1,2,4-Oxadiazoles: A new class of anti-prostate cancer agents

Article abstract of DOI:10.1016/j.bmcl.2012.01.059

Sulfide and sulfonyl derivatives of 1,2,4-oxadiazoles were synthesized and screened by MTT assay on the prostate cancer cells, DU-145. Six compounds were identified as potential anti-prostate cancer agents with IC₅₀ values ranging from 0.5 to 5

Full text of DOI:10.1016/j.bmcl.2012.01.059

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1912–1916
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
1,2,4-Oxadiazoles: A new class of anti-prostate cancer agents
Gopal L. Khatik a, Jasmine Kaur b, Varun Kumar a, Kulbhushan Tikoo b, Vipin A. Nair a,
⇑
a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
b Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfide and sulfonyl derivatives of 1,2,4-oxadiazoles were synthesized and screened by MTT assay on the
prostate cancer cells, DU-145. Six compounds were identified as potential anti-prostate cancer agents
with IC50 values ranging from 0.5 to 5.1 lM. These compounds exhibited good activity on the androgen
independent cells PC-3, while the results were moderate on androgen dependent LNCaP cells, suggesting
the possibility of a mechanism of action different from that of the bioisosteric bicalutamide. Also a very
low cytotoxicity was observed on non-cancerous cells MCF-10A.
Received 1 October 2011
Revised 2 January 2012
Accepted 17 January 2012
Available online 28 January 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
1,2,4-Oxadiazole
Prostate cancer
DU-145 cells
MTT assay
Carcinoma of the prostate (CaP) is one of the most frequently
diagnosed noncutaneous cancer in men.1,2 The specific causes of
prostate cancer remain unknown till date. Dihydrotestosterone
and testosterone are the main androgenic hormones which are
implicated in the initiation and promotion of the disease.3 In vitro
studies using the AR+ human prostate cancer cell line, LNCaP, pro-
vided the first evidence that structural alteration in the AR is
responsible for prostate cancer.4
In addition to the identification of AR gene mutations in hor-
mone-relapsed prostate cancer cases, amplification of the AR gene
in recurrent prostate tumors has also been reported.5 The elevated
AR levels resulting from AR gene amplification probably increases
sensitivity to residual circulating androgens facilitating tumor
growth.
Currently, there are two main classes of antiandrogens that are
clinically used (Fig. 1).6 A few steroidal ligands have been used as
antiandrogens, including cyproterone, oxendolone and spironolac-
tone. However, the clinical application of steroidal antiandrogens
has been limited greatly by poor oral bioavailability, lack of tissue
selectivity, poor pharmacokinetic properties and potential side ef-
fects like hepatotoxicity, androgenic effects and feminizing side ef-
fects like gynecomastia and loss of libido in men.7 Moreover, the
rigid steroid backbone does not allow wide structural modifications
for newer drug development. Non-steroidal antiandrogens are the
current pharmacological treatment of choice for progressive andro-
gen-dependent prostate cancer, either as monotherapy or with
adjuvant castration or luteinizing hormone-releasing hormone
(LHRH) superagonists to block the synthesis of endogenous testos-
terone. The non-steroidal ligands are more favorable for clinical and
therapeutic applications because of the lack of cross-reactivity with
other steroidal receptors which eliminates the unwanted side ef-
fects.7 Moreover, they demonstrate a highly improved oral bioavail-
ability as compared to their steroidal counterparts and are also
open to various structural modifications. The propionanilide deriv-
atives are the first developed non-steroidal antiandrogens and in-
clude drugs such as flutamide (EulexinÒ), hydroxyflutamide,
nilutamide and bicalutamide (CasodexÒ). However, the clinical
application of these non-steroidal ligands has been limited by its
hepatotoxicity after long-term administration.8
The drawbacks of currently available drugs emphasize the need
for the development of new candidates with high anti-prostate
cancer activity and low adverse effects. In recent years develop-
ment of various scaffolds as novel anti-prostate cancer agents have
been reported.6 Lately abiraterone acetate (Zytiga)9 in combination
with prednisone was approved by FDA for the castration resistant
prostate cancer (CRPC) from the steroidal antiandrogen class,
whereas Medivation (MDV3100)10 and Orteronel (TAK-700)11 are
novel potential agents from the non-steroidal antiandrogen class
(Fig. 2).
Our interests and research works on heterocyclic scaffolds12
helped us to unravel highly potent 4-oxo-2-thioxoimidazolidines
as a new class of anti-prostate cancer agents.13 Research pursuits to-
ward second generation anti-prostate cancer agents led us to 1,2,4-
oxadiazoles with substitutions at 3rd and 5th positions. 1,2,4-Oxa-
diazoles have demonstrated their utility as benzodiazepine receptor
agonists,14 muscarinic agonists,15 GABA modulators,16 and antirhi-
novirus agents.17 They are also known to possess anticancer,18 anti-
viral19 and antiparasitic properties.20 Literature reports indicate
their efficacy as angiotensin II receptor antagonists19 and HIV-1
⇑
Corresponding author. Tel.: +91 172 2292045; fax: +91 172 2214692.
E-mail addresses: vnair@niper.ac.in, vn74nr@yahoo.com (V.A. Nair).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.059

G. L. Khatik et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1912–1916
1913
O
(A) Steroidal agents
O
OH
O
OH
O
O
S
O
O
Cl
Oxendolone
Cyproterone
Spironolactone
(B) Non-steroidal agents
F
O
N
O2N
F3C
NH
O
HO
O
O
O
H
N
F3C
O2N
F3C
NC
S
N
H
O
Flutamide
Nilutamide
Bicalutamide
Figure 1. Steroidal (A) and non-steroidal (B) anti-prostate cancer agents.
N
O
F
N
F3C
NC
N
N
H
S
H
N
OH
N
H
N
O
H
O
H
HO
Abiraterone
TAK700
MDV3100
Figure 2. Novel antiandrogens.
reverse transcriptase inhibitors21 (Fig. 3). We assumed that a suit-
ably substituted aryl ring at the 3rd position with an electron with-
drawing substituent, and a mercapto aryl linkage at the 5th position
of the heterocyclic nucleus should serve as a suitable bioisostere of
bicalutamide. Investigations in this direction led us to a facile one-
pot synthetic strategy for the pharmacophore, and evaluation of
its cytotoxicity on prostate cancer cells, helped us to identify a
few compounds with high anti-prostate cancer activity.
The synthesis of 1,2,4-oxadiazole (Scheme 1) was initiated by
the conversion of methyl methacrylate (1) to methyl 2-methyloxi-
rane-2-carboxylate (2) using oxone (potassium peroxy monosul-
fate, 2KHSO5ꢀKHSO4ꢀK2SO4).22 The epoxide formed was then
reacted with various thiophenols 3(i–iv) to afford the desired hy-
droxy esters 4(i–iv), which were further hydrolysed with 10% aq
NaOH in ethanol to yield the hydroxy acids 5(i–iv). The amidox-
imes 7(a–d), were prepared from the corresponding nitriles
6(a–d), by refluxing with K2CO3 and hydroxylamine hydrochloride
in methanol. Synthesis of 1,2,4-oxadiazoles usually involves O-
acylation of an amidoxime with an acid chloride15 or an anhy-
dride23 followed by cyclization in refluxing pyridine. Though this
method works well on simple substrates, the reaction has a limited
scope on substrates having functional groups; for instance, hydro-
xy groups if present have to be protected prior to the reaction.15
Alternatively, to avoid complications arising from the reaction con-
dition, diglyme was used as a solvent with a peptide coupling re-
agent,24 but the result was disappointing. The reaction of 5(i)
with 7(a), using the coupling reagent N-(3-dimethylaminopro-
pyl)-N0-ethylcarbodiimide hydrochloride (EDCꢀHCl), and 1-hydrox-
Cl
O
N
NH2
N
N
O
Cl
O
N
N
N
N
O
N
OH
N
C5H9O
H3CO
N
Cl
Anticancer
Anticonvulsant
Antimycobacterial
O
N
O
N
N
H
N
HN N
N
N
NHCOCH3
CO2H
N
O
Selective avb3 receptor antagonists
Anti-trypanosoma cruzi agent
Figure 3. Biologically active 1,2,4-oxadiazole scaffolds.

1914
G. L. Khatik et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1912–1916
HS
R3
O
O
O
R3
Oxone, MeOH
Aq. KOH
3(i-iv)
MeO
S
MeO
MeO
OH
4(i-iv)
O
K2CO3, CH3CN
2
1
Aq. NaOH (10%)
Ethanol, rt
R1
R2
R3
a
b
c
d
H
Cl
H
i
H
F
R3
O
H
ii
F
Cl
CF3
iii Cl
iv Br
HO
S
OH
5(i-iv)
NO2
NH2
R2
CN
NH2OH.HCl
K2CO3
R2
OH
N
(a) EDC, HOBt, CH3CN
(b) Toluene, reflux
R1
R1
Methanol, reflux
7(a-d)
6(a-d)
R2
R2
HO
HO
O2
S
m-CPBA
S
N
N
R1
R1
A
A
B
B
DCM
O
O
N
N
R3
R3
8(a-d)(i-iv)
9(a-d)(i-iv)
Scheme 1. Synthesis of 1,2.4-oxadiazole derivatives.
ylbenzotriazole (HOBt), in acetonitrile afforded the intermediate I
(identified by mass and 1H NMR spectral methods). Attempts to cy-
clize the intermediate using pyridine under reflux conditions led to
poor yield. However, when refluxed in toluene the intermediate I
cyclized to afford the desired product in good yield (Scheme 2).
The scope of this reaction condition was successfully examined
by synthesizing different sulfide derivatives 8(a–d)(i–iv) in a
one-pot methodology. The sulfides were then oxidized with m-
CPBA in DCM to give corresponding sulfonyl oxadiazoles deriva-
tives 9(a–d)(i–iv).
All the synthesized compounds were then screened in triplicate
at concentrations varying from 10ꢁ3 ng/mL to 105 ng/mL (Table 1)
using the MTT in vitro assay25–27 on the prostate cancer cells DU-
145 (androgen independent, moderately metastatic).28 The cells
were cultured in DMEM or RPMI1640, containing 10% FBS and 1%
penicillin–streptomycin. Compounds 8(b)(i and iv), 8(c)(i–iv),
8(d)(i–iv) showed good cytotoxicity on DU-145 cells and the
dose–response curves are illustrated in Figure 4. With an IC50 value
(Table 1). Phenyl substituents at the 3rd position of 1,2,4-oxadiaz-
ole and at the end of the thioalkyl linkage did not show any anti-
cancer activity. An incremental induction of electron
withdrawing groups on the aryl ring B did not alter the outcome.
On the other hand, electron withdrawing aryl rings at the 3rd posi-
tion of oxadiazole significantly improved the cytotoxicity (Table 1,
entries 5–16). This prompted us to explore the activity of oxadiaz-
oles having electron withdrawing substituents on both the aryl
rings A and B, and the results were encouraging. We anticipated
that the inductive effect (ꢁI) of the aryl ring A at the 3rd position
of the heterocycle plays a more prominent role than the aryl ring
B at the end of the thioalkyl linkage at the 5th position of oxadiaz-
ole. As expected, 3-chloro-4-fluorophenyl and 4-nitro-3-trifluoro-
methyl phenyl rings gave highly impressive results. Needles to
mention, with IC50 values in the range of 0.50–8.80 lM, the cyto-
toxicity of the compounds 8(b)(i and iv), 8(c)(i–iv), 8(d)(i–iv) were
in comparable limits with that of doxorubicin. This validated our
conjecture on the essential structural features required for the
pharmacophore.
of 0.50
lM, the compound 8(c)(iii), showed activity 11.6-fold bet-
ter than doxorubicin (IC50 = 5.8
aromatic rings exerted considerable influence on the potency
l
M). In general, electron deficient
Since no significant variation in cytotoxicity was observed with
the substituents on the aryl ring B, we decided to examine the role
O
N
O
EDC, HOBt, CH3CN
NH2
O
S
HO
S
OH
OH
NH2
Intermediate I
OH
5(i)
N
Toluene
7(a)
reflux
HO
O
S
N
N
8(a)(i)
Scheme 2. One-pot formation of intermediate and cyclization to 1,2,4-oxadiazole.

G. L. Khatik et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1912–1916
1915
Table 1
Table 2
Cytotoxicity studies on DU-145 cells by MTT assaya
Cytotoxicity studies of most active compounds on PC-3 and LNCaP cellsa
S. No.
Compound
R1
R2
R3
IC50 on DU-145 cells (
lM
SD)
S.
No.
Compound
IC50 on PC-3 cells
SD)
IC50 on LNCaP cells
(lM SD)
(lM
1
2
3
4
5
6
7
8
8(a)(i)
H
H
H
H
Cl
Cl
Cl
Cl
F
F
F
F
NO2
NO2
NO2
NO2
H
H
H
H
Cl
Cl
Cl
Cl
F
F
F
F
NO2
NO2
NO2
NO2
—
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
CF3
CF3
CF3
CF3
H
H
H
H
H
H
F
Cl
Br
H
F
Cl
Br
H
F
Cl
Br
H
F
Cl
Br
H
F
Cl
Br
H
F
Cl
Br
H
F
Cl
Br
H
F
>100
>100
70.69
>100
8(a)(ii)
8(a)(iii)
8(a)(iv)
8(b)(i)
8(b)(ii)
8(b)(iii)
8(b)(iv)
8(c)(i)
8(c)(ii)
8(c)(iii)
8(c)(iv)
8(d)(i)
8(d)(ii)
8(d)(iii)
8(d)(iv)
9(a)(i)
9(a)(ii)
9(a)(iii)
9(a)(iv)
9(b)(i)
9(b)(ii)
9(b)(iii)
9(b)(iv)
9(c)(i)
9(c)(ii)
9(c)(iii)
9(c)(iv)
9(d)(i)
9(d)(ii)
9(d)(iii)
9(d)(iv)
DXRb
1
2
3
4
5
6
7
8
8(c)(ii)
8(c)(iii)
8(d)(i)
8(d)(ii)
8(d)(iii)
8(d)(iv)
DXR
11.50 0.43
10.00 0.13
3.50 0.12
5.50 0.59
3.00 0.23
51.00 0.40
1.05 0.09
>100
26.40 0.40
9.67 0.50
8.15 0.89
>100
4.50 0.16
36.25 1.81
14.50 0.87
6.50 0.44
5.50 0.45
2.90 0.36
0.50 0.06
8.80 0.71
3.00 0.28
5.10 0.56
1.30 0.12
1.60 0.19
>100
>100
>100
>100
>100
>100
>100
>100
>100
40.00 0.57
ndb
Bicalutamide [77]30
1.71 0.12 [2.2 ]30
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
a
The data represents the mean of three experiments standard deviation.
nd = not determined.
b
H
H
H
Cl
Cl
Cl
Cl
CF3
CF3
CF3
CF3
—
>100
35.50
75.00
>100
>100
91.00
>100
Figure 5. Dose–response curves on PC-3 cells.
Cl
Br
—
—
5.80 0.58
Bicalutamide
—
—
[64]30
a
The data represents the mean of three experiments standard deviation.
DXR = doxorubicin.
b
Figure 6. Dose–response curves on LNCaP cells.
PC-3 (Fig. 5) and LNCaP cells (Fig. 6). Doxorubicin was taken as
the standard in case of DU-145 and PC-3 cells due to ineffective-
ness of bicalutamide on these androgen independent cells.30
An examination of the comparative cytotoxicity data at 1.0 lM
on DU-145, PC-3, LNCaP and MCF-10 A cells (non-cancerous epi-
thelial cells)31 indicate comparable results on the androgen inde-
pendent cells DU-145 and PC-3 (Table 3), while the results were
moderate on the androgen dependent LNCaP cells (Fig. 7). This
observation points to the possibility of an alternate mechanism
of inhibition for 1,2,4-oxadiazoles unlike that for the propionani-
lide based androgen receptor antagonists. Very low cytotoxicity
Figure 4. Dose–response curves on DU-145 cells.
of the thiol linkage at the 5th position. The sulfonyl group is be-
lieved to play a significant role in the binding interactions of R-
bicalutamide. The distance between the adjacent chiral hydroxyl
group and the sulfonyl oxygen in R-bicalutamide is suitable for
an intramolecular hydrogen bonding.6b Consequently a bent con-
formation is adopted by the molecule facilitating better ligand
receptor interactions within the binding pocket of the androgen
receptor. However, in the case of 1,2,4-oxadiazoles a sulfonyl
group instead of the thiol linkage illustrated drastic decrease in
activity. Based on the data obtained from the evaluation on DU-
145 cells, six potent compounds 8(c)(ii and iii), 8d(i–iv) having
cytotoxicity better than doxorubicin were screened on PC-3 cells
(androgen independent, moderately metastatic)28 and LNCaP cells
(androgen dependent, poorly metastatic).29 The results are docu-
mented in Table 2 and the dose–response curves are plotted for
Table 3
Comparative cytotoxicity at 1.0
l
M concentration on DU-145, PC-3, LNCaP and MCF-
Cytotoxicity (%)
10A cells by MTT assaya
Compound
DU-145 cells
PC-3 cells
LNCaP cells
MCF-10A cells
8(c)(ii)
8(c)(iii)
8(d)(i)
8(d)(ii)
8(d)(iii)
8(d)(iv)
47.84
68.41
49.62
47.28
48.93
48.71
40.77
44.39
49.02
46.89
39.61
31.77
32.86
33.85
31.10
26.88
28.93
27.45
12.44
10.62
12.62
11.35
10.35
10.55
a
The data represents the mean of three experiments.

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Figure 7. Comparative cytotoxicities at 1.0 lM.
was observed on MCF-10A cells suggesting the nontoxic nature of
these compounds on non-cancerous cells.
In conclusion, the biological evaluation of the synthesized com-
pounds helped in identifying a highly potent pharmacophore based
on 1,2,4-oxadiazole skeleton. The thiol linkage was found to be an
essential requirement for the pharmacophore, whereas switching
to sulfonyl group leads to loss of activity. Also aryl groups with
electron withdrawing substituents are necessary for cytotoxicity.
Compounds 8(b)(i and iv), 8(c)(i–iv), 8(d)(i–iv) exhibited excellent
potency against the androgen independent prostate cancer cells
DU-145 and PC-3, while the cytotoxicity was moderate on andro-
gen dependent LNCaP cells. A very low cytotoxicity was observed
on non-cancerous MCF-10A cells. The cytotoxicity exhibited on
the androgen insensitive metastatic prostate cancer cells provide
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Funding for this research work from the Department of Science
and Technology (DST), Government of India and a research fellow-
ship from the University Grants Commission (UGC) to G.L.K., is
gratefully acknowledged.
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