Syntheses and anti-cancer activities of 2-[1-(indol-3-yl-/pyrimidin-5-yl-/pyridine-2-yl-/quinolin-2-yl)-but-3-enylamino]-2-phenyl-ethanols

Article abstract of DOI:10.1016/j.bmc.2007.01.018

Schiff bases prepared by the reactions of substituted amines with indole-/, pyrimidine-/, pyridine-/, and quinoline-aldehydes are made to undergo indium mediated allylation whereby a (substituted amine, allyl)methyl group has been introduced at C-3 of ind

Full text of DOI:10.1016/j.bmc.2007.01.018

Bioorganic & Medicinal Chemistry 15 (2007) 2386–2395
Syntheses and anti-cancer activities of 2-[1-(indol-3-yl-/pyrimidin-
5-yl-/pyridine-2-yl-/quinolin-2-yl)-but-3-enylamino]-2-
phenyl-ethanols
Palwinder Singh,a,* Pervinder Kaur,a Vijay Luxami,a
Satwinderjit Kaurb and Subodh Kumara,*
aDepartment of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
bDepartment of Botanical & Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, India
Received 15 November 2006; revised 11 January 2007; accepted 12 January 2007
Available online 17 January 2007
Abstract—Schiff bases prepared by the reactions of substituted amines with indole-/, pyrimidine-/, pyridine-/, and quinoline-alde-
hydes are made to undergo indium mediated allylation whereby a (substituted amine, allyl)methyl group has been introduced at
C-3 of indole, C-5 of pyrimidine, and C-2 of pyridine and quinoline. Amongst the 16 compounds investigated for anti-cancer activ-
ities at 59 human tumor cell lines 3, 9–12, and 14 show appreciable activities. The structure–activity relationship studies point that
the contribution of phenylglycinol moiety as a part of side chain at C-3 of indole and C-5 of pyrimidine seems to be crucial for
exhibiting anti-cancer activities.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
and economical, demand the presence of various ligating
sites along with the presence of hydrophobic moieties in
the molecule. In continuation of our efforts6 for develop-
ing the suitable leads for anti-cancer drugs, in the present
contribution, following simple synthetic methodology,
we have introduced appropriate substituent at C-3 of
indole, C-5 of pyrimidine, and C-2 of pyridine and quin-
oline. The substituent carries nitrogen and oxygen as two
ligating sites along with hydrophobic moieties, the essen-
tial requirement for multiple target ligands. The
pre-screening of these compounds for their anti-cancer
activities at three cell lines was followed by the detailed
investigations of selected compounds at 59 human tumor
cell lines. Some of these compounds show appreciable
anti-cancer activities and it is remarkable that the pres-
ence of phenyl glycinol on the side-chain nitrogen of
indole and pyrimidine significantly enhances their
anti-cancer activities.
The uncontrolled growth of cells in the body, started
due to certain stimuli, lays the foundation of cancer
and the complete process of cell multiplication is medi-
ated by various enzymes, some of which have been iden-
tified.1 A large number of anti-cancer compounds
available in the NIH database have been classified in
accordance with their mechanism of action (target
sites).2 Still the difficulty to diagnose the disease at the
early stage, narrow therapeutic indices of anti-cancer
compounds, and the problem of multidrug resistance3
are some of the major hurdles in the successful practice
of chemotherapy for cancer.
Heterocycles like indole, pyrimidine, pyridine, quinoline,
etc. are an integral part of a huge number of natural and
synthetic compounds and play important roles in the
biological systems.4 The structural features of multiple
target drugs,5 which are proven to be more effective
2. Chemistry
Keywords: Heterocycles; Schiff bases; Indium; Allylation; In vitro;
Anti-cancer activities.
The imines derived from pyridine-/, pyrimidine-/, indole-
aldehydes and appropriate amines on allylation provide
a facile route to homoallylic amines.7 A similar synthetic
methodology has been adopted here to procure the
*
Corresponding authors. Tel.: +91 183 2258802x3206/3495; fax: +91
183 2258819; e-mail addresses: palwinder_singh_2000@yahoo.com;
subodh_gndu@yahoo.co.in
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.01.018

P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
2387
R
OH
H
O
HN
N
H
O
N
N
ia, ii
H
H
N
i
ii
COOEt
COOEt
1a
2'
8
N
i (b-d), ii
HO
COOEt
COOEt
1a
HO
1'
HN
1
2
OH
R
2'
2'
1'
HN
1'
HN
1
CH3
H
H
H
2
CH3
4
1
2
2
HN
3
3
3
N
N
4
4
H
H
N
N
N
R =H
iii
COOEt
COOEt
COOEt
9
N
10
11
HO
HN
COOEt
COOEt
3, R = H
4, R = Cl
5
O
H
H
ic, ii
Scheme 1. Reagents and conditions: (i) benzyl-/p-Cl-benzyl amine, dry
THF, MgSO4, stir, rt; (ii) pre-generated In2(allyl)3Br3, THF/Toluene
(1:2), 27 ꢁC; (iii) benzyl chloride, CH3CN, K2CO3, TBA HSO4, reflux.
N
S
O
N
S
O
O
O
CH3
12
1b
CH3
desired compounds carrying suitable fragments at the
carbon and nitrogen of C@N of imine. 3-Formyl-in-
dole-1-carboxylic acid ethyl ester (1a)8 after reaction
with benzyl amine over anhydrous MgSO4 in dry THF
was treated with pre-generated In2(allyl)3Br3 reagent in
THF/Toluene (1:2) to get a thick liquid 83%, [M+ m/z
348] which from its NMR spectral data has been
assigned structure 3 (Scheme 1). This reaction (in conso-
nance with three-component reaction) has been proceed-
ed through the initial formation of Schiff base 2 which
readily undergoes allylation at C@N to provide
compound 3. Similarly, 1a on reaction with p-chlorob-
enzyl amine followed by treatment with pre-generated
In2(allyl)3Br3 reagent provided compound 4. Reaction
of 3 with benzyl chloride under phase transfer catalytic
conditions gave compound 5 (Scheme 1).
Scheme 3. Reagents and conditions: (i) dry THF, MgSO4, stir, rt;
a—2-aminoethanol (for 8); b—(S)-2-phenylglycinol (for 9); c—(R)-2-
phenylglycinol (for 10 and 12); d—(S)-2-amino-3-methylbutanol-1 (for
11); (ii) pre-generated In2(allyl)3Br3, THF/Toluene (1:2), 27 ꢁC.
Similarly, the reactions of 1a with 2-aminoethanol,
(S)-2-phenylglycinol, (R)-2-phenylglycinol, (S)-2-ami-
no-3-methyl-1-butanol and reaction of 1b8 with (R)-2-
phenylglycinol followed by allylation gave compounds
8–12, respectively (Scheme 3). In these reactions (except
the formation of 8), the initially formed Schiff bases
(analogues of 2, Scheme 1) undergo diastereoselective
allylation (dr > 99:1, 1H, 13C NMR spectrum) with
pre-generated In2(allyl)3Br2 reagent to provide enantio-
merically pure or highly enriched compounds 9–12.
The stereochemistry at C-1 of 9–12 has been speculated
on the basis of Cram’s chelation model where the allyl
group approaches to the carbon of C@N from the face
anti to phenyl group.9
Under the same reaction conditions as followed for the
formation of compound 3, the reactions of 1a with
o-anisidine and p-anisidine gave compounds 6 and 7,
respectively (Scheme 2).
It was found that the benzyl groups at N-1 and N-3 of
pyrimidines contribute toward the anti-cancer activities6
and taking into consideration the electronic contribu-
tions of chlorine for interacting with the target enzymes,
here, diastereoselective synthesis of compounds 14 and
15 was achieved by the allylation of imines, obtained
from 1310 and (R)-/(S)-phenylglycinol, with pre-generat-
ed allyl indium reagent (Scheme 4).
R
HN
N
O
N
H
H
i, ii
COOEt
COOEt
1a
Likewise, the diastereoselective synthesis of pyridine
derivatives 16 and 17 was achieved by the reaction
of pyridine-2-carbaldehyde with (R)-2-phenylglycinol
and (S)-2-phenylglycinol, respectively, followed by
the allylation with pre-generated allyl indium reagent
(Scheme 5).
6, R = o-OCH3
7, R = p-OCH3
Scheme 2. Reagents and conditions: (i) o-/p-anisidine, dry THF,
MgSO4, stir, rt; (ii) pre-generated In2(allyl)3Br3, THF/Toluene (1:2),
27 ꢁC.

2388
P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
HO
Therefore, a simple reaction strategy using three compo-
nents leads to the synthesis of target compounds. Dia-
stereoselective allylation of Schiff bases (analogues of
2, Scheme 1) provides enantiomerically pure compounds
9–12 and 14–19. All these compounds have been charac-
terized on the basis of NMR spectral data, mass spectra,
and elemental analysis, and the stereochemistry at car-
bon C-1/10 has been ascertained on the basis of anti
addition of allyl group with respect to phenyl group
(Cram’s chelation model).
1'
Cl
O
N
HN
1
N
3
2
O
Cl
O
N
O
N
H
Cl
i, ii
14
O
HO
Cl
Cl
O
HN
13
3. Anti-cancer activities
N
O
N
All the indole-based compounds were subjected to
pre-screening for their anti-cancer activities at three
cancer cell lines namely NCI-H460, MCF7, and
SF-268 of non-small cell lung cancer, breast cancer,
and CNS cancer, respectively. Pre-screening data
(Table 1) of 10 compounds showed appreciable anti-
cancer activities of compounds 3 and 9–12. On the
basis of these data, 11 (nine of them have 2-phenyleth-
anol moiety on amine nitrogen) compounds have been
evaluated for their anti-cancer activities against all the
59 human tumor cell lines following the standard pro-
cedure11 at NCI, Bethesda (USA). The results of these
studies in terms of 50% growth inhibitory concentra-
tions of respective compounds (GI50) have been given
in Table 2.
Cl
15
Scheme 4. Reagents and conditions: (i) dry THF, MgSO4, stir, rt;
(R)-2-phenylglycinol (for 14), (S)-2-phenylglycinol (for 15); (ii) pre-
generated In2(allyl)3Br3, THF/Toluene (1:2), stir, 27 ꢁC.
HO
1
2
HN
1'
3'
2'
O
N
16
H
i, ii
HO
HN
N
4. Discussion
The pre-screening anti-cancer data of indole-based com-
pounds 3–12 at 10ꢀ4 M concentration in terms of
growth percentage at three cancer cell lines (NCI-
H460, MCF7, and SF-268) have been given in Table 1.
All these compounds differ from one another in the nat-
ure of group present at the nitrogen of C-3 substituent
of indole. Compound 3 with benzyl group at nitrogen
shows moderate growth inhibition of tumor cells at
NCI-H460 and MCF7 cell lines. Substitution of benzyl
group of compound 3 with p-chloro-benzyl in com-
pound 4 has considerably reduced the growth inhibition
of tumor cells at all the three cell lines. Introduction of
another benzyl group at nitrogen (compound 5) has
not reduced the growth inhibition of tumor cells rather
it promotes the growth. Compounds 6 and 7 with
o-methoxyphenyl and p-methoxyphenyl group, respec-
tively, at nitrogen show very poor growth inhibition of
tumor cells at all the three cell lines. The presence of
hydroxy ethyl chain on nitrogen in case of compound
8 leads to moderate inhibition of tumor cells. Com-
pounds 9 and 10 with respective (S)- and (R)-phenylgly-
N
17
Scheme 5. Reagents and conditions: (i) dry THF, MgSO4, stir, rt,
(R)-2-phenylglycinol (for 16), (S)-2-phenylglycinol (for 17); (ii) pre-
generated In2(allyl)3Br3, THF/Toluene (1:2), 27 ꢁC.
The reactions of quinolin-2-carbaldehyde with (R)-2-phe-
nylglycinol and (S)-2-phenylglycinol with subsequent
allylations of Schiff bases result in diastereoselective
formation of compounds 18 and 19, respectively
(Scheme 6).
HO
2
HN
1'
3'
2'
N
O
18
HO
HN
i, ii
H
N
Table 1. Growth percentage of tumor cells in the presence of
compounds 3–12 at 10ꢀ4 M concentration
N
Cell line
Growth percentage (10ꢀ4 M)
Compound:
3
4
5
6
7
8
9
10 11 12
19
NCI-H460
MCF7
SF-268
14 71 105
27 46 118
98
55
97 68 3
60 58 21
0
0
1
5
35 21
Scheme 6. Reagents and conditions: (i) dry THF, MgSO4, stir, rt;
(R)-2-phenylglycinol (for 18), (S)-2-phenylglycinol (for 19); (ii) pre-
generated In2(allyl)3Br3, THF/toluene (1:2), 27 ꢁC.
73 81
81 111 116 95 42 16 50 35

P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
2389
Table 2. Concentrations of compounds resulting in growth inhibitions of 50% (log GI50) of in vitro human tumor cell lines
Panel/cell line
Compound
3
9
10
11
12
14
15
16
17
18
19
Leukemia
CCRF-CEM
HL-60 (TB)
K-562
ꢀ4.71
ꢀ4.72
ꢀ4.62
ꢀ4.65
ꢀ4.81
ꢀ4.75
nd
ꢀ4.36
ꢀ4.65
nd
ꢀ4.65
ꢀ4.97
ꢀ5.23
ꢀ5.17
nd
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
>ꢀ4.0
ꢀ4.41
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
4.13
>ꢀ4.0
ꢀ4.31
>ꢀ4.0
nd
ꢀ4.34
ꢀ4.91
ꢀ4.44
nd
nd
nd
ꢀ4.62
ꢀ4.47
ꢀ5.63
ꢀ5.0
ꢀ5.07
ꢀ4.75
ꢀ4.15
ꢀ4.95
ꢀ4.81
ꢀ4.88
nd
ꢀ5.57
ꢀ4.82
ꢀ5.16
MOLT-4
RPMI-8226
SR
nd
nd
ꢀ4.88
ꢀ5.43
nd
>ꢀ4.0
>ꢀ4.0
ꢀ4.49
ꢀ4.74
>ꢀ4.0
>ꢀ4.0
ꢀ4.52
ꢀ4.77
nd
nd
nd
Non-small cell lung cancer
A549/ATCC
EKVX
HOP-62
ꢀ4.50
ꢀ4.68
ꢀ4.61
ꢀ4.86
ꢀ4.46
ꢀ4.45
ꢀ4.69
ꢀ4.78
ꢀ4.64
ꢀ4.69
ꢀ4.69
ꢀ4.58
ꢀ4.66
ꢀ4.88
ꢀ4.76
ꢀ4.84
ꢀ4.74
ꢀ4.82
ꢀ4.80
ꢀ4.86
ꢀ4.43
ꢀ4.82
ꢀ4.60
ꢀ4.64
ꢀ4.54
ꢀ4.85
nd
ꢀ4.90
ꢀ4.60
ꢀ4.77
ꢀ4.60
ꢀ4.82
ꢀ4.79
ꢀ4.92
ꢀ5.41
ꢀ4.86
ꢀ4.71
ꢀ4.57
ꢀ4.74
ꢀ4.84
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.13
>ꢀ4.0
nd
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
HOP-92
NCI-H226
NCI-H23
NCI-H322M
NCI-H460
NCI-H522
nd
nd
>ꢀ4.0
ꢀ4.22
>ꢀ4.0
nd
>ꢀ4.0
>ꢀ4.0
Nd
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
ꢀ4.75
ꢀ4.48
>ꢀ4.0
ꢀ4.70
ꢀ4.72
ꢀ4.60
ꢀ4.49
ꢀ4.75
ꢀ4.69
ꢀ4.95
>ꢀ4.0
ꢀ4.73
nd
>ꢀ4.0
ꢀ4.59
ꢀ4.19
Colon cancer
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
ꢀ4.55
ꢀ4.85
ꢀ4.89
ꢀ4.68
ꢀ4.53
ꢀ4.55
ꢀ4.74
ꢀ4.70
ꢀ4.79
ꢀ4.81
ꢀ4.72
ꢀ4.63
ꢀ4.82
ꢀ4.54
ꢀ4.71
ꢀ4.80
ꢀ4.83
ꢀ4.73
ꢀ4.51
ꢀ4.78
4.59
ꢀ4.60
ꢀ4.77
ꢀ4.62
ꢀ4.49
ꢀ4.44
ꢀ4.66
ꢀ4.55
ꢀ4.45
ꢀ4.80
ꢀ4.77
ꢀ4.63
ꢀ4.51
ꢀ4.70
ꢀ4.50
ꢀ4.83
ꢀ4.97
ꢀ5.19
ꢀ5.03
ꢀ4.96
ꢀ4.76
ꢀ4.61
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
KM12
SW-620
CNS cancer
SF-268
SF-295
SF-539
SNB-19
SNB-75
U251
>ꢀ4.0
ꢀ4.66
ꢀ5.26
ꢀ4.19
ꢀ4.37
ꢀ4.72
ꢀ4.64
ꢀ4.68
ꢀ4.69
nd
ꢀ4.49
ꢀ4.81
ꢀ4.73
ꢀ4.65
ꢀ4.64
ꢀ4.75
ꢀ4.48
ꢀ4.80
ꢀ4.55
ꢀ4.22
ꢀ4.16
ꢀ4.56
>ꢀ4.0
ꢀ5.09
ꢀ4.67
ꢀ4.22
ꢀ4.18
ꢀ4.75
ꢀ4.73
ꢀ5.09
ꢀ4.82
ꢀ4.45
ꢀ4.78
ꢀ4.95
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
nd
nd
>ꢀ4.0
>ꢀ4.0
nd
>ꢀ4.0
>ꢀ4.0
nd
>ꢀ4.0
>ꢀ4.0
nd
nd
ꢀ4.75
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
Melanoma
LOX IMVI
MALME-3M
M14
ꢀ4.77
>ꢀ4.0
ꢀ4.73
ꢀ4.88
ꢀ4.38
ꢀ4.86
ꢀ4.62
ꢀ4.65
ꢀ4.78
ꢀ4.77
ꢀ4.74
ꢀ4.47
ꢀ4.47
ꢀ4.85
ꢀ4.64
ꢀ4.52
ꢀ4.80
ꢀ4.71
nd
ꢀ4.86
nd
ꢀ5.20
ꢀ4.46
ꢀ5.21
ꢀ4.72
ꢀ4.70
ꢀ4.83
ꢀ4.63
ꢀ5.12
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.25
ꢀ4.13
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
>4.0
ꢀ4.05
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
nd
4.84
4.74
ꢀ4.67
ꢀ4.37
ꢀ4.27
ꢀ5.00
ꢀ4.74
ꢀ4.64
ꢀ4.84
ꢀ4.49
ꢀ4.38
ꢀ4.58
ꢀ4.97
ꢀ4.82
SK-MEL-2
SK-MEL-28
SK-MEL-5
UACC-257
UACC-62
ꢀ4.55
ꢀ4.76
<ꢀ8.0
ꢀ4.79
>ꢀ4.0
>ꢀ4.0
ꢀ4.49
>ꢀ4.0
Ovarian cancer
IGROV1
ꢀ4.73
ꢀ4.76
ꢀ4.29
ꢀ4.80
ꢀ4.62
ꢀ4.35
ꢀ4.64
ꢀ4.80
ꢀ4.09
ꢀ4.63
ꢀ4.50
ꢀ4.31
ꢀ5.07
ꢀ4.94
ꢀ4.43
ꢀ4.79
ꢀ4.87
ꢀ4.50
ꢀ5.11
ꢀ4.78
ꢀ4.30
ꢀ4.31
ꢀ4.66
ꢀ4.09
ꢀ4.84
>ꢀ4.0
ꢀ4.13
>ꢀ4.0
ꢀ4.97
ꢀ4.22
ꢀ4.87
ꢀ5.06
ꢀ4.57
ꢀ4.59
ꢀ4.82
ꢀ4.20
nd
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.59
>ꢀ4.0
>ꢀ4.0
nd
ꢀ4.34
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.53
ꢀ4.24
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
OVCAR-3
OVCAR-4
OVCAR-5
OVCAR-8
SK-OV-3
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
Renal cancer
786-0
A498
ꢀ4.73
nd
ꢀ4.74
ꢀ4.59
ꢀ4.62
ꢀ4.87
ꢀ4.64
ꢀ4.67
ꢀ4.63
ꢀ4.49
ꢀ4.82
nd
ꢀ4.55
nd
>ꢀ4.0
nd
ꢀ4.90
ꢀ4.96
ꢀ5.32
ꢀ5.35
ꢀ5.07
ꢀ4.84
ꢀ4.33
ꢀ5.16
>ꢀ4.0
ꢀ4.87
>ꢀ4.0
ꢀ4.13
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.33
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.64
>ꢀ4.0
ꢀ4.03
>ꢀ4.0
ꢀ4.53
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>4.0
ꢀ4.03
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.17
>4.0
ACHN
CAKI-1
RXF 393
SN12C
TK-10
ꢀ4.73
ꢀ4.73
ꢀ4.72
ꢀ4.59
ꢀ4.78
ꢀ4.52
ꢀ4.79
ꢀ4.91
ꢀ6.01
ꢀ4.74
ꢀ4.78
ꢀ4.79
ꢀ4.49
ꢀ4.86
ꢀ4.72
ꢀ4.71
ꢀ4.86
ꢀ4.34
ꢀ4.74
ꢀ4.94
nd
ꢀ4.77
ꢀ5.44
ꢀ4.02
UO-31
ꢀ4.05
Prostate cancer
PC-3
ꢀ4.64
ꢀ4.65
ꢀ4.63
ꢀ4.80
ꢀ4.75
ꢀ5.39
ꢀ4.08
>ꢀ4.0
>4.0
>ꢀ4.0
>ꢀ4.0
(continued on next page)

2390
P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
Table 2 (continued)
Panel/cell line
Compound
3
9
10
11
12
14
15
16
17
18
19
DU-145
ꢀ4.68
ꢀ4.56
ꢀ4.71
ꢀ4.52
ꢀ4.57
ꢀ4.63
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
Breast cancer
MCF7
ꢀ4.29
ꢀ4.67
ꢀ4.74
ꢀ4.70
ꢀ4.69
ꢀ4.67
ꢀ4.48
ꢀ4.53
ꢀ4.72
ꢀ4.69
ꢀ4.68
ꢀ4.64
ꢀ4.48
ꢀ4.59
ꢀ4.45
ꢀ4.80
ꢀ4.80
ꢀ4.71
ꢀ4.74
ꢀ4.70
ꢀ4.60
ꢀ4.46
ꢀ4.66
ꢀ4.88
ꢀ4.64
ꢀ4.69
ꢀ4.61
ꢀ4.40
>ꢀ4.0
ꢀ4.72
ꢀ4.97
ꢀ4.61
ꢀ4.72
ꢀ4.69
ꢀ4.25
ꢀ4.79
ꢀ5.03
ꢀ5.43
ꢀ4.59
ꢀ4.80
<ꢀ8.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
nd
nd
nd
NCI/ADR-RES
MDA-MB-2321/ATCC
HS 578T
>ꢀ4.0
>ꢀ4.0
ꢀ4.65
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.34
>ꢀ4.0
>ꢀ4.0
>ꢀ4.0
ꢀ4.21
MDA-MB-435
BT-549
T-47D
>ꢀ4.0
nd, not done (the evaluation has not been performed at this cell line).
cinol moieties at nitrogen, that is, possessing both benzyl
and ethanol units show best growth inhibition of tumor
cells at all the three cell lines. Compound 11, with
iso-propyl group in place of phenyl group in 9, exhibits
less growth inhibition in comparison to 9. The replace-
ment of ester moiety at N-1 of indole in compound 10
with p-toluenesulfonyl does not improve the growth
inhibitory property of compound 12.
ration of phenylglycinol is quite significant in case of
pyrimidine derivatives 14 and 15. Compound 14 (aver-
age GI50 1.16 · 10ꢀ5 M) with same side chain as in com-
pounds 10 and 12 but on the pyrimidine moiety shows
better anti-cancer activity than its analogue 15
(GI50 > 10ꢀ4 M) with S-configuration on the chiral car-
bon carrying phenyl group (C-10). Compound 14 inhib-
its 50% growth of BT-549 cell line of breast cancer at
<10ꢀ8 M concentration. The replacement of pyrimidine
moieties of compounds 14 and 15 with pyridine in com-
pounds 16 and 17 or with quinoline in compounds 18
and 19 leads to considerable decrease in their anti-cancer
activities.
Therefore, it was found that amongst the 10 compounds
subjected to pre-screening anti-cancer investigations,
compounds 9 and 10 possessing (S)- and (R)-phenylgly-
cinol give best results in terms of growth inhibition of
tumor cells and were chosen for further detailed studies
at 59 human tumor cell lines along with compounds 3,
11, and 12. Moreover, based upon these results six more
compounds with the same substituent as present at C-3
of 9 and 10 but at C-5 of pyrimidine (14 and 15), C-2 of
pyridine (16 and 17), and C-2 of quinoline (18 and 19)
were included for studying anti-cancer activities at 59
cancer cell lines.
Therefore, amongst the 11 compounds investigated over
all the 59 human tumor cell lines, compounds with
indole and pyrimidine as the central core exhibit better
anti-cancer activities than those with pyridine and
quinoline moieties as the central part of the molecule.
5. Conclusions
All the 11 compounds subjected to 59 Human tumor cell
lines carry a similar side chain of but-3-enylamino-2-hy-
drogen-/phenyl-/isopropyl-ethanol on indole, pyrimi-
dine, pyridine, and quinoline heterocyclic moiety
except for compound 3. It is evident from the data of
anti-cancer activities given in Table 2 that almost all
the compounds are active against the 59 Human tumor
cell lines assays. Some of the compounds are more spe-
cific for certain cell lines and show inhibitory activities at
sub-micromolar concentrations. Compounds 9–11 show
average GI50 over the entire cell lines in the range
1.58 · 10ꢀ5 to 2.27 · 10ꢀ5 M which is quite similar to
the anti-cancer activity shown by 5-fluorouracil (average
GI50 1.77 · 10ꢀ5 M). Amongst compounds 3–10,
remarkable anti-cancer activity of 10 has been observed
against UACC-257 cell line of melanoma cancer
(GI50 < 10ꢀ8 M). Change of ester group present at N-1
of indole in compound 10 with tosyl group in compound
12 results in decrease in the anti-cancer activities (aver-
age GI50 2.83 · 10ꢀ5 M). Significantly, in contrast to
the preliminary investigations where 3 shows poor activ-
ity in comparison to 9–11 (Table 1), the detailed investi-
gations over 59 tumor cell lines show the anti-cancer
activity of 3 (average GI50 2.29 · 10ꢀ5 M) quite similar
to those of compounds 9–11. The effect of R/S-configu-
Schiff bases formed from indole-/, pyrimidine-/, pyri-
dine-/, quinoline-aldehydes and substituted amines on
indium mediated allylation provide a versatile synthetic
methodology for incorporating hydrophilic as well as
hydrophobic groups at the respective heterocyclic sys-
tem. Out of the 16 compounds studied here, six (3, 9–
12, and 14) compounds show appreciable anti-cancer
activities which are quite similar to anti-cancer activity
of 5-fluorouracil and out of these compounds 10 and
14 bearing (R)-2-phenylglycinol as part of side chain
at C-3 of indole and C-5 of pyrimidine show best anti-
cancer activities.
6. Experimental
6.1. General details
Melting points were determined in capillaries and are
uncorrected. 1H and 13C NMR spectra were run on
JEOL 300 and 75 MHz NMR spectrometer, respective-
ly, using CDCl3 as solvent. Chemical shifts are given in
parts per million with TMS as an internal reference.
J values are given in Hertz. Chromatography was

P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
2391
performed with silica 100–200 mesh and reactions were
monitored by thin layer chromatography (TLC) with
silica plates coated with silica gel HF-254. Indole-3-
carbaldehyde, pyridine-2-carbaldehyde, and quinoline-
2-carbaldehyde were obtained form Aldrich.
CH), 128.38 (+ve, CH), 129.28 (+ve, CH), 129.47 (ab,
CH), 132.50 (ab, C), 135.13 (+ve, CH), 136.00 (ab, C),
138.92 (ab, C), 150.97 (ab, C); FAB mass (M+) m/z
382, 384 (3:1), 341, 343 (M+-allyl). Anal. Calcd for
C22H23ClN2O2: C, 69.01%; H, 6.05%; N, 7.32%. Found:
C, 69.30%; H, 6.18%; N 7.48%.
6.2. General procedure for the synthesis of compounds 3,
4, and 6–12
6.2.3. 3-(1-Dibenzylamino-but-3-enyl)-indole-1-carboxylic
acid ethyl ester (5). A mixture of 3 (0.001 mol), benzyl
chloride (0.0012 mol), K2CO3 (0.0012 mol), and TBAH-
SO4 (phase transfer catalyst) in dry CH3CN was refluxed
with stirring. After completion of the reaction (TLC,
15 h), the solid suspension was filtered off and washed
twice with chloroform (20 ml). The solvent was removed
under reduced pressure and the crude product was col-
umn chromatographed and crystallized to isolate pure
The solution of 3-formyl-indol-1-carboxylic acid ethyl
ester [1-(toluene-4-sulfonyl)-1H-indole-3-carbaldehyde
for 12 (1 mmol)] and appropriate amine (1.2 mmol) in
dry THF was stirred at 27 ꢁC over anhydrous MgSO4
for 24 h. After completion of the formation of imine
(TLC), the suspended MgSO4 was filtered and the
solvent was removed under vacuum. The imine thus
obtained was taken in THF/toluene (1:2) and
transferred to the cooled solution of allylindium reagent
obtained by refluxing a solution of allyl bromide
(5 mmol) and indium (2 mmol) in dry THF (2 ml) for
1 h. The reaction mixture was stirred at 27 2 ꢁC. The
progress of the reaction was monitored by TLC. On
completion, the reaction mixture was diluted with 5 ml
of water and extracted with CHCl3 (3· 25 ml). The
organic phase was dried over Na2SO4. The removal of
solvent provided a dark yellow brown liquid. The crude
reaction mixture was column chromatographed over
silica gel to isolate the pure homoallylic amine.
1
5. Yield 69%, solid, mp 123 ꢁC; H NMR (300 MHz): d
1.51 (t, J = 7.2 Hz, 3H, CH3), 1.94 (br s, 1H, NH,
exchanges with D2O), 2.63–2.65 (m, 1H, CH2), 2.92–
2.96 (m, 1H, CH2), 3.53 (d, J = 13.2 Hz, 2H, NCH2),
3
3.71 (d, J = 13.2 Hz, 2H, NCH2), 4.14 (dd, J = 6.0 Hz,
3J = 8.7 Hz, 1H, NCH), 4.49 (q, J = 7.2 Hz, 2H,
OCH2), 4.99–5.13 (m, 2H, @CH2), 5.78–5.87 (m, 1H,
@CH), 7.15–7.51 (m, 13H, ArH), 7.52 (s, 1H, InH-2),
8.13 (d, J = 7.8 Hz, 1H, InH-2); 13C NMR (normal/
DEPT-135) (75 MHz): d 14.39 (+ve, CH3), 33.61 (ꢀve,
CH2), 53.87 (ꢀve, CH2), 54.04 (+ve, CH), 63.87 (ꢀve,
CH2), 115.00 (+ve, CH), 116.37 (ꢀve, CH2), 120.51
(+ve, CH), 122.55 (+ve, CH), 123.32 (ab, C), 124.46
(+ve, CH), 126.87 (+ve, CH), 128.16 (+ve, CH), 129.02
(+ve, CH), 129.35 (ab, C), 135.29 (ab, C), 136.39 (+ve,
CH), 140.01 (+ve, CH), 140.43 (ab, C), 150.97 (ab, C);
FAB mass (M+) m/z 438. Anal. Calcd for C29H30N2O2:
C, 79.42%; H, 6.89%; N, 6.39%. Found: C, 79.12%; H,
6.64%; N, 6.32%.
6.2.1. 3-(1-Benzylamino-but-3-enyl)-indole-1-carboxylic
acid ethyl ester (3). Yield 83%, liquid, 1H NMR
(300 MHz): d 1.45 (t, J = 7.2 Hz, 3H, CH3), 1.94 (br s,
1H, NH, exchanges with D2O), 2.51–2.71 (m, 2H, CH2),
3.79 (d, J = 13.2 Hz, 2H, NCH2), 4.03 (t, J = 6.6 Hz,
1H, CH), 4.48 (q, J = 7.2 Hz, 2H, OCH2), 5.04–5.24 (m,
2H, @CH2), 5.69–5.87 (m, 1H, @CH), 7.24–7.36 (m,
7H, ArH), 7.58 (s, 1H, indole H-2), 7.73 (d, J = 7.8 Hz,
1H, InH), 8.19 (d, J = 6.9 Hz, 1H, InH); 13C NMR
(normal/DEPT-135) (75 MHz): d 14.39 (+ve, CH3),
40.79 (ꢀve, CH2), 51.47 (ꢀve, CH2), 54.04 (+ve, CH),
63.03 (ꢀve, CH2), 115.28 (+ve, CH), 117.65 (ꢀve, CH2),
119.97 (+ve, CH), 122.56 (+ve, CH), 122.85 (+ve, CH),
123.32 (ab, C), 124.49 (+ve, CH), 126.82 (+ve, CH),
128.11 (+ve, CH), 128.29 (+ve, CH), 129.35 (ab, C),
135.29 (ab, C), 135.96 (+ve, CH), 140.43 (ab, C), 150.97
(ab, C). FAB mass (M+) m/z 348, 307 (M+-allyl). Anal.
Calcd for C22H24N2O2: C, 75.83%; H, 6.94; N, 8.04.
Found: C, 75.60%; H, 6.72%; N, 8.25%.
6.2.4. 3-[1-(2-Methoxy-phenylamino)-but-3-enyl]-indole-
1-carboxylic acid ethyl ester (6). Yield 68%, liquid, H
1
NMR (300 MHz): d 1.43 (t, J = 7.2 Hz, 3H, CH3),
1.54 (br s, 1H, NH, exchanges with D2O), 2.70–2.76
(m, 2H, CH2), 3.86 (s, 3H, OCH3), 4.40 (q, J = 7.2 Hz,
2H, OCH2), 4.69 (deformed t, J = 6.6 Hz, 1H, NCH),
5.11–5.23 (m, 2H, @CH2), 5.73–5.86 (m, 1H, @CH),
6.48 (d, J = 7.5 Hz, 1H, ArH), 6.63 (t, J = 7.5 Hz, 1H,
ArH), 6.69 (t, J = 7.5 Hz, 1H, ArH), 6.75 (d,
J = 7.5 Hz, 1H, ArH), 7.26 (t, J = 8.0 Hz, 1H, InH),
7.32 (t, J = 8 Hz, 1H, InH), 7.52 (s, 1H, InH-2), 7.64
(d, J = 7.8 Hz, 1H, InH), 8.18 (d, J = 7.8 Hz, 1H,
InH); 13C NMR (normal/DEPT-135) (75 MHz): d
14.43 (+ve, CH3), 40.57 (ꢀve, CH2), 50.21 (+ve, CH),
55.52 (+ve, CH3), 63.07 (ꢀve, CH2), 109.45 (+ve, CH),
110.98 (+ve, CH), 115.46 (+ve, CH), 116.66 (+ve,
CH), 118.17 (ꢀve, CH2), 119.24 (+ve, CH), 121.18
(+ve, CH), 122.72 (+ve, CH), 123.35 (ab, C), 124.57
(+ve, CH), 128.93 (ab, C), 134.51 (+ve, CH), 136.12
(ab, C), 137.29 (ab, C), 146.91 (ab, C), 150.97 (ab, C);
FAB mass (M+) m/z 364, 323 (M+-allyl). Anal. Calcd
for C22H24N2O3: C, 72.50%; H, 6.64%; N, 7.69%.
Found: C, 72.30%; H, 6.62%; N, 7.80%.
6.2.2. 3-[1-(4-Chlorobenzylamino)-but-3-enyl]-indole-1-car-
boxylic acid ethyl ester (4). Yield 86%, liquid, H NMR
1
(300 MHz): d 1.47 (t, J = 7.2 Hz, 3H, CH3), 1.64 (br s,
1H, NH, exchanges with D2O), 2.53–2.65 (m, 2H,
CH2), 3.74 (d, J = 13.2 Hz, 2H, NCH2), 3.99 (t,
J = 6.9 Hz, 1H, CH), 4.49 (q, J = 7.2 Hz, 2H, CH2),
5.01–5.07 (m, 2H, @CH2), 5.69–5.82 (m, 1H, @CH),
7.17–7.37 (m, 6H, ArH), 7.55 (s, 1H, InH-2), 7.72 (d,
J = 7.8 Hz, 1H, InH), 8.19 (d, J = 7.8 Hz, 1H, InH);
13C NMR (normal/DEPT-135) (75 MHz): d 14.41
(+ve, CH3), 40.78 (ꢀve, CH2), 50.71 (ꢀve, CH2), 54.10
(+ve, CH), 63.10 (ꢀve, CH2), 115.34 (+ve, CH),
117.76 (ꢀve, CH2), 119.94 (+ve, CH), 122.60 (+ve,
CH), 122.91 (+ve, CH), 123.10 (ab, C), 124.57 (+ve,
6.2.5. 3-[1-(4-Methoxy-phenylamino)-but-3-enyl]-indole-
1-carboxylic acid ethyl ester (7). Yield 71%, liquid, H
1
NMR (300 MHz): d 1.46 (t, J=7.2 Hz, 3H, CH3), 1.56

2392
P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
(br s, 1H, NH, exchanges with D2O), 2.72–2.78 (m, 2H,
CH2), 3.71 (s, 3H, OCH3), 4.45 (q, J = 7.2 Hz, 2H,
OCH2), 4.61 (t, J = 6.3 Hz, 1H, NCH), 5.13–5.23 (m,
2H, @CH2), 5.71–5.84 (m, 1H, @CH), 6.54 (d,
J = 6.6 Hz, 2H, ArH), 6.72 (d, J = 6.6 Hz, 2H, ArH)
7.26 (t, J = 7.8 Hz, 1H, InH-2), 7.35 (t, J = 7.8 Hz, 1H,
InH), 7.37 (s, 1H, InH-2), 7.64 (d, J = 7.8 Hz, 1H,
InH), 8.17 (d, J = 7.8 Hz, 1H, InH); 13C NMR (nor-
mal/DEPT-135) (75 MHz): d 14.43 (+ve, CH3), 40.45
(ꢀve, CH2), 51.31 (+ve, CH3), 63.12 (ꢀve, CH2),
114.68 (+ve, CH), 115.04 (+ve, CH), 115.43 (+ve,
CH), 118.34 (ꢀve, CH2), 119.18 (+ve, CH), 122.69
(+ve, CH), 128.57 (ab, C), 134.50 (+ve, CH), 150.97
(ab, C). FAB mass (M+) m/z 364, 323 (M+-allyl). Anal.
Calcd for C22H24N2O3: C, 72.50%; H, 6.64%; N, 7.69%.
Found: C, 72.30%; H, 6.62%; N, 7.80%.
(M+ꢀCH(C6H5)CH2OH) m/z 242. Anal. Calcd for
C23H26N2O3: C, 72.99%; H, 6.92%; N, 7.40%. Found:
C, 72.80%; H, 6. 75%; N, 7.53%.
6.2.8. (1R,10R)-3-[1-(2-Hydroxy-1-phenyl-ethylamino)-but-
3-enyl]-indole-1-carboxylic acid e thyl ester (10). Yield
1
65%, liquid, [a]25 = ꢀ20.60 (c 0.66, CHCl3); H NMR
(CDCl3): d 1.46 (t, J = 7.2 Hz, 3H,CH3), 2.26 (br s,
1H, NH, exchanges with D2O), 2.62–2.67 (m, 2H,
CH2), 3.41 (br s, 1H, OH, exchangeable with D2O),
3.54 (dd, J = 8.0 Hz, J = 10.8 Hz, 1H, CH2OH), 3.74
(dd, J = 4.5 Hz, J = 10.8 Hz, 1H, CH2OH), 3.96 (dd,
J = 4.5 Hz, J = 8 Hz, 1H, CH), 4.01 (t, J = 6.6 Hz, 1H,
NCH), 4.46 (q, J = 7.2 Hz, 2H, CH2), 5.00–5.09 (m,
2H, @CH2), 5.64–5.78 (m, 1H, @CH), 7.15–7.33 (m,
7H, ArH), 7.43 (d, J = 7.2 Hz, 2H, ArH), 8.14 (d,
J = 7.8 Hz, 1H, InH-2); 13C NMR (normal/DEPT-135)
(75 MHz): d 14.38 (+ve, CH3), 38.94 (ꢀve, CH2allyl),
51.74 (+ve, NCH), 61.60 (+ve, PhCH), 63.08 (ꢀve,
OCH2), 66.06 (ꢀve, CH2OH), 115.26 (+ve, H-6indole),
117.55 (ꢀve, @CH2), 119.56 (+ve, CH), 122.56 (+ve,
CH), 122.73 (+ve, CH), 123.36 (ab, C), 124.55 (+ve,
CH), 127.11 (+ve, CH), 127.51 (+ve, CH), 128.50
(+ve, CH), 128.98 (ab, C), 134.65 (+ve, @CH), 135.70
(ab, C), 140.60 (ab, C), 150.85 (ab, C); decoupling of
2H multiplet at d 2.62–2.67 changes 1H triplet at d
4.01 to singlet and multiplet at d 5.64–5.78 into double
doublet. Decoupling of dd at d 3.54 converts double
6.2.6. 3-[1-(2-Hydroxy-ethylamino)-but-3-enyl]-indole-1-
carboxylic acid ethyl ester (8). Yield 70%, liquid, 1H
NMR (300 MHz): d 1.47 (t, J=7.2 Hz, 3H,CH3), 1.62
(br s, 1H, NH, exchanges with D2O), 3.41 (br s, 1H,
OH, exchanges with D2O), 2.62 (m, 2H, CH2) 2.75 (t,
J=5.4 Hz, 2H, NCH2), 3.41–3.64 (m, 2H, CH2OH),
4.01 (t, J = 6.6 Hz, 1H, NCH), 4.48 (q, J = 7.2 Hz, 2H,
OCH2), 5.06–5.15 (m, 2H, @CH2), 5.71–5.82 (m, 1H,
@CH), 7.25 (t, J = 7.5 Hz, 1H, ArH), 7.33 (t,
J = 7.5 Hz, 1H, InH), 7.53 (s, 1H, In H-2), 7.69 (d,
J = 7.5 Hz, 1H, InH-2), 8.18 (d, J = 7.5 Hz, 1H, InH-
2); 13C NMR (normal/DEPT-135) (75 MHz): d 14.43
(+ve, CH3), 40.49 (ꢀve, CH2), 48.80 (ꢀve, CH2), 54.64
(+ve, CH), 61.32 (ꢀve, CH2), 63.17 (ꢀve, CH2),
115.45 (+ve, CH), 117.86 (ꢀve, CH2), 119.61 (+ve,
CH), 122.74 (+ve, CH), 122.80 (ab, C), 123.05 (ab, C),
124.67 (+ve, CH), 129.23 (ab, C), 134.98 (+ve, CH),
150.98 (ab, C). FAB mass (M++1) m/z 303, 361 (M+-al-
lyl). Anal. Calcd for C17H22N2O3: C, 67.53%; H, 7.33%;
N, 9.26%. Found: C, 67.45%; H, 7.18%; N, 9.35%.
1
doublets at d 3.74 and 3.96 into doublets. In H–13C
HETCOR spectrum, cross peaks are observed between:
carbon at d 14.38 and triplet at d 1.46 (CH3); CH2 car-
bons at d 38.94 and multiplet at d 2.62–2.74; CH2 at d
117.55 and multiplet at d 5.00–5.09; CH at d 51.74 and
triplet at d 4.01; carbon at d 61.60 and dd at d 3.96;
CH2carbon at d 63.08 and quartet at d 4.46 (OCH2); car-
bon at d 66.06 and dds at d 3.54 and 3.74; carbon at d
115.26 and doublet at d 8.14; carbon at d 136.65 and
multiplet at d 5.64–5.78; carbons at d 119.56, 122.56,
122.73, 124.55, 127.11, 127.51, and 128.50 with multiplet
at d 7.15–7.33 and doublet at d 7.43 (ArH). FAB mass
(M+ꢀCH(C6H5)CH2OH) m/z 242. Anal. Calcd for
C23H26N2O3: C, 72.99%; H, 6.92%; N, 7.40%. Found:
C, 72.80%; H, 6. 75%; N, 7.53%.
6.2.7. (1S,10S)-3-[1-(2-Hydroxy-1-phenyl-ethylamino)-but-
3-enyl]-indole-1-carboxylic acid ethyl ester (9). Yield 68%,
liquid, [a]25 = +19.0 (c 0.70, CHCl3); 1H NMR
(300 MHz): d 1.46 (t, J = 7.2 Hz, 3H,CH3), 1.62 (br s,
1H, NH, exchanges with D2O), 2.62–2.67 (m, 2H,
CH2), 3.41 (br s, 1H, OH, exchangeable with D2O),
3.53 (dd, J = 8.0 Hz, J = 10.8 Hz, 1H, CH2OH), 3.74
(dd, J = 4.5 Hz, J = 10.8 Hz, 1H, CH2OH), 3.95 (dd,
J = 4.5 Hz, J = 8 Hz, 1H, CH), 4.01 (t, J = 6.6 Hz, 1H,
NCH), 4.47 (q, J = 7.2 Hz, 2H, OCH2), 5.00–5.09 (m,
2H, @CH2), 5.65–5.79 (m, 1H, @CH), 7.15–7.30 (m,
7H, ArH), 7.43 (d, J = 7.2 Hz, 2H, ArH), 8.14 (d,
J = 7.8 Hz, 1H, InH-2); 13C NMR (normal/DEPT-135)
(75 MHz): d 14.41 (+ve, CH3), 39.03 (ꢀve, CH2),
51.77 (+ve, CH), 61.58 (+ve, CH), 63.11 (ꢀve, CH2),
66.12 (ꢀve, CH2), 115.29 (+ve, CH), 117.55 (ꢀve,
CH2), 119.60 (+ve, CH), 122.59 (+ve, CH), 122.70
(+ve, CH), 123.49 (ab, C), 124.57 (+ve, CH), 127.12
(+ve, CH), 127.53 (+ve, CH), 128.54 (+ve, CH),
129.00 (ab, C), 134.71 (+ve, CH), 135.73 (ab, C),
140.72 (ab, C), 150.88 (ab, C); decoupling of 2H multi-
plet at d 2.62–2.67 changes 1H triplet at d 4.01 to singlet
and multiplet at d 5.64–5.79 into double doublet.
Decoupling of dd at d 3.53 converts double doublets
6.2.9. (1S,10S)-3-[1-(1-Hydroxymethyl-2-methyl-propyl-
amino)-but-3-enyl]-indole-1-carboxylic acid ethyl ester
(11). Yield 64%, liquid, [a]25 = ꢀ15.99 (c 0.58, CHCl3)1H
NMR (300 MHz): d 0.77–0.92 (m, 6H, 2· CH3), 1.47 (t,
J = 6.9 Hz, 3H,CH3), 1.50 (br s, 1H, NH, exchanges
with D2O), 1.73–1.77 (m, 1H, CH(CH3)2), 2.41–2.44
(m, 1H,CH–CH2OH), 2.58–2.63 (m, 2H, CH2), 3.39
(dd, J = 4.2 Hz, J = 10.8 Hz, 1H, CH2OH), 3.42 (br s,
1H, OH, exchanges with D2O), 3.64 (dd, J = 5.4 Hz,
J = 10.8 Hz, 1H, CH2OH), 4.04 (t, J = 6.6 Hz, 1H,
NCH), 4.49 (q, J = 7.2 Hz, 2H, OCH2), 5.01–5.10 (m,
2H, @CH2), 5.73–5.75 (m, 1H, @CH), 7.22–7.34 (m,
2H, ArH), 7.51 (s, 1H, InH-2), 7.66 (d, J = 7.8 Hz,
1H, InH), 8.18 (d, J = 7.5 Hz, 1H, InH-2); 13C NMR
(normal/DEPT-135, DEPT-90) (75 MHz):
d 14.36
(+ve, CH3), 18.74 (+ve, CH3), 19.51 (+ve, CH3), 29.3
(+ve, CH), 55.2 (+ve, CH), 40.79 (ꢀve, CH2), 60.13
(ꢀve, CH2), 61.37 (+ve, CH), 63.11 (ꢀve, CH2),
117.38 (ꢀve, CH2), 117.43 (+ve, CH), 119.73 (+ve,
at
d 3.74 and 3.95 into doublets; FAB mass

P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
2393
CH), 122.59 (+ve, CH), 122.62 (ab, C), 122.61 (+ve,
CH), 124.59 (+ve, CH), 128.98 (ab, C) 135.12 (+ve,
CH), 135.38 (ab, C), 150.93 (ab, C); decoupling of mul-
tiplet at d 0.77–0.92 converts multiplet at d 1.73–1.77
into doublet. Decoupling of triplet at d 4.04 converts
multiplet at d 2.58–2.63 into doublet. Decoupling of
multiplet at d 5.73–5.75 converts the multiplet at d
2.58–2.63 into doublet, FAB mass (M++1) m/z 345,
303 (M+-allyl). Anal. Calcd for C20H28N2O3: C,
69.74%; H, 8.19%; N, 8.13%. Found: C, 69. 82%; H,
8.02%; N, 8.25%.
(ab, C), 134.79 (+ve, ArCH), 140.02 (+ve, ArCH),
142.10 (+ve, CH), 150.74 (ab, C), 161.95 (ab, C); FAB
mass (M++1) m/z 551. Anal. Calcd for C30H29Cl2N3O3:
C, 65.46%; H, 5.31%; N, 7.63%. Found: C, 65.12%; H,
5.62%; N, 7.51%.
6.3.2. (1S,10S)-1,3-Bis-(2-chlorobenzyl)-5-[1-(2-hydroxy-
1-phenyl-ethylamino)-but-3-enyl]-1H-pyrimidin-2,4-dione
(15). Yield 70%, [a]25 = ꢀ39.4 (c, 0.40, CHCl3), liquid,
1H NMR (300 MHz): d 2.44 (t, J = 7.2 Hz, 2H, CH2),
3.44–3.47 (m, 1H, CHPh), 3.62–3.68 (m, 1H, CHNH),
3.74–3.78 (m, 2H, CH2OH), 4.82 (s, 2H, CH2Ph), 4.91
(s, 2H, CH2Ph), 4.99–5.10 (m, 2H, @CH2), 5.71–5.78
(m, 1H, @CH), 7.17–7.39 (m, 8H, ArH), 7.51 (s, 1H,
Uracil H-6); 13C NMR (normal/DEPT-135) (75 MHz):
d 38.99 (ꢀve, CH2), 42.60 (ꢀve, CH2Ph), 49.72 (ꢀve,
CH2Ph), 62.87 (+ve, NCH), 65.12 (+ve, CHPh), 66.78
(ꢀve, CH2OH), 116.89 (ꢀve, CH2), 126.44 (+ve, ArCH),
126.68 (+ve, CH), 126.74 (+ve, ArCH), 127.18 (+ve,
ArCH), 127.96 (+ve, ArCH), 128.19 (+ve, ArCH),
129.23 (ab, C), 129.41 (+ve, ArCH), 130.59 (+ve,
ArCH), 130.76 (+ve, ArCH), 131.54 (+ve, ArCH),
133.14 (ab, C), 133.88 (ab, C), 133.99 (ab, C), 134.61
(ab, C), 134.79 (+ve, ArCH), 140.02 (+ve, ArCH),
142.10 (+ve, CH), 150.74 (ab, C), 161.95 (ab, C); FAB
mass (M++1) m/z 551. Anal. Calcd for C30H29Cl2N3O3:
C, 65.46%; H, 5.31%; N, 7.63%. Found: C, 65.52%; H,
5.68%; N, 7.48%.
6.2.10. (1R,10R)-3-[1-(2-Hydroxy-1-phenyl-ethylamino)-
but-3-enyl]-indole-1-p-toluenesulfonyl (12). Yield 67%, li-
quid, [a]25 = ꢀ14.15 (c 0.42, CHCl3); 1H NMR
(300 MHz): d 2.58 (s, 3H, CH3), 2.56–2.60 (m, 2H,
CH2), 3.53 (dd, J = 7.8 Hz, J = 10.5 Hz, 1H, CH2OH),
3.71 (dd, J = 4.5 Hz, J = 10.5 Hz, 1H, CH2OH), 3.89
(dd, J = 4.5 Hz, J = 7.8 Hz, 1H, CH), 3.97 (t,
J = 6.3 Hz, 1H, NCH), 4.82–5.00 (m, 2H, @CH2),
5.54–5.68 (m, 1H, @CH), 7.12–7.39 (m, 9H, ArH),
7.69 (d, J = 8.1 Hz, 2H, ArH), 7.78 (d, J = 8.7 Hz, 1H,
InH-2); 13C NMR (normal/DEPT-135) (75 MHz): d
21.52 (+ve, CH3), 38.84 (ꢀve, CH2), 51.85 (+ve, CH),
61.67 (+ ve, CH), 66.12 (ꢀve, CH2), 113.79 (+ve, CH),
117.78 (ꢀve, CH2), 120.02 (+ve, CH),122.98 (ab, C),
123.01 (+ve, CH), 123.63 (+ve, CH), 124.678 (+ve,
CH), 126.76 (+ve, CH), 127.12 (+ve, CH), 127.64
(+ve, CH), 128.58 (+ve, CH), 129.36 (ab, CH), 129.74
(+ve, CH), 134.37 (+ve, CH), 135.14 (ab, C), 135.44
(ab, C), 140.44 (ab, C), 144.82 (ab, C); decoupling of
dd at d 3.53 converts dd at d 3.71 and double doublet
at d 3.89 into doublets. Decoupling of multiplet at d
2.56–2.60 converts triplet at d 3.97 into singlet; FAB
mass (M+ꢀCH(C6H5)CH2OH) m/z 329. Anal. Calcd
for C27H28N2O3S: C, 70.41%; H, 6.13%; N, 6.08%.
Found: C, 70.55%; H, 6.21%; N, 6.13%.
6.3.3. (10R,2R)-2-Phenyl-2-(10-pyridin-2-yl-but-30-enyl-
amino)ethanol (16). Yield 80%, liquid, [a]25 = +24.4 (c
0.60, CHCl3), 1H NMR (300 MHz): d 2.78 (m, 2H,
CH2), 3.90 (br s, 2H, 1H of OH, 1H of NH), 3.44–
3.53 (m, 1H, CHPh), 3.58–3.74 (m, 1H, CHNH),
3.74–3.77 (m, 2H, CH2OH), 4.96–5.10 (m, 2H,
@CH2), 5.57–5.70 (m, 1H, @CH), 6.96–7.12 (m, 7H,
ArH), 7.39–7.46 (m, 1H, ArH), 8.34 (d, 1H, ArH);
13C NMR (normal/DEPT-135) (75 MHz): d 38.53
(ꢀve, CH2), 62.14 (+ve, CH), 64.22 (+ve, CH), 64.31
(ꢀve, CH2), 119.79 (ꢀve, CH2), 123.18 (+ve, CH),
127.92 (+ve, CH), 128.74 (+ve, CH), 128.88 (+ve,
CH), 131.91 (ab, C), 131.91 (ab, C), 136.86 (+ve,
CH), 149.04 (+ve, CH), 156.36 (ab, C). FAB mass
(M++1) m/z 269. Anal. Calcd for C17H20N2O: C,
76.09%; H, 7.51%; N, 10.44%. Found: C, 76.31%; H,
7.62%; N, 10.46%.
6.3. General procedure for the synthesis of compounds
14–19
Same reaction procedure has been followed as given in
Section 6.2 except the use of pyrimidin-5-carbaldehyde,
pyridine-2-carbaldehyde, and quinolin-2-carbaldehyde
instead of indol-2-carbaldehyde.
6.3.1. (1R,10R)-1,3-Bis-(2-chlorobenzyl)-5-[1-(2-hydroxy-
1-phenyl-ethylamino)-but-3-enyl]-1H-pyrimidin-2,4-dione
(14). Yield 80%, liquid, [a]25 = +38.0 (c, 0.40, CHCl3),
1H NMR (300 MHz): d 2.46 (t, J = 7.2 Hz, 2H, CH2),
3.38–3.45 (m, 1H, CHPh), 3.34–3.45 (m, 1H, CHNH),
3.58–3.61 (m, 2H, CH2OH), 4.78 (s, 2H, CH2Ph), 4.89
(s, 2H, CH2Ph), 4.94–5.20 (m, 2H, @CH2), 5.67–5.80
(m, 1H, @CH), 7.07–7.37 (m, 8H, ArH), 7.48 (s, 1H,
Uracil H-6); 13C NMR (normal/DEPT-135) (75 MHz):
d 38.95 (ꢀve, CH2), 42.52 (ꢀve, CH2Ph), 49.64 (ꢀve,
CH2Ph), 62.81 (+ve, NCH), 64.10 (+ve, CHPh), 66.08
(ꢀve, CH2OH), 117.76 (ꢀve, CH2), 126.46 (+ve, ArCH),
126.78 (+ve, CH), 128.74 (+ve, ArCH), 127.18 (+ve,
ArCH), 127.96 (+ve, ArCH), 128.12 (+ve, ArCH),
128.23 (ab, CH), 129.41 (+ve, ArCH), 129.59 (+ve,
ArCH), 129.76 (+ve, ArCH), 130.54 (+ve, ArCH),
133.14 (ab, C), 133.85 (ab, C), 133.57 (ab, C), 133.61
6.3.4.
(10S,2S)-2-Phenyl-2-(10-pyridin-2-yl-but-30-enyl-
amino)ethanol (17). Yield 85%, liquid, [a]25 = ꢀ23.4 (c
0.40, CHCl3), 1H NMR (300 MHz): d 2.53–2.58 (m,
2H, CH2), 2.58 (br s, 2H, 1H of OH, 1H of NH),
3.56–3.60 (m, 1H, CHPh), 3.70–3.71 (m, 1H,CHNH),
3.71–3.83 (m, 2H, CH2OH), 4.99–5.06 (m, 2H,
@CH2), 5.56 (m, 1H, @CH), 7.05–7.07 (m, 2H,
ArH), 7.14–7.27 (m, 6H, ArH), 7.49 (m, 1H, ArH),
8.46 (d, J = 7.5 Hz, 1H, ArH); 13C NMR (normal/
DEPT-135) (75 MHz): d 40.62 (ꢀve, CH2), 61.19
(+ve, CH), 62.56 (+ve, CH), 65.88 (ꢀve, CH2),
117.48 (ꢀve, CH2), 121.82 (+ve, CH), 122.12 (+ve,
CH), 127.19 (+ve, CH), 128.24 (+ve, CH), 134.81
(+ve, CH), 134.97 (ab, C), 136.02 (+ve, CH), 141.00
(ab, C), 149.02 (+ve, CH), 162.36 (ab, C); FAB mass
(M++1) m/z 269. Anal. Calcd for C17H20N2O: C,

2394
P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
76.09%; H, 7.51%; N, 10.44%. Found: C, 76.31%; H,
7.62%; N, 10.46%.
C21H22N2O: C, 79.21%; H, 6.96%; N, 8.80%. Found:
C, 79.34%; H, 7.05%; N, 8.93%.
6.3.5. (10R,2R)-2-Phenyl-2-(10-quinolin-2-yl-but-30-enyl-
amino)ethanol (18). Yield 80%, liquid, [a]25 = +47.5
(c, 0.40, CHCl3), H NMR (300 MHz): d 2.62 (br s,
6.4. In vitro anti-caner activities
1
The pre-screening of compounds at three cell lines fol-
lowed by the detailed evaluation for anti-cancer activi-
ties at 59 human tumor cell lines was carried out by
screening unit of NCI at NIH Bethesda, USA, following
their standard procedure (www.dtp.nci.nih.gov/). For
pre-screening, the compounds were evaluated only at
10ꢀ4 M concentration. Evaluations at the complete cell
line panel were carried out at five concentrations viz.
10ꢀ4, 10ꢀ5, 10ꢀ6, 10ꢀ7, and 10ꢀ8 M. The percentage
growth of tumor cells was calculated at each cell line
for each concentration of the compound. The results
are expressed as growth inhibition of 50% (GI50) which
is the concentration of the compound causing 50%
reduction in the net protein increase (as measured by
SRB staining) in control cells during drug incubation.
However, in these studies the particular cellular target
of the compounds has not been identified.
1H, NH, exchanges with D2O), 2.66 (m, 2H, CH2),
3.64 (dd, J = 7.5 Hz, J = 10.8 Hz, 1H, 1H of CH2OH),
3.78 (dd, J = 4.5 Hz, J = 10.8 Hz, 1H, 1H of CH2OH),
3.90 (dd, J = 4.5 Hz, J = 7.5 Hz, 1H, CHPh), 4.08 (t,
J = 6.3, 1H, CHNH), 5.01–5.12 (m, 2H, @CH2),
5.73–5.82 (m, 1H, @CH), 7.10–7.28 (m, 6H, ArH),
7.47–7.52 (m, 1H, ArH), 7.65–7.76 (m, 2H, ArH),
7.97–8.04 (m, 2H, ArH); 13C NMR (normal/DEPT-
135) (75 MHz): d 40.73 (ꢀve, CH2), 61.42 (+ve,
NCH), 62.68 (+ve, CHPh), 65.77 (ꢀve, CH2OH),
117.89 (ꢀve, CH2), 119.98 (+ve, CH), 126.1 (+ve,
CH), 127.20 (ab, C), 127.26 (+ve, CH), 127.45 (+ve,
CH), 128.27 (+ve, CH), 128.97 (+ve, CH), 134.65
(+ve, CH), 136.18 (+ve, CH), 140.83 (ab, C), 147.33
(ab, C), 162.61 (ab, C); decoupling of 2H multiplet at
d 2.66 converts the 1H triplet at d 4.08 to singlet and
1H multiplet at d 5.73–5.82 into double doublet and as-
signs these signals to HN–CHCH2–CH = moiety. The
decoupling of 1H dd at d 3.90 converts two 1H dds
at d 3.64 and 3.78 into doublets and assigns these sig-
nals to CHCH2OH moiety. In 1H–13C HETCOR
experiment, the correlation of CH2 (ꢀve signal in
DEPT-135) at d 65.77 with two 1H signals at d 3.64
and 3.78 assigns these protons to CH2OH group;
FAB mass (M++1) m/z 318. Anal. Calcd for
C21H22N2O: C, 79.21%; H, 6.96%; N, 8.80%. Found:
C, 79.34%; H, 7.05%; N, 8.93%.
Acknowledgments
The financial assistance from CSIR, New Delhi, and
DST, New Delhi, is gratefully acknowledged. Authors
are thankful to NIH, Bethesda (USA), for carrying
out the anti-cancer studies.
References and notes
6.3.6. (10S,2S)-2-Phenyl-2-(10-quinolin-2-yl-but-30-enyl-
amino)ethanol (19). Yield 85%, liquid, [a]25 = ꢀ47.5
(c, 0.40 CHCl3), 1H NMR (300 MHz): d 2.50 (br s,
1H, NH, exchanges with D2O), 2.63 (m, 2H, CH2),
3.63 (dd, J = 7.5 Hz, J = 10.8 Hz, 1H, 1H of
CH2OH), 3.80 (dd, J = 4.5 Hz, J = 10.8 Hz, 1H, 1H
of CH2OH), 3.89 (dd, J = 4.5 Hz, J = 7.5 Hz, 1H,
CHPh), 4.05 (t, J = 6.3 Hz, 1H, CHNH), 5.01–5.11
(m, 2H, @CH2), 5.73–5.82 (m, 1H, @CH) 7.09–7.26
(m, 6H, ArH), 7.46–7.52 (m, 1H, ArH), 7.65–7.76
(m, 2H, ArH), 7.96–8.04 (m, 2H, ArH); 13C NMR
(normal/DEPT-135) (75 MHz): d 40.80 (ꢀve, CH2),
61.39 (+ve, CH), 62.61 (+ve, CH), 65.86 (ꢀve,
CH2), 117.76 (ꢀve, CH2), 119.99 (+ve, CH), 126.06
(+ve, CH), 127.18 (+ve, CH), 127.24 (+ve, CH),
127.44 (+ve, CH), 128.25 (+ve, CH), 128.97 (+ve,
CH), 129.36 (+ve, CH), 134.78 (+ve, CH), 136.13
(+ve, CH), 141.03 (ab, C), 147.3 (ab, C), 162.8 (ab,
C); decoupling of 2H multiplet at d 2.63 converts
the 1H triplet at d 4.05 to singlet and 1H multiplet
at d 5.73–5.82 into double doublet and assigns these
signals to HN–CHCH2–CH = moiety. The decoupling
of 1H dd at d 3.89 converts two 1H dds at d 3.63
and d 3.80 into doublets and assigns these signals
to CHCH2OH moiety. In 1H–13C HETCOR experi-
ment, the correlation of CH2 (ꢀve signal in DEPT-
135 spectrum) at d 65.86 with 1H signals at d 3.63
and 3.80 assigns these protons to CH2OH group;
FAB mass (M+) m/z 318. Anal. Calcd for
1. (a) Nitiss, J. L. Biochem. Biophys. Acta 1998, 1400, 63; (b)
Wang, J. C. Nat. Rev. Mol. Cell Biol. 2002, 3, 430; (c)
Fantin, V. R.; St-Pierre, J.; Leder, P. Cancer Cell 2006, 9,
425; (d) Furukawa, T.; Yoshimura, A.; Sumizawa, T.;
Haraguchi, M.; Akiyama, S.; Fukui, K.; Ishikawa, M.;
Yamada, Y. Nature 1992, 356, 668; (e) Haraguchi, M.;
Miyadera, K.; Uemura, K.; Sumizawa, T.; Furukawa, T.;
Yamada, Y.; Akiyama, S. Nature 1994, 368, 198; (f)
Matsushita, S.; Nitanda, T.; Furukawa, T.; Sumizawa, T.;
Tani, A.; Nishimota, K.; Akiba, S.; Miyadera, K.;
Fukushima, M.; Vamada, Y.; Yoshida, H.; Kanzaki, T.;
Akiyama, S. Cancer Res. 1999, 59, 1911; (g) Sakamoto, S.;
Kuwa, K.; Tsukada, K.; Sagara, T.; Noriyuki, K.;
Okamoto, R. Carcinogenesis 1987, 8, 405; (h) Carreras,
C. W.; Santi, D. V. Annu. Rev. Biochem. 1995, 64, 721; (i)
Rode, W.; Les, A. Acta Biochim. Pol. 1996, 43, 133.
2. NIH, USA, has classified the anticancer drugs according
to their mechanism of action. See NIH website:
www.dtp.nci.nih.gov/.
3. (a) Teodori, E.; Dei, S.; Scapecchi, S.; Gualtieri, F. IL
Farmaco 2002, 57, 385; (b) Krishna, R.; Mayer, L. D. Eur.
J. Pharm. Sci. 2000, 11, 265.
4. (a) Sundberg, R. J. In Comprehensive Heterocyclic Chem-
istry II; Katritzky, A. R., Rees, C. W., Eds.; Oxford:
Pergamon, 1996; Vol. 4, pp 370–376; (b) Fritz, J. E.;
Hipskind, P. A.; Lobb, K. L.; Nixon, J. A.; Threlkeld, P. G.;
Gitter, B. D.; McMillian, C. L.; Kaldor, S. W. Bioorg. Med.
Chem. Lett. 2001, 11, 1643; (c) Meagher, K. L.; Mewshaw,
R. E.; Evrard, D. A.; Zhou, P.; Smith, D. L.; Scerni, R.;
Spangler, T.; Abulhawa, S.; Shi, X.; Schechter, L. E.;
Andree, T. H. Bioorg. Med. Chem. Lett. 2001, 11, 1885; (d)
Andreani, A.; Granaiola, M.; Leoni, A.; Locatelli, A.;

P. Singh et al. / Bioorg. Med. Chem. 15 (2007) 2386–2395
2395
Morigi, R.; Rambaldi, M.; Garaliene, V.; Farruggia, G.;
Masotti, L. Bioorg. Med. Chem. 2004, 12, 1121; (e) Lehr, M.
J. Med. Chem. 1997, 40, 2694; (f) Stolc, S. Life Sci. 1999, 65,
1943; (g) Tfelt-Hansen, O.; De Vries, P.; Saxena, P. R. Drugs
2000, 60, 1259; (h) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.;
Bovers, A.; Fruttarolo, F.; Romagnoli, B.; Zaid, N. A.;
Moorman, A. R.; Varani, K.; Borea, P. A. J. Med. Chem.
2005, 48, 5001; (i) Davioud-Charvet, E.; Delarue, S.; Biot,
C.; Schwobel, B.; Boehme, C. C.; Mussigbrodt, A.; Maes,
L.; Sergheaert, C.; Grellier, P.; Schirmer, R. H.; Becker, K.
J. Med. Chem. 2001, 44, 4268, and references therein; (j)
Mekouar, K.; Mouscadet, J.-F.; Desmaele, D.; Subra, F.;
Leh, H.; Savoure, D.; Auclair, C.; d’Angelo, J. J. Med.
Chem. 1998, 41, 2846; (k) Ma, Z.; Hano, Y.; Nomura, T.;
Chen, Y. Heterocycles 1997, 46, 541; (l) Sun, F.; Xing, Q. Y.
J. Nat. Prod. 1989, 52, 1180; (m) Wild, D.; Toth, G.; Humpf,
H.-U. J. Agric. Food Chem. 2003, 51, 5493; (n) Hockova, D.;
Holy, A.; Masojidkova, M.; Andrei, G.; Snoeck, R.; De
Clerq, E.; Balzarini, J. Bioorg. Med. Chem. 2004, 12, 3197,
and references therein; (o) Breyholz, H.-J.; Schafers, M.;
Wagner, S.; Holtke, C.; Faust, A.; Rabeneck, H.; Levkau,
B.; Schober, O.; Kopka, K. J. Med. Chem. 2005, 48, 3400.
5. (a) Morphy, R.; Rankovic, Z. J. Med. Chem. 2005, 48,
6523; (b) Charlier, C.; Michaux, C. Eur. J. Org. Chem.
2003, 38, 645; (c) de Leval, X.; Julemont, F.; Delarge, J.;
Pirotte, B.; Dogne, J.-M. Curr. Med. Chem. 2002, 9, 941;
(d) Pommery, N.; Taverne, T.; Telliez, A.; Goossens, L.;
Charlier, C.; Pommery, J.; Goossens, J.-F.; Houssin, R.;
Durant, F.; Henichart, J. P. J. Med. Chem. 2004, 47, 6195.
6. Singh, P.; Paul, K. Bioorg. Med. Chem. 2006, 14, 8622.
7. (a) Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589; (b)
Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467; (c)
Vilaivan, T.; Winotapan, C.; Shinada, T.; Ohfune, Y.
Tetrahedron Lett. 2001, 42, 9073; (d) Bernardi, L.; Cere,
V.; Femoni, C.; Pollicino, S.; Ricci, A. J. Org. Chem.
2003, 68, 3348; (e) Loh, T. P.; Ho, D. S. C.; Xu, K. C.;
Sim, K. Y. Tetrahedron Lett. 1997, 38, 865; (f) Kumar,
S.; Kumar, V.; Chimni, S. S. Tetrahedron Lett. 2000, 41,
5073; (g) Berger, R.; Rabbat, P. M. A.; Leighton, J. L.
J. Am. Chem. Soc. 2003, 125, 9596.
8. 1a and 1b were obtained by the reaction of indol-3-
carbaldehyde with ethyl chloroformate and p-tolunesulfo-
nyl chloride, respectively, under PTC conditions using
K2CO3 as base, tetrabutylammonium hydrogen sulfate
(TBA HSO4) as catalyst in CH3CN.
9. (a) Kumar, S.; Kaur, P.; Mittal, A.; Singh, P. Tetrahedron
2006, 62, 4018; (b) Singh, P.; Mittal, A.; Kaur, P.; Kumar,
S. Tetrahedron 2006, 62, 1063; (c) Kaur, P.; Singh, P.;
Kumar, S. Tetrahedron 2005, 61, 8231.
10. (a) Malik, V.; Singh, P.; Kumar, S. Tetrahedron 2005, 61,
4009; (b) Malik, V.; Singh, P.; Kumar, S. Tetrahedron 2006,
62, 5944; (c) 1,3-Bis-(2-chlorobenzyl)-5-formylpyrimidin-2,4-
dione was prepared by the POCl3-DMF mediated formyla-
tion of 1,3-bis-(2-chlorobenzyl)-pyrimidin-2,4-dione.
11. (a) Ally, M. C.; Scudiero, D. A.; Monks, P. A.; Hursy, M.
L.; Czerwinski, M. J.; Fine, D. A.; Abbott, B. J.; Mayo, J.
G.; Showmaker, R. H.; Boyd, M. R. Cancer Res. 1988, 48,
589; (b) Grever, M. R.; Schepartz, S. A.; Chabner, B. A.
Semin. Oncol. 1992, 19, 622; (c) Boyd, M. R.; Paull, K. D.
Drug Dev. Res. 1995, 34, 91.