D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer agents: Synthesis and biological evaluation

Article abstract of DOI:10.1016/j.steroids.2010.02.015

A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported. The scheme involves the transformation of the starting pregnenolone acetate into pregnenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the 'click chemistry' approach. These derivatives were screened for their anticancer activity against seven human cancer cell lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with compound 5e as the most active in this study.

Full text of DOI:10.1016/j.steroids.2010.02.015

Steroids 75 (2010) 801–804
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Steroids
journal homepage: www.elsevier.com/locate/steroids
D-ring substituted 1,2,3-triazolyl 20-keto pregnenanes as potential anticancer
agents: Synthesis and biological evaluation
Abid H. Bandaya,b,∗, Shameem A. Shameema, B.D. Guptab, H.M. Sampath Kumarb
a Department of Chemistry, Islamia College of Science and Commerce, Srinagar 190009, India
b Synthetic Chemistry Division, Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi 180001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity
is reported. The scheme involves the transformation of the starting pregnenolone acetate into preg-
nenolone, conversion of pregnenolone to 21-bromo pregnenolone and finally the one-pot, two-step in
situ conversion of the bromo derivative to the 21-triazolyl pregnenolone using the ‘click chemistry’
approach. These derivatives were screened for their anticancer activity against seven human cancer cell
lines. The compounds especially 5a, 5b, 5c, 5e, 5g and 5h exhibited significant anticancer activity with
compound 5e as the most active in this study.
Received 12 December 2009
Received in revised form 23 February 2010
Accepted 24 February 2010
Available online 4 March 2010
Keywords:
Triazoles
Pregnenolone
Click chemistry
© 2010 Elsevier Inc. All rights reserved.
1. Introduction
is their ability to interact with cell membranes and thus pave the
way for biological activity of such hybrid molecules. Attention has
Steroids have always attracted considerable attention because
of being a fundamental class of biological signaling molecules.
Their profound biological, scientific and clinical importance is now
well validated [1]. They can regulate a variety of biological pro-
cesses and thus have the potential to be developed as drugs for
the treatment of a large number of diseases including cardiovas-
cular [2], autoimmune diseases [3], brain tumours, breast cancer,
prostate cancer, osteoarthritis, etc. [4]. Presence of different func-
tional groups located around the rigid tetracyclic core leads to
diversity in the biological actions as these serve as substrates for
different targets. Enhancing the target binding properties of these
biologically important molecules has become a major research
problem and it has invited exhaustive efforts for the generation
of better fit ligands. This is primarily done by the preparation of
novel steroidal analogs via reactions chemically simpler and eas-
ier. This would also provide a platform to approach the synthesis
of new drugs for tackling important biological problems. Most of
the steroid based pharmaceuticals are semi-synthetic compounds
prepared by connecting a special functionality to the core struc-
ture of a steroid [5]. Most important of such functionalities are
the heterocyclic systems because of their potent receptor binding
properties. The advantage of employing hydrophobic steroid units
been devoted in the literature to the synthesis of several steroidal
heterocycles that exhibit valuable pharmacological activities [6–8].
This approach of treatment has also the advantage of overcom-
ing the problems associated with the clinical use of new drugs, i.e.
relatively high risk of toxicity, bacterial resistance and/or pharma-
cokinetic deficiencies because of being structurally unrelated to the
existing molecules and having very low toxicity levels [9]. The azole
moiety often shows some special biological activity when it is intro-
duced to biologically active compounds [9]. However, it is unusual
that a steroid contains an azole moiety at C-21 position [10]. The
basicity and hydrophilicity of an azole in theory might alter the
biological function of a steroid. Moreover, the azole might interact
with some enzymes, e.g. cytochrome P. 450, as a part of the whole
pharmaceutical [11,12]. Steroidal azoles have also been found to
be potent inhibitors of 17␣-hydroxylase-C17,20-Lyase, the enzyme
which catalyzes the conversion of progesterone and pregnenolone
into the androgens. Since androgens are implicated in the etiology
of a number of androgen dependant diseases, e.g. prostate cancer,
inhibitors of such enzymes are useful for the treatment of these dis-
eases [11,12]. Steroidal azoles have also been found to have strong
inhibitory effect on 5␣-reductases which makes them promising
against various types of tumours. Keeping all the facts about the
importance of steroidal azoles into consideration, we, in continua-
tion of our programme for the synthesis of novel steroidal D-ring
heterocycles [13], planned a synthesis of steroidal azoles using an in
situ one-pot “click chemistry” approach. “Click chemistry” is a con-
cept introduced by Sharpless and co-workers as a way of describing
∗
Corresponding author at: Department of Chemistry, Islamia College of Science
and Commerce, Srinagar 190009, India. Tel.: +91 9697301630; fax: +91 194 2429014.
E-mail address: abidrrl@gmail.com (A.H. Banday).
0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.02.015

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A.H. Banday et al. / Steroids 75 (2010) 801–804
a reaction that quickly and efficiently produces new substances by
joining smaller molecules together in the same way as nature joins
small modular units together to produce large elaborate ones [14].
The synthesis was started from 21-bromo pegnenolone which in
turn was synthesized from pregnenolone through well known liter-
ature methods. Our method thus provides a very expedient, simple
and fast access to the novel steroidal azoles involving a simple
and high yielding regioselective copper catalyzed azide-acetylene
cycloaddition (CuAAC).
evaporated in vaccuo. The product was precipitated using hex-
ane:ethylacetate mixture. Solid white compounds obtained were
characterized using various spectral techniques. Spectral details of
some representative triazolyl compounds such as 5c, 5e and 5g are
listed below
(1) 1-(3-Hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahyd-ro-1H-cyclopenta[a]phenanthren-17-yl)-2-(4-
phenoxymethyl-[1,2,3]triazol-1-yl)-ethanone (5c): M.P.: 95 ◦C;
[␣]D25: (+)67; IR (KBr, cm−1): 760, 1076, 1225, 1415, 1589,
1670, 1715, 2845, 2885, 2935, 3401; 1H NMR (CDCl3): ı 0.56
and 0.99 (2s, 6H), 3.33 (s, 1H), 3.49 (s, 1H), 3.90 (s, 3H), 5.25 (d,
1H, J = 10.50), 5.36 (s, 2H), 6.56–6.64 (m, 2H), 7.09 (m, 2H), 7.45
(m, 1H), 7.74 (s, 1H); 13C NMR (500 MHz, CDCl3): ı 13.26, 17.80,
20.65, 22.74, 23.85, 31.20, 33.39, 35.39, 36.80, 40.41, 44.12,
50.68, 52.48, 55.09, 58.57, 59.91, 60.03, 62.86, 63.77, 113.80,
120.81, 122.67, 123.66, 126.41, 127.46, 129.98, 143.89, 153.33,
164.29, 170.19, 198.65 and 200.83; ESI-MS: 580 (M++Na); Anal.
calcd. for C34H43N3O4: C, 73.22; H, 7.77; N, 7.53. Found: C,
73.25; H, 7.63; N, 7.76.
2. Experimental
2.1. General methods
Melting points were recorded on Buchi Melting point appara-
tus D-545; IR spectra (KBr discs) were recorded on Bruker Vector
22 instrument. NMR spectra were recorded on Bruker DPX200
instrument in CDCl3 with TMS as internal standard for protons and
solvent signals as internal standard for carbon spectra. Chemical
shift values are mentioned in ı (ppm) and coupling constants are
given in Hz. Mass spectra were recorded on EIMS (Shimadzu) and
ESI-esquire 3000 Bruker Daltonics instrument. The progress of all
reactions was monitored by TLC on 2 × 5 cm pre-coated silica gel 60
F254 plates of thickness of 0.25 mm (Merck). The chromatograms
were visualized under UV 254-366 nm and iodine.
(2) 2-[4-(4-acetyl-phenoxy)-[1,2,3]triazol-1-yl]-1-(3-hydroxy-10-
13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-17-yl)-ethanone
(5e):
M.P.:
107 ◦C; [␣]D25: (+)70; IR (KBr, cm−1): 772, 1092, 1283, 1312,
1465, 1590, 1682, 2745, 2863, 2954, 3388; 1H NMR: ı 0.57
and 0.97 (2s, 6H), 3.35 (m, 2H), 5.19 (s, 1H), 5.31 (s, 2H), 7.04
(d, 2H, J = 9.80), 7.73 (s, 1H), 7.95 (d, 2H, J = 9.80); 13C NMR
(500 MHz, CDCl3): ı 13.28, 19.44, 21.13, 22.87, 24.53, 31.81,
36.56, 37.30, 38.87, 42.23, 44.09, 50.01, 52.98, 56.36, 63.77,
71.73, 118.51, 120.12, 122.638, 124.81, 128.97, 130.65, 134.30,
135.34, 136.97, 137.14 140.81, 148.84 and 209.99; ESI-MS:
554 (M++Na); Anal. calcd. for C32H41N3O4: C, 72.29; H, 7.77; N,
7.90. Found: C, 72.34; H, 7.74; N, 7.93.
2.2. Chemical synthesis
2.2.1. 21-Bromo-3ˇ-hydroxy-5-pregnen-20-one (3)
To a solution of pregnenolone (3.16 g, 10 mmol, 1 eq.) in
methanol (100 ml) was added three drops of aqueous HBr solu-
tion (48%). Bromine (1.7 g, 1 eq.) was dissolved in methanol (20 ml)
and the resulting solution was added drop wise to the reaction
mixture over 1 h at ambient temperature in dark. After com-
pletion, the reaction mixture was quenched and precipitated
with water. The precipitate was filtered, dried and recrystal-
lized from EtOAc:hexane to give white powder as product (78%).
M.P.: 157–159 ◦C; IR (KBr) cm−1 3550, 1720 (C O), 1060; 1H NMR
(CDCl3): ı 0.67 (s, 3H), 1.00 (s, 3H), 1.61 (s, 3H), 2.38–2.40 (s, 4H),
3.50 (br m, 1H); 3.92 (s, 2H, 21-CH2); 5.38 (s, 1H); MS (ESI, m/z
394 (M+H); Anal. calcd. for C21H29BrO2: C, 64.12; H, 7.43; Br, 20.31.
Found C, 64.07; H, 7.52; Br, 20.34.
(3) 2-[4-(3-chloro-phenoxy)-[1,2,3]triazol-1-yl]-1-(3-hydroxy-10-
13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-17-yl)-ethanone (5g): M.P.: 98 ◦C;
[␣]D25: (+)67; IR (KBr, cm−1): 756, 1094, 1253, 1404, 1510,
1600, 1668, 2845, 2873, 2928, 3392; 1H NMR: ı 0.58 and 0.97
(2s, 6H), 3.49 (s, 2H), 5.14 (s, 1H), 5.21 (s, 2H), 6.92 (m, 1H),
7.12 (m, 2H), 7.38 (m, 1H), 7.75 (s, 1H); 13C NMR (500 MHz,
CDCl3): ı 13.29, 19.45, 21.15, 22.88, 24.55, 31.83, 36.58, 37.32,
38.90, 42.29, 44.09, 50.04, 53.20, 56.70, 63.78, 71.77, 118.56,
120.91, 121.47, 122.66, 124.86, 130.67, 135.73, 140.82, 209.75;
ESI-MS: 524 (M++H); Anal. calcd. for C30H38ClN3O3: C, 68.75;
H, 7.31; Cl, 6.76; N, 8.02. Found: C, 68.65; H, 7.34; Cl, 6.73; N,
8.03.
2.2.2. p-Propargyl-oxy benzaldehyde (4a)
Appropriate phenols, e.g. p-hydroxy benzaldehyde (1 eq.) were
treated with propargyl bromide in acetone under reflux conditions
using potassium carbonate as a base. The reaction is fast and gives a
quantitative yield of the product within a short period of time. After
the completion of the reaction, the reaction mixture was filtered
and the filtrate evaporated to give the product in its pure form.
1H NMR (CDCl3): ı 2.57 (t, 1H, J = 2.34), 4.78 (d, 2H, J = 2.34),
7.10 (d, 2H, J = 8.73), 7.87 (d, 1H, J = 8.73); 9.91 (s, 1H); ESI-MS: 161
(M++H).
2.3. Biology
The human cancer cell lines used for the test were DU-145, PC-
3 (prostrate), SF-295 (CNS), HCT-15, 502713 (colon), HEP-2 (liver)
and A-549 (lung). Cellular viability in the presence and absence
of experimental agents was determined using the standard Sul-
forhodamine B assay. Briefly, cells in their log phase of growth were
harvested, counted and seeded (104 cells/well in 100 ␮L medium)
in 96-well microtitre plates. After 24 h of incubation at 37◦ and 5%
CO2 to allow cell attachment, cultures were treated with varying
concentrations (0.1–10 ␮M) of test samples made with 1:10 serial
dilutions. Four replicate wells were set up for each experimen-
tal condition. Test samples were left in contact with the cells for
48 h under same conditions. Thereafter, cells were fixed with 50%
chilled trichloroacetic acid (TCA) and kept at 4 ◦C for 1 h, washed
and air dried. Cells were stained with Sulforhodamine B dye. The
adsorbed dye was dissolved in Tris-Buffer and plates were gen-
tly shaken for 10 min, on a mechanical shaker. The optical density
(OD) was recorded on ELISA reader at 540 nm. The cell growth was
2.2.3. To a solution
To a solution of 21-bromo pregnenolone (1 eq.) in a mixture
of tert. butanol and water was charged sodium azide (1.2 eq.) and
the reaction was stirred for 30 min. Appropriate terminal alkyne
(1 eq.) was charged into the reaction mixture along with cop-
per sulphate pentahydrate (1.2 eq.) and stirring was continued
for further 10 min, so as to allow complexation to occur. Sodium
ascorbate (5 eq.) was added to the above mixture and the whole
reaction mass was allowed to stir at ambient conditions for 8–10 h.
After completion, the reaction mixture was diluted with 80 mL
of water and extracted with ethylacetate (2 × 20 mL). The com-
bined extracts were washed with brine, dried over Na2SO4 and

A.H. Banday et al. / Steroids 75 (2010) 801–804
803
Table 2
calculated by subtracting mean OD value of respective blank from
the mean OD value of experimental set. Percent growth in presence
of test material was calculated considering the growth in absence
of any test material as 100% and in turn percent growth inhibition
in presence of test material was calculated. Finally the IC50 values
(Table 2) were calculated using Microsoft Office Excel. The different
steroidal derivatives (test material) were dissolved in a mixture of
DMSO:water (1:1) and then introduced into the medium containing
the cancer cell lines.
IC50 values (␮M) of 21-triazolyl pregnenolone derivatives against a panel of human
cancer cell lines.
Entry
Prostate
DU-145
CNS
Colon
Liver
Lung
PC-3
SF-295
HCT-15
502713
HEP-2
A-549
5a
5b
5c
5d
5e
5f
5g
5h
5i
1.04
1.19
0.51
4.16
0.20
4.37
1.12
0.29
3.57
0.19
1.03
1.18
1.37
0.03
1.63
0.48
1.03
3.45
0.74
0.96
0.84
3.11
0.68
4.20
0.78
0.70
1.00
0.46
0.34
0.34
4.22
0.37
1.58
0.16
0.40
1.45
1.78
0.62
1.72
1.98
0.56
1.21
0.61
0.68
2.88
1.14
1.50
1.37
1.25
0.65
4.10
2.64
3.96
1.26
7.88
5.17
3.99
8.63
2.78
7.43
6.10
7.46
2.24
3. Results and discussion
Development of highly functional molecules from simple build-
ing blocks has always been the curiosity of synthetic chemists.
Multi component reactions have proven to be the practical way
for achieving such ends because these reactions generally are one
part and afford good yields [15]. In addition to this, these reac-
tions result in fewer operations by avoiding isolation, handling
and chromatography. Recently, Sharpless and co-workers have
reported a high yielding synthesis of triazoles using a Cu(I) cat-
alyst with an excellent regiospecificity, quantitative yields and
the capacity to tolerate a wide variety of other functional groups.
This approach termed as ‘click chemistry’ approach has been the
most widely used method for the synthesis of libraries of a large
number of biologically active molecular frameworks particularly
for the regioselective synthesis of 1,2,3-triazoles, which involves
the copper(I)-catalyzed cycloaddition reaction between azides and
terminal alkynes (CuAAC). This reaction has been termed the ‘cream
of the crop’ of ‘click reactions’ and has found application in various
facets of drug discovery as it enables a modular approach to gener-
ate novel pharmacophores utilizing a collection of reliable chemical
reactions. Thus, the development of the copper (I)-catalyzed ‘tri-
azole click chemistry’ has led to many interesting applications
including the synthesis, medicinal chemistry, molecular biology
and material science. Despite its growing impact in the field of
bioconjugation and materials science, the application of this reac-
tion is still hampered by the apprehension of handling organic
azides which are toxic and explosive in nature. In this direction, the
present work describes the exploitation of the facile ‘click chem-
Table 1
Substituted steroidal triazolesa generated through in situ ‘click chemistry’ approach.
.
b
Entry
a
Alkyne
R
+[a]2D5
M.P. (◦C)
91
Yield (%)
95
p-CHO
65
b
p-CH3
83
104
92
c
d
e
f
p-CHCHCOCH3
H
42
73
93
70
95
102
107
103
90
92
93
94
p-COCH3
p-OCH3
g
m-CI
67
51
125
98
90
93
h
o-CH3
i
m-CH3
78
105
91
a
All the products were characterized by 1H, 13C NMR/DEPT, ESI-MS and elemental analysis.
Concentration of all the samples for specific rotation was constant, i.e. 20 mg/mL.
b

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A.H. Banday et al. / Steroids 75 (2010) 801–804
Scheme 1. ‘Click chemistry’ approach for the synthesis of the 21-triazolyl pregnenolone derivatives.
istry’ synthetic strategy for the rational design and construction
of heterocyclic analogs of pregnanes at the D-ring. Acetyl preg-
nenolone was hydrolysed using methanolic NaOH which upon
precipitation in water yielded pregnenolone in quantitative yield.
Pregnenolone was then treated with Br2/MeOH in dark to obtain
the 21-bromo derivative in almost 70% yield. The bromo compound
was treated directly with sodium azide, copper sulphate, Sodium
ascorbate and appropriate alkyne in a 1:1 mixture of tert. butanol
and water to give the target compounds in their pure form after
precipitation with EtOAc/hexane. Thus this method describes the
first synthetic strategy for the construction of biologically promis-
ing steroidal heterocycles through a facile in situ ‘click chemistry’
approach (Scheme 1 and Table 1).
be carried out with a focus on the mechanistic studies of the most
promising candidates.
Acknowledgement
The authors thank Principal ICSC and Director IIIM, for their inter-
est and encouragement.
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