Synthesis and antiproliferative activity of novel A-homo-B-norsteroid thiadiazole derivatives

Article abstract of DOI:10.1016/j.tetlet.2017.06.041

Using cholesterol as a starting material, two novel steroidal thiadiazole derivatives possessing a structure of A-homo lactam and a B-nor steroidal skeleton were designed and synthesized by six steps of reactions, and their antiproliferative activities were assayed against various cancer cell lines. The result shows that compound 7b displays an excellent selective inhibition to A-549 (human lung carcinoma) cancer cell lines with an IC₅₀ value of 8.0?μM.

Full text of DOI:10.1016/j.tetlet.2017.06.041

Accepted Manuscript
Synthesis and Antiproliferative activity of Novel A-Homo-B-Norsteroid Thia-
diazole Derivatives
Yanmin Huang, Chunhui Yang, Junyan Zhan, Chunfang Gan, Zhiping Liu,
Chunling Pang, Haifeng Chen, Jianguo Cui
PII:
S0040-4039(17)30772-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.041
TETL 49033
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
23 May 2017
11 June 2017
13 June 2017
Please cite this article as: Huang, Y., Yang, C., Zhan, J., Gan, C., Liu, Z., Pang, C., Chen, H., Cui, J., Synthesis and
Antiproliferative activity of Novel A-Homo-B-Norsteroid Thiadiazole Derivatives, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.06.041
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Synthesis and Antiproliferative activity of Novel A-Homo-B-Norsteroid
Thiadiazole Derivatives
a
a
a
a
a
Yanmin Huang Chunhui Yang Junyan Zhan Chunfang Gan Zhiping Liu
a
b
a,b*
Chunling Pang Haifeng Chen Jianguo Cui
a
b
College of Chemistry and Material Science, Guangxi Teachers Education University, Nanning, 530001, PR China
Guangxi Colleges and University Key Laboratory of Beibu Gulf Oil and Natural Gas Resource Effective Utilization, Qizhou University, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Using cholesterol as a starting material, two novel steroidal thiadiazole derivatives possessing a
structure of A-homo lactam and a B-nor steroidal skeleton were designed and synthesized by six steps
of reactions, and their antiproliferative activities were assayed against various cancer cell lines. The
result shows that compound 7b displays an excellent selective inhibition to A-549 (human lung
carcinoma) cancer cell lines with an IC50 value of 8.0 µM.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
cholesterol
B-norsteroid
A-homosteroids
A-Homo-B-Nor-steroidal derivatives
steroidal thiosemicarbazone
[
21]
It is well known that steroids play an important biological
role in the life. However, the applications of natural steroids were
greatly restricted because of their limited amount and low content
in nature. So introducing specified functional groups into the
steroidal skeleton or changing the structure of natural steroids to
get new compounds with higher bioactivity and some special
biofunction has become a focus of research on the steroidal
tuberculosis . In our previous studies, we synthesized some
novel B-norsteroids and investigated their cytotoxic activity
against different types of cancer cells
[22-25]
. The results
demonstrated that B-norsteroids with a cholesteric side-chain and
a 6-hydroximino, 6-thiosemicarbazone or 6-benzimidazole group
displayed good antiproliferative activity against some cancer
cells through inducing cancer cell apoptosis.
Basing on the results of our previous work, in order to
investigate the bioactivity of new steroidal derivatives as new
anticancer drugs, two novel steroidal compounds possessing both
a structure of A-homo lactam and a B-nor steroidal skeleton were
designed and synthesized by combining the structure of A-
homosteroid with B-norsteroid in the present study, and their
antiproliferative activities were assayed against various cancer
cell lines.
[
1-4]
chemistry in recent years
.
Aza-homosteroids are a class of steroid compounds which
are synthesized and modified in order to increase biological
activity of steroids. These compounds have been tested
[
5-9]
[10]
successfully as anti-cancer
, antileukemic agents. In order
to find novel and effective anti-tumor agents, we synthesized a
series of aza-homosteroids with aza-substitution on various
position of the steroidal skeleton, and determined the
antiproliferative activity of the compounds against various cancer
cell lines. The results proved that these compounds showed a
The synthetic route and the structure of target compounds
7a-b are outlined in Scheme 1. First, cholesterol (1) was
ozonolyed in a mixture of CH
[
11-
high antiproliferative acitivity to some tumor cell line in vitro
.
2
Cl and MeOH (CH
2
2 2
Cl /MeOH =
1
5]
o
Our research results showed also that aza-homosteroids with
4:1) at -78 C. Then, adding Me S to decompose the produced
2
aza-A-homo- and aza-B-homo-configuration possessed a better
ozonide, the compound 2 was obtained. The 2 was subjected to
[
16-17]
cytotoxicity to tested tumor cell line
.
neutral alumina to realize the intramolecular aldol condensation
[
22]
B-norsteroid is a kind of novel steroidal compound
possessing a special skeleton of [6-5-6-5] fused rings. These
affording compound 3 . Next, compound 4 was obtained by
the oxidation of 3 using Jone’s reagent as oxidative agent. The
compound 4 was converted to the compound 5 by the reaction of
4 with thiosemicarbazide. Furthermore, an oximation of 3-
carbonyl group in compound 5 gave compound 6. The structure
[
18-19]
compounds were discovered in marine organism
and land
[
20]
plant . The results of bioactivity assay had shown that these
kinds of compounds displayed an excellent antiproliferative
activity and good inhibitory activity against Mycobacterium

2
Tetrahedron
of all synthesized compounds were confirmed by their spectral
6c
18.7
>80
28.5
15
>80
20.5
>80
10
33
>80
30
7.8
>80
8.0
>80
>80
>80
11
data.
7a
7
b
Cisplatin
10
20.8
a
b
c
From the data shown in Table 1, compound 6c with 6-(N-
phenyl)thiosemicarbazone group and 7b with 6-(5'-
methylamino)thiadiazole ring show a better selective cytotoxicity
on A-549 cells with IC50 value of 7.8 and 8.0µM, and are almost
inactive on HEK293T cells. Both compounds display a better
antiproliferative activities than a positive control cisplatin
(20.8µM), and deserve further study.
HO
HO
O
HO
CHO
OH CHO
1
2
3
d
e
S
S
HO
N
N
R
N
R
O
CHO
O
N
H
N
N
N
H
H
H
4
5
H
H
6
: a R = H; b R = CH3; c R = Ph
3 3 2 2 3
Reagents and conditions: a: O /(CH ) S; b: Al O /Ph; c: Jones reagent; d:
o
Acknowledgments
NH
2
NHCSNH
2
, 80 C; e: NH
2
OH.HCl/AcONa.
Scheme 1
The authors acknowledge the financial support of the
National Natural Science Foundation of China (No: 21462009),
the Natural Science Foundation of Guangxi Province (No:
2014GXNSFAA118052) and the Guangxi Colleges and
University Key Laboratory Foundation of Beibu Gulf Oil and
Natural Gas Resource Effective Utilization (No: 2016KLOG10).
Last, Beckman rearrangement of hydroxyimino group of
compound 6a-6b in SOCl /THF gave A-homo-lactame ring.
2
During the process of the reaction, 6-thiosemicarbazone group
was converted to thiadiazole ring to obtain target products 7a-7b.
In the H NMR of 7a, the chemical shift of C
1
7
-H at 2.89 ppm
appears as a dd-peak with a coupling constant of 17.7 and 4.5
ppm which illustrate that the C7-H and C8-H are located on an
anti-form position of a-bond. This result shows that the
stereochemistry of C-7 is the β-configuration. On the other side,
compound 6c couldn’t be transformed into compound 7c because
there is a larger benzene ring in the structure of its 6-substituted
group
Conflict of Interest
The authors declare no conflict of interest.
References and notes
1
2
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HN
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3
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S
O
N
NHR
a
N
S
7a: R = H; 7b: R = CH3
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4.
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N
H
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6a-6c
No Product
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6
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Reagents and conditions: a: SOCl /THF.
Scheme 1
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vitro on HeLa (human cervical carcinoma), CNE-2
nasopharyngeal carcinoma), HEPG2 (human liver carcinoma),
A-549 (human lung carcinoma) cancer cell lines and HEK293T
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Table 1. Antiproliferative activity of compounds 4-7 (IC50 in µM)（MTT
method）
Comp.
HeLa
>80
>80
>80
>80
>80
>80
CNE-2
>80
HEPG2
>80
A-549
>80
>80
>80
>80
>80
>80
HEK293T
>80
4
5
5
a
>80
>80
>80
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>80
>80
>80
5
6
c
>80
>80
>80
a
16.5
>80
>80
>80
6
b
>80
>80

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Click here to remove instruction text...
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4
1
Tetrahedron
Highlights
. Two novel steroidal derivatives possessing both
a A-homo lactam and a B-nor structure were
designed and synthesized.
2
3
4
. Synthesis starting from very cheap cholesterol.
. Their antiproliferative activities were assayed.
. Compounds 6c and 7b displayed an excellent
inhibited selectivity to A-549 cancer cells.
. The studied result may be useful for the design
of novel chemotherapeutic drugs.
5