Open AccessSynthesis and Biological Evaluation of 3‐(Prop‐2‐enyl)‐ and 3‐(Prop‐2‐ynyl)pyrrolidine‐2,5‐dione Derivatives as Potential Aromatase Inhibitors
Author(s) -
BARRELL K. J.,
WOO W. L.,
AHMADI M.,
SMITH H. J.,
NICHOLLS P. J.
Publication year - 1996
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1111/j.2042-7158.1996.tb07115.x
Subject(s) - pyrrolidine , aromatase , substrate (aquarium) , chemistry , enzyme , stereochemistry , biochemistry , biology , medicine , ecology , cancer , breast cancer
3‐(4′‐Aminophenyl)pyrrolidine‐2,5‐dione (WSP3), a known reversible inhibitor of P450 aromatase, was modified using molecular graphics and our model of reversible inhibitor and substrate binding to resemble 10β‐prop‐2‐ynylestr‐4‐ene‐3,17‐dione (PED), a mechanism‐based inactivator of the enzyme. The analogues prepared were 3‐substituted 3‐(prop‐2‐enyl) or 3‐(prop‐2‐ynyl) pyrrolidine‐2,5‐diones and their N ‐alkyl derivatives. The reported compounds demonstrated no irreversible (time‐dependent) inhibition of the human placental P450 aromatase enzyme. However, some reversible activity was seen in several of the 3‐(prop‐2‐ynyl) compounds.