INTERNATIONAL JOURNAL OF RECENT ADVANCES IN PHARMACEUTICAL RESEARCH
APRIL 2015; 5(2): 9-17
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SYNTHESIS AND ANTIPROLIFERATIVE ACTIVITY OF
3-SUBSTITUTED ESTERS OF 17-OXO-17a-AZA-D-HOMO-3,5ANDROSTADIEN-3-OIC ACID AS 5α-REDUCTASE INHIBITORS
TINA SHARMA*a, SHILPA GARGa, AMANDEEP SINGHb,
MANAV MALHOTRAa, T. R. BHARDWAJa
RESEACH LAB, DEPARTMENT OF PHARMACEUTICAL CHEMISTRY,
ISF COLLEGE OF PHARMACY, MOGA, PUNJAB, INDIAa
DEPARTMENT OF BIOTECHNOLOGY, CENTENNIAL COLLEGE, TORONTO, CANADA. b
ABSTRACT
In this study, we describe the synthesis of 3-substituted esters of 17-Oxo-17a-aza-D-homo-3,5-androstadien3-oic acid 14(a-e) from commercially available 16-Dehydropregnenolone acetate as starting material.
Compounds were tested for their 5α-reductase inhibitory activity against prostate cancer cell line PC-3 and
compared with Dutasteride as reference drug. The compounds 14d and 14e found to be potent inhibitors
against 5α-reductase while 14a exhibited moderate inhibitory activity but the compounds 14b and 14c
displayed weak inhibition against prostate cancer cell lines.
Keywords: Dutasteride, Prostate cancer, 5α-reductase, PC-3.
INTRODUCTION
Benign prostatic hyperplasia (BPH) is the most
common benign tumor affecting about 60% of men
aged over 50 years and after the age of 70, the
proportion increases to 80% [1]. It clinically
manifests as lower urinary tract symptoms (LUTS)
which include frequency, hesitancy, urgency,
nocturia, slow urinary stream and incomplete
emptying [2,3]. Androgens (testosterone and
dihydrotestosterone) are responsible for male
phenotype sexual differentiation and maturation
through their actions at the androgen receptor [46]. The corresponding relationship between
prostatic
growth
and
elevated
prostatic
dihydrotestosterone (DHT) has been observed in
BPH patients [7]. In many androgen sensitive
tissues, the nuclear membrane bound enzyme 5αreductase converts the major circulating hormone
testosterone (T) to the more potent intracellular
5α-reduced metabolite DHT [8,9].
____________________________________________________________
CORRESPONDING AUTHOR*
MS. TINA SHARMA
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
ISF COLLEGE OF PHARMACY,
MOGA, PUNJAB, INDIA.
E-MAIL: tinasharma996@gmail.com
MOBILE: +919888999638
The raised levels of DHT cause pathological
conditions like BPH, prostate cancer [10-15], acne
[16], hirsutism [17-19] and androgenic alopecia [20,
21].
Study of mechanism of 5α-reductase and its
inhibition is an area of biological and
pharmaceutical interest as the enzyme catalyzes the
irreversible reduction of the C-4-C-5 double bond of
3-oxo-4-ene steroids to their corresponding 5α-3oxo-steroid derivatives, using a nicotinamide
adenine dinucleotide hydrogen phosphate (NADPH)
as cofactor [22, 23]. Although several steroidal and
non-steroidal compounds have been reported as
5α-reductase inhibitors during the last two decades
[24-27], steroidal compounds have attracted more
attention. It has been observed that a conjugate
system (sp2-sp2-sp2) must be present together with
lipophilic group in the steroidal system. Therefore,
remarkable progress has been made in the design
and synthesis of steroidal inhibitors by modifying 3, 4-, 5- and 17-position of steroids: the two best
known series of compounds are 3-carboxy steroids
and 4-azasteroids [28-35]. Finasteride (MK-906) (1)
[35, 36] and Dutasteride (GG745) (2) [37] have
been approved by United states food and drug
administration for the symptomatic treatment of
BPH (Fig. 1). These drugs belong to a category of Aring lactam of 3-oxo-4-azasteroids with different
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substituents at 17-position. Epristeride (SK & F
105657) (3) belongs to class of carboxysteroids,
found to be potent inhibitor of 5α-reductase in
clinical trials [38-40]. It is evident from above
mentioned drugs that planarity is required in ring A
of steroidal nucleus to enter active site of enzyme.
The double bond present between C-1 and C-2 in
case of finasteride (1) and dutasteride (2) and
conjugate double bonds at C-3 and C-5 in
epristeride (3) provide the planarity.
Therefore, in present work it was envisaged to
synthesize epristeride (3) related analogues (Fig. 2)
having 3,5-dien-3-oic acid moiety and 3-carboxyl
group is further substituted with different aliphatic
and aromatic groups to enhance lipophilicity the
molecule. Also, compounds contain 17-oxo-17a-azaD-homo lactam in ring D instead of ring A as in
finasteride (1). In this communication, we have
reported the synthesis of new steroidal 5αreductase inhibitors and their pharmacological
evaluation.
2.0. MATERIALS AND METHODS
Melting point of the synthesized compounds was
determined in an open-glass capillaries on Stuart
SMP10 melting point apparatus and were
uncorrected. The purity of the compounds was
checked by thin layer chromatography (TLC). Silica
gel plates kiesel gel 0.25 mm, 60 GF254, precoated
sheets obtained from Merck, Darmstadt (Germany)
were used for TLC and the spots were visualized by
iodine vapors/ultraviolet light as visualizing agent.
The IR spectra (υ, cm-1) were obtained with a
Perkin-Elmer 1600 FTIR spectrometer in KBr
pellets. 1H-NMR spectra (δ, ppm) were recorded in
CDCl3 solutions on a Varian-Mercury 300 MHz
spectrometer using tetramethylsilane as the
internal reference. Mass spectra were recorded on a
Shimadzu GCMSQP 1000 EX aparatus. Elemental
analyses were performed on an ECS 4010 Elemental
Combustion System. The necessary chemicals were
purchased from Loba Chemie, Fluka and Sigma
Aldrich.
2.1. GENERAL PROCEDURE FOR THE SYNTHESIS
OF 3-SUBSTITUTED ESTERS OF 17-OXO-17aAZA-D-HOMO-3,5-ANDROSTADIEN-3-OIC ACID
14(a-e)
2.1.1.
3-Bromo-17a-aza-D-homo-3,5androstadien-17-one (11)
17a-Aza-D-homo-4-androstene-3,17-dione
(10)
(3.33 g, 9.16mmol) was dissolved in glacial acetic
acid (25.0 ml) and 1.61 ml of phosphorus
tribromide (4.60 g, 17.0 mmol) was added drop
wise to the mixture at room temperature. The dark
solution was kept at 8-10 ⁰C for 24 h during which
the product got precipitated from the solution. The
solid product was filtered and washed with cold
glacial acetic acid, followed by cold water (3x 50.0
ml). The product was dried under vacuum to afford
3-Bromo-17a-aza-D-homo-3,5-androstadien-17-one
(11).
Molecular formula: C19H26BrNO, yield: 82.7%, mp:
239-241oC. IR (KBr, ѵ cm-1): 3163 (N-H), 2941 (C-H
str), 1681 (C=O lactam), 1628 (C=C), 637 (C-Br). 1H
NMR (300 MHz, CDCl3, δ): 0.96 (s, 3H, 18-CH3), 1.42
(s, 3H, 19-CH3), 1.23-2.22 (m, 17H, steroidal ring),
5.43 (s, 1H, 6-vinylic) 6.62 (s, 1H, 4-vinylic), 7.15 (s,
1H, CONH). MS (ESI) m/z = 371 (M+1). Elemental
analysis: Calcd. C, 62.64; H, 7.19; N, 3.84. Found: C,
62.66; H, 7.15; N, 3.86
2.1.2.
3-Cyano-17a-aza-D-homo-3,5androstadien-17-one (12)
3-Bromo-17a-aza-D-homo-3,5-androstadien-17-one
(11) (1.08 g, 3.0 mmol) was dissolved in
dimethylformamide (25.0ml) and to this solution
was added cuprous cyanide (0.27 g, 3.0 mmol). The
reaction mixture was refluxed for 5 h and allowed
to cool to around 100⁰C and quenched with stirring
into a solution of 20.0 ml of concentrated aqueous
ammonia and 40.0ml of water. The resulting
suspension was extracted twice with 100.0 ml of
dichloromethane and organic phase was washed
with three 50.0 ml portions of 50/50 v/v
concentrated aqueous ammonia/water followed by
water. The organic phase was concentrated under
vacuum and crystallised from absolute ethanol. The
solid product was filtered and dried under vacuum
to
afford
3-Cyano-17a-aza-D-homo-3,5androstadien-17-one (12).
Molecular formula: C20H26N2O, yield: 51.8%, mp:
288-290oC. IR (KBr, ѵ cm-1): 3163 (N-H), 2941 (C-H
str), 2245 (CN str), 1681 (C=O lactam), 1628 (C=C).
1H NMR (300 MHz, CDCl , δ): 0.96 (s, 3H, 18-CH ),
3
3
1.42(s, 3H, 19-CH3), 1.24-2.28 (m, 17H, steroidal
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ring), 5.79 (s, 1H, 6- vinylic), 6.62 (s, 1H, 4-vinylic),
7.15 (s, 1H, CONH). MS (ESI) m/z = 310 (M+1).
Elemental analysis: Calcd, C, 77.38; H, 8.44, N, 9.02.
Found: C, 77.31; H, 8.47; N, 9.06.
residue obtained was crystallized from acetonehexane to yield 3-substituted esters of 17-Oxo-17aaza-D-homo-3,5-androstadien-3-oic acid 14(ae).
2.1.3.
17-Oxo-17a-aza-D-homo-3,5androstadien-3-oic acid (13)
2.2.1. 3-Isopropyloxycarbonyl-17a-aza-D-homo3,5-androstadien-17-one (14a)
3-Cyano-17a-aza-D-homo-3,5-androstadien-17-one
(12) (0.31 g, 1.0 mmol) was dissolved in 20.0 ml of
absolute alcohol, to the solution 50% aqueous
sodium hydroxide (2.0 ml) was added and allowed
to reflux for 24 h. The reaction was monitored with
the help of TLC, after completion of reaction it was
cooled to 500C and to this was added with stirring
mixture of 50% hydrochloric acid (5.0 ml) and
dichloromethane (50.0 ml). The aqueous phase pH
was kept between pH 1.5-2.0. The aqueous layer
was extracted with dichloromethane (3×50.0 ml),
combined organic layers were washed with water
and dried. The dichloromethane was removed
under vacuum and ethyl acetate (30.0 ml) was
added. This was refluxed for 2 h, and then kept at 05 0C. The precipitated compound was filtered and
dried under vacuum to afford 17-Oxo-17a-aza-Dhomo-3, 5-androstadien-3-oic acid (13) (0.18 g,
57.6%).
Molecular formula: C20H27NO3, yield: 57.6%, mp:
194-196oC. IR (KBr, ѵ cm-1): 3426 (O-H str), 3163
(N-H), 2941 (C-H str), 1714 (C=O str), 1681 (C=O
lactam), 1628 (C=C), 1275 (C-O str). 1H NMR (300
MHz, CDCl3, δ): 0.87(s, 3H, 18-CH3), 1.17 (s, 3H, 19CH3), 1.26-2.24 (m, 17H, steroidal ring), 5.43 (s, 1H,
6- vinylic), 6.67 (s, 1H, 4-vinylic), 7.04 (s, 1H, CONH),
11.34 (s, 1H, COOH). MS (ESI) m/z = 329 (M+1).
Elemental analysis: Calcd. C, 72.92; H, 8.26; N, 4.25.
Found: C, 72.91, H, 8.28, N, 4.24.
Molecular formula: C23H33NO3, yield: 74%, mp: 242244oC. IR (KBr, ѵ cm-1): 3326 (NH), 2927 (C-H str),
1720 (C=O str), 1681 (C=O lactam), 1626 (C=C),
1275 (C-O str). 1H NMR (300 MHz, CDCl3, δ): 0.83 (s,
3H, 18-CH3), 1.13 (s, 3H, 19-CH3), 1.15- 1.29 (m, 6H,
2 x CH3), 1.28-2.29 (m, 17H, steroidal ring), 3.463.48 (m, 1H, COOCH), 5.35 (s, 1H, 6-vinylic), 6.96 (s,
1H, 4-vinylic), 7.41 (s, 1H, CONH). MS (ESI) m/z =
371 (M+1). Elemental analysis: Calcd. C, 74.36; H,
8.95; N, 3.77. Found. C, 74.33; H, 8.96; N, 3.79.
2.2. 3-substituted esters of 17-Oxo-17a-aza-Dhomo-3,5-androstadien-3-oic acid 14(a-e)
A
solution
of
17-Oxo-17a-aza-D-homo-3,5androstadien-3-oic
acid
(13)
(0.1g)
and
dicyclohexylcarbodiimide (DCC) (0.06 g) in
anhydrous dichloromethane (30.0 ml) was stirred
to which alcohol/phenol (0.0003 mol) was added.
Stirring was continued at room temperature till
reaction completion and was confirmed by TLC. The
precipitates of dicyclohexylurea (DCU) were filtered
and the remaining solvent was removed. The
2.2.2. 3-Butyloxycarbonyl-17a-aza-D-homo-3,5androstadien-17-one (14b)
Molecular formula: C24H35NO3, yield: 81%, mp: 264167oC. IR (KBr, ѵ cm-1): 3163 (N-H), 2941 (C-H str),
1730 (C=O str ester), 1681 (C=O lactam), 1628
(C=C), 1275 (C-O str). 1H NMR (300 MHz, CDCl3, δ):
0.81 (s, 3H, 18-CH3), 1.16 (s, 3H, 19-CH3), 1.07 (t, 3H,
4′ CH3), 1.32-2.25 (m, 17H, steroidal ring), 1.431.52 (m, 4H, 2 x CH2), 3.15 (m, 2H, 1′ CH2 ), 5.71(m,
1H, 6-vinylic), 6.76 (s,1H, 4-vinylic), 7.41 (s, 1H,
CONH). MS (ESI) m/z = 385 (M+1). Elemental
analysis: Calcd. C, 74.77; H, 9.15; N, 3.63. Found. C,
74.75; H, 9.19; N, 3.61.
2.2.3.
3-Benzyloxycarbonyl-17a-aza-D-homo3,5-androstadien-17-one (14c)
Molecular formula: C27H33NO3, yield: 69.8%, mp:
228-230oC. IR (KBr, ѵ cm-1): 3348 (N-H), 2912 (C-H
str), 1729 (C=O str ester), 1691 (C=O lactam), 1628
(C=C), 1552 (C=C Ar), 1269 (C-O str). 1H NMR (300
MHz, CDCl3, δ): 1.01 (s, 3H, 18-CH3), 1.13 (s, 3H, 19CH3), 1.27-2.26 (m, 17H, steroidal ring), 5.27 (s, 2H,
CH2), 5.68 (s, 1H, 6-vinylic), 7.01 (s, 1H, 4-vinylic),
7.14-7.23 (m, 5H, Ar-H), 7.41 (s, 1H, CONH). MS
(ESI) m/z = 419 (M+1). Elemental analysis: Calcd. C,
77.29; H, 7.93; N, 3.34. Found. C, 77.28; H, 7.90; N,
7.97.
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2.2.4. 3-(2-Methylphenyloxycarbonyl)-17a-azaD-homo-3,5-androstadien-17-one (14d)
Molecular formula: C27H33NO3, yield: 69.4%, mp:
287-289oC. IR (KBr, ѵ cm-1): 3324 (N-H), 2930 (C-H
str), 1734 (C=O str ester), 1691 (C=O lactam), 1631
(C=C), 1558 (C=C Ar), 1278 (C-O str). 1H NMR (300
MHz, CDCl3, δ): 1.14 (s, 3H, 18-CH3), 1.23-2.29 (m,
17H, steroidal ring), 1.52 (s, 3H, 19-CH3), 2.39 (s,
3H, CH3), 5.60 (s, 1H, 6-vinylic), 6.27 (s, 1H, 4vinylic), 6.83-7.19 (m, 4H, Ar-H), 7.41 (s, 1H, CONH).
MS (ESI) m/z = 419 (M+1). Elemental analysis:
Calcd. C, 77.29; H, 7.93; N, 3.34. Found. C, 77.28; H,
7.93; N, 3.35.
2.2.5. 3-(2,4-Dichlorophenyloxycarbonyl)-17aaza-D-homo-3,5-androstadien-17-one (14e)
Molecular formula: C26H29 Cl2 NO3, yield: 48.9%, mp:
202-204oC. IR (KBr, ѵ cm-1): 3334 (N-H), 2928 (C-H
str), 1731 (C=O str ester), 1691 (C=O lactam), 1628
(C=C), 1552 (C=C Ar), 1275 (C-O str), 769 (C-Cl). 1H
NMR (300 MHz, CDCl3, δ) : 0.83 (s, 3H, 18-CH3), 1.13
(s, 3H, 19-CH3), 1.24-2.29 (m, 17H, steroidal ring),
5.34 (s,1H, 6-vinylic), 6.90 (s, 1H, 4-vinylic), 7.08 (d,
2H, 5′ & 6′ Ar-H, J= 7.08 Hz ), 7.25 (s, 1H, 3′ Ar-H),
7.41 (s, 1H, CONH). MS (ESI) m/z = 473 (M+1).
Elemental analysis: Calcd. C, 65.82; H, 6.16; N, 2.95.
Found. C, 65.86; H, 6.13; N, 2.94.
2.3. Biological evaluation
Compounds were evaluated for their in vitro
inhibitory activity (Table 1) against PC-3 using
Dutasteride as a standard drug. PC-3 cell line was
purchased from NCCS, Pune (India). Cell line was
maintained in appropriate culture media
supplemented with 10% inactivated foetal bovine
serum, 100 IU/ml penicillin and 100µl/ml
streptomycin incubated at 37ºC and 5% CO2 in
humidified incubator. After achieving 80%
confluence, cells were then subcultured by
trypsinization with trypsin solution under sterile
condition. The cells were seeded in 96 well plates
before 24 h of testing at the concentration of 3000
cells/ well in 100µl of the medium. The cells in
triplicate were incubated for overnight and then
treated with varying concentration of compounds
ranging from 1-100 µm/ ml with dutasteride as
standard. After 3 days of incubation, each well was
replaced by 2 µl of MTT 3-(4, 5- dimethylthiazol-2yl) 2, 5 diphenyltetrazolium bromide solution (5
mg/ml) and kept in an incubator for 3 h. The
relative percentage of metabolically active cells and
untreated controls was determined on the basis of
mitochondrial reduction of MTT to Formazan
crystals in dimethyl sulfoxide (DMSO). Stock
solution and other dilutions (1µM/ml, 10µM/ml,
50µM/ml and 100µM/ml) were prepared in DMSO.
The inhibitory concentration (IC50) of samples was
calculated by measuring their spectrophotometric
absorbance with the help of microplate reader
(BIORAD) at 570/ 630 nm. IC50 value was calculated
for the compounds at different concentrations and
all the procedures were carried out thrice. All data
was expressed in terms of S.D and mean value.
Wherever appropriate, the data was also subjected
to unpaired two tailed student’s t test. A value of p <
0.05 was considered as significant.
3.0. RESULTS AND DISCUSSION
For the synthesis of compounds 14(a-e), 17-Oxo17a-aza-D-homo-3,5-androstadien-3-oic acid (13)
was used as starting material. Compound (13) was
synthesized from commercially available 16Dehydrpregnenolone acetate (4) according to
literature (Fig. 3) [41-44]. (13) was treated with
different alcohols and phenols in dichloromethane
containing dicyclohexylcarbodiimide to give desired
3-substituted esters of 17-Oxo-17a-aza-D-homo3,5-androstadien-3-oic acid 14(a-e).
Purity of synthesized compounds was
checked by different techniques such as TLC,
melting point and structures were confirmed by
spectral techniques (IR, 1H NMR, and Mass): IR
spectra of all compounds 14(a-e) showed
absorption band at around 3245-3329, 2895-2985,
1664-1695, 1628-1659, 1598-1648 and 1511-1589
cm-1 regions, conforming the presence of NH, CH,
CONH (lactam), CONH, C=C, C=C Ar, respectively.
Synthesized derivatives showed 1H NMR spectra
which was verified on the basis of chemical shifts,
multiplicities and coupling constants. The spectra of
most compounds determined the characteristic 3H
protons of 18-CH3 at 0.86-1.15 ppm, 3H protons of
19-CH3 at δ 1.14-1.54 ppm, 19H protons of steroidal
ring were found at around δ 1.19-2.61 ppm, 1H
proton of 3α-H at δ 3.50-3.85 ppm, 1H 4-vinylic
proton were at δ 3.73-4.28 ppm, CONH (lactam)
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FIGURE 1: STRUCTURES OF 5α-REDUCTASE INHIBITORS
FIGURE 2: PROPOSED STRUCTURE OF COMPOUND(S) TO BE SYNTHESIZED BASED ON EPRISTERIDE
AND FINASTERIDE AS 5α-REDUCTASE INHIBITORS
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FIGURE 3: SYNTHESIS OF 3-SUBSTITUTED ESTERS OF 17-OXO-17a-AZA-D-HOMO-3,5-ANDROSTADIEN3-OIC ACID REAGENTS AND CONDITIONS: (I) NH2OH.HCl, PYRIDINE, REFLUX 2 H, 85°C (II) POCl3,
PYRIDINE, HCl, STIR 1 H, 0°C (III) NH2OH.HCl, CH3COONa, REFLUX 3 H (IV) SOCl2, BENZENE, STIR 17
MIN, 15°C (V) KOH, CH3OH REFLUX 2 H (VI) Al(O-i-Pr)3, CYCLOHEXANONE, DIOXAN, TOLUENE, REFLUX
5 H (VII) PBr3, GLACIAL CH3COOH AT 0-5O C, 24 H (VIII) CuCn, DMF REFLUX 8 H (IX) NaOH, ABSOLUTE
ALCOHOL 24 H, REFLUX (X) DICYCLOHEXYLCARBODIIMIDE, DICHLOROMETHANE, SUBSTITUTED
ALCOHOLS/PHENOLS, STIR 48 H, 35°C
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TABLE 1: IN VITRO ANTIPROLIFERATIVE ACTIVITY AGAINST PC-3a CANCER CELL LINES
a
Compound
R
Log Pb
IC50 (μM)c
14a
isopropyl
3.02
45.434±0.284
14b
butyl
3.60
114.022±1.138
14c
benzyl
4.09
72.382±0.977
14d
2-methyl phenyl
4.51
29.690±1.767
14e
2,4-dichlorophenyl
5.14
22.327±0.379
Dutasteride
-
-
37.756±0.935
Human prostate cancer cell lines.
b Log
P values calculated by Chem Draw Ultra 8 software.
c Each
value is the mean of three independent experiments.
proton were around δ 5.96-7.22 ppm and
characteristic proton of CONH found around δ 7.338.59 ppm.
The biological evaluation was carried out in vitro
against prostate cancer cell line PC-3 by MTT (3-(4,
5- dimethylthiazol-2-yl) 2, 5 diphenyltetrazolium
bromide) assay. IC50 values of compounds 14(a-e)
obtained are mentioned in the (Table 1) and
compared with Dutasteride used as positive control.
nature of 2-methyl phenyl substituent at 3-carboxyl
group. Comparing enzyme inhibitory activity of
compounds (14b) and (14c) with (14a), compound
(14a) demonstrated greater inhibition of cell
growth. This is due to the fact that butyl and benzyl
substituents at 3-carboxyl cause steric hindrance to
reach active site of the enzyme.
3.1. Structure-activity relationship (SAR)
5α-reductase enzyme is responsible for BPH in men
as it catalyzes the reduction of testosterone to more
potent dihydrotestosterone and therefore, it is
necessary to suppress its action. In series of
analogues of 3-substituted esters of 17-Oxo-17aaza-D-homo-3,5-androstadien-3-oic acid (14a-e)
that we have synthesized, compounds with
substituents such as 2,4-dichloro phenyl, 2-methyl
phenyl and isopropyl linked through ester linkage
at C-3 of ring A have shown great activity due to
high lipophilicity. On the other hand, substituents
that cause steric hindrance resulted in decrease in
activity. Thus, we have examined the compounds by
alternating size and polarity of C-3 substituents. The
results of this study give an idea about the
antiproliferative potential of the compounds and
that it might be result of the interaction of
compound’s electronic, steric and hydrophobic
factors with the cell. The synthesized compounds
The active site of enzyme is electrophilic which
resides in hydrophobic pocket. Therefore, the
synthesized compounds contain 6-membered
lactam ring D to bind with the active site. The
flatness require in steroidal moiety to enter this site
is provided by conjugate double bonds at C-3 and C5. The lipophilicity of the molecule is increased by
substituting 3-carboxyl group with different
aliphatic and aromatic substituent as indicated by
log P values calculated by using Chem Draw Ultra 8
software. Compound (14e) with IC50 value
(concentration required to cause 50% inhibition in
cell growth) of 22.59μM showed an excellent
inhibitory potency as compared to dutasteride used
as standard due to tight binding of chlorine atoms to
cell line. Compound (14d) was also found to be good
inhibitor (IC50= 29.42μM) due to hydrophobic
4.0. CONCLUSION
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SHARMA ET AL
INT J RECENT ADV PHARM RES, 2015; 5(2): 9-17
ISSN: 2230-9306; WWW.IJRAPRONLINE.COM
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INTERNATIONAL JOURNAL OF RECENT ADVANCES IN PHARMACEUTICAL RESEARCH
APRIL 2015; 5(2): 9-17
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show mild to an excellent activity against 5αreductase enzyme as compared to standard drug
Dutasteride that may possibly prove useful for the
treatment of BPH.
ACKNOWLEDGEMENTS
We wish to express our gratitude to Shri. Parveen
Garg, Chairman, ISF College of Pharmacy, Moga,
Punjab, India for his inspiration and constant
support. We deeply acknowledge Ms. Richa Dhingra
and Mr. Vivek Sharma, assistant professor, ISF
College of Pharmacy, Moga for undertaking the
pharmacological
screening
of
synthesized
compounds.
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