REQUIREMENTS FOR P-GLYCOPROTEIN RECOGNITION BASED ON STRUCTURE-ACTIVITY-RELATIONSHIPS IN THE PODOPHYLLOTOXIN SERIES

Podophyllotoxin and epipodophyllotoxin react with tubulin at the same binding site as colchicine, but in contrast to colchicine, do not appe ar to exert their cytotoxicities by mechanisms dependent on P-glycopro tein (Pgp) expression. To investigate structural requirements for Pgp recognition a series of podophyllotoxin and epipodophyllotoxin derivat ives have been synthesized. Their interactions with the multidrug resi stance-related protein Pgp have been studied by evaluating their relat ive cytotoxicities versus P388-sensitive murine leukemic cells and a c lassic multidrug-resistant (MDR) Pgp-overexpressing subline (P388/ADR) , and their relative tubulin polymerization inhibitory activities agai nst microtubular proteins have been determined. Based on tridimensiona l structure-activity relationships within this series of compounds, st ructural requirements for Pgp recognition have been identified. Moreov er, proposals are made for extending these criteria to other chemical classes of anticancer drugs.