is also
acknowledged.

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