D-ring modified estrone derivatives as novel potent inhibitors of steroid sulfatase

被引:56
作者
Fischer, DS
Woo, LWL
Mahon, MF
Purohit, A
Reed, MJ
Potter, BVL [1 ]
机构
[1] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
[2] Univ Bath, Sterix Ltd, Bath BA2 7AY, Avon, England
[3] Univ Bath, Dept Chem, Bath BA2 7AY, Avon, England
[4] Univ London Imperial Coll Sci Technol & Med, St Marys Hosp, Fac Med, London W2 1NY, England
[5] Univ London Imperial Coll Sci Technol & Med, St Marys Hosp, Fac Med, Sterix Ltd, London W2 1NY, England
基金
英国工程与自然科学研究理事会;
关键词
D O I
10.1016/S0968-0896(03)00042-7
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A series of novel D-ring modified derivatives of estrone was synthesized and tested as inhibitors of steroid sulfatase (STS). The steroidal D-ring was cleaved via an iodoform reaction and thermal condensation of the resulting marrianolic acid derivative gave 16,17-seco-estra-1,3,5(10)-triene-16,17-imide derivatives, where a piperidinedione moiety is in place of the D-ring. This synthetic approach was found to give a higher overall yield than the literature method of Beckmann rearrangement. A range of alkyl side chains have been introduced on the nitrogen atom of the imido-ring and the corresponding 3-O-sulfamates synthesized. The new D-ring modified estrone derivatives bearing a propyl (39) and a 1-pyridin-3-ylmethyl (46) moiety had IC50 values of 1 nM when tested in placental microsomes for the inhibition of STS. These compounds are therefore up to 18-fold more potent than EMATE, the very first highly potent irreversible steroidal STS inhibitor. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1685 / 1700
页数:16
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