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Guo-Xin Hu
a,
, Guang Liang
a,
, Yanhui Chu
d
, Xiaokun Li
a
, Qing-Quang Lian
b,
*
, Han Lin
b
, Yi He
a
,
Yadong Huang
c,e
, Dianne O. Hardy
c
, Ren-Shan Ge
b,c,
*
a
School of Pharmacy, Wenzhou Medical College, Wenzhou 325000, PR China
b
The 2nd Afliated Hospital, Wenzhou Medical College, Wenzhou 325000, PR China
c
Population Council, 1230 York Avenue, New York, NY 10065, USA
d
Heilongjiang Key Laboratory of Anti-brosis Biotherapy, Mudanjiang Medical University, Heilongjiang, PR China
e
Institutes of Life and Health Engineering, Jinan University, Guangzhou, Guangdong 510632, PR China
a r t i c l e i n f o
Article history:
Received 10 January 2010
Revised 23 February 2010
Accepted 24 February 2010
Available online 1 March 2010
Keywords:
Steroids
Curcumin derivatives
Steroidogenesis
Androgens
17b-HSD3
Leydig cells
a b s t r a c t
Non-steroidal compounds that inhibit 17b-hydroxysteroid dehydrogenase isoform 3 (17b-HSD3), an
enzyme catalyzing the nal step in testosterone biosynthesis in Leydig cells, are under development
for male contraceptive or treatment of androgen dependent diseases including prostate cancer. A series
of curcumin analogues with more stable chemical structures were compared to curcumin as inhibitors of
17b-HSD3 in rat intact Leydig cells as well as rat and human testis microsomes.
2010 Elsevier Ltd. All rights reserved.
Inhibitors of testosterone (T) biosynthesis are widely sought for
treatment of androgen-dependent disorders such as benign pros-
tate hyperplasia, hormone-dependent prostate cancer, acne, sebor-
rhea, hirsutism, androgenic alopecia, and precocious puberty and
also for suppression of spermatogenesis as male contraceptives.
The last step T biosynthesis from androstenedione is catalyzed by
17b-hydroxysteroid dehydrogenase type 3 (17b-HSD3).
1
This en-
zyme accounts for most of the circulatory T in males, as a genetic
mutation of 17b-HSD3 causes the autosomal recessive genetic dis-
order male pseudohermaphroditism in which males often are born
with female external genitalia and without a prostate.
2,3
Thus,
drugs that inhibit 17b-HSD3 have potential for therapies where
anti-androgenic action is desired.
The development of specic inhibitors of 17b-HSD3 and other
17b-HSDisoforms is the subject of a recent review.
4
These chemicals
are: (1) androsterone (ADT) derivatives;
57
(2) biphenyl-p-benzo-
quinone (IC
50
= 2.7 lM);
8
and (3) glycyrrhetinic acid.
9,10
ADT is a
weak androgen that is twice as potent as androstenedione in the
inhibition of 17b-HSD3.
5
A drawback of some of these derivatives
such as 3b-phenylethyl-ADT (IC
50
= 57 nM) is that they are also
androgenic in the range of potencies similar to dihydrotestos-
terone.
5
Glycyrrhetinic acid also potently inhibits 11b-hydroxyster-
oid dehydrogenase 2 to cause hypertension.
11
We hypothesize that
small molecules that block the active site of 17b-HSD3 inhibit the
enzymatic activity. Therefore, we began to identify lead compounds
from plant-derived phytochemicals. These nature chemicals gener-
ally are expected to have lowtoxicity and therefore could be poten-
tially used for therapeutic use. Therefore, we screened many
phytochemicals to inhibit 17b-HSD3. One of them is curcumin
(Fig. 1), 1,7-bis(4-hydroxy-3-methoxypentyl)-1,6-hepadiene-3,5-
dione, from turmeric. Recently, we synthesized many curcumin
derivatives.
12
Then we screened these curcumin derivatives
(Fig. 1) to inhibit rat and human 17b-HSD3 in intact rat Leydig cells,
rat andhumantestis microsomes. Themicrosomal andcellular assay
for 17b-HSD3 activity was performed.
13
The potencies of inhibiting
17b-HSD3inrat intact Leydigcells, rat andhumantestis microsomes
for curcumin were IC
50
= 9.0 1.0 (mean SEM, n = 4), 2.3 1.2
(n = 3) and 67.3 11.9 lM (n = 3), respectively. The inhibitory
potencies of these curcumin derivatives are shown in Table 1. For
the inhibition of human 17b-HSD3, the following chemicals were
more potent than parent chemical curcumin: compound C3
(IC
50
= 0.1 lM) > B4 (2.4 lM) > B6 (2.7 lM). However, these com-
pounds wereless potent toinhibit 17b-HSD3inrat testis microsome.
For example, IC
50
of C3was 1.8 lMfor theinhibitionof rat testis 17b-
HSD3. There is species-dependent difference for the potencies of
0960-894X/$ - see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.089
* Corresponding authors. Tel.: +1 212 327 8761; fax: +1 212 327 7678 (R.-S.G.).
E-mail addresses: qingquanlian@yahoo.com.cn (Q.-Q. Lian), rge@popcbr.rock
efeller.edu (R.-S. Ge).