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Enantioselectivity of aromatase inhibitors: Substituted 3‐(4‐aminophenyl)pyrrolidine‐2,5‐diones
Author(s) -
Pepper Christopher,
Smith H. John,
Nicholls Paul J.,
Barrell Kevin J.,
Ahmadi Massoud
Publication year - 1995
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.530070511
Subject(s) - chemistry , pyrrolidine , aromatase , combinatorial chemistry , stereochemistry , organic chemistry , medicine , breast cancer , cancer
Abstract The (+)‐, (−)‐, and (±)‐forms of 1‐ and 1,3‐substituted 3‐(4‐aminophenyl)pyrrolidine‐2,5‐dione have been examined as inhibitors of P450 AROM and P450 CSCC . The inhibitory potency for P450 AROM resided in the (+)‐enantiomers of ( 1 ), ( 2 ), and ( 4 ) and the (−)‐enantiomers of ( 3 ) and ( 5 ). These findings have been accommodated within a molecular graphics‐derived model for binding of P450 AROM inhibitors to the substrate binding site. Crystallography showed that (+)‐( 2 ) has the (R)‐configuration. Spectral binding studies with human placental P450 AROM showed type II binding but although the K S values were in line with the IC 50 values for individual compounds there was no overall correlation between K S and IC 50 within the series. There was little difference in the inhibitory potency of the enantiomers and racemate of individual compounds toward P450 CSCC . © 1995 Wiley‐Liss, Inc.