Synthesis and structure-activity relationship of 3-O-acylated (-)-epigallocatechins as 5α-reductase inhibitors.
A series of 3-O-acylated (-)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (-)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3-O-acylated (-)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound 4h) with an IC50 of 0.53 μM, which was ∼12-fold more potent than EGCG (IC50=6.29 μM). Introduction of monounsaturated fatty acid provided the most potent compound 6 (IC50=0.48 μM), which showed moderate anti-tumor activity in vivo.
Development Center for Biotechnology, No. 101, Lane 169, Kangning Street, Xizhi City, Taipei County, Taiwan 221, ROC.
Shu Fu
SF
Lin
Yu-Hsiang
YH
Lin
Mengju
M
Lin
Yi-Feng
YF
Kao
Ru-Wen
RW
Wang
Li-Wei
LW
Teng
Shih-Hsien
SH
Chuang
Jia-Ming
JM
Chang
Ta-Tung
TT
Yuan
Kuo Chu
KC
Fu
Kuan Pin
KP
Huang
Ying-Shuen
YS
Lee
Chao-Cheng
CC
Chiang
Sheng-Chuan
SC
Yang
Chun-Liang
CL
Lai
Chu-Bin
CB
Liao
Paonien
P
Chen
Young-Sun
YS
Lin
Kuei-Tai
KT
Lai
Hung-Jyun
HJ
Huang
Ju-Ying
JY
Yang
Chia-Wei
CW
Liu
Win-Yin
WY
Wei
Chi-Kuan
CK
Chen
Richard A
RA
Hiipakka
Shutsung
S
Liao
Jiann-Jyh
JJ
Huang
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D058891:5-alpha Reductase Inhibitors; D000970:Antineoplastic Agents; D002392:Catechin; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C057580:gallocatechol