11-Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action.

摘要: The synthesis of various new structures a library 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines (BP) and 6-aminobenzo[c]phenanthridines (BP-D) is presented. These structures, further synthetic modifications, the preparation follow-up products which delivered about 40 derivatives are described. Their potential as antiproliferative drug candidates was investigated by comparison NCI 60 developmental therapeutics program (DTP) human tumor cell line screening data based on results in vitro growth inhibition, including hitherto unpublished compound test with up to cancer lines. NCI-COMPARE studies helped suggest modes action highly active drugs. findings supported biological investigations showing either inhibition tubulin polymerization depolymerization or topoisomerase inhibition. Together physicochemical parameters candidates, structure–activity relationships critically discussed. Tubulin interaction topoisomerase I IIα/β activity two rationales that can explain observed in DTP screen. However, it also be reasonably assumed these compounds address several targets, thus prohibiting identification simple relationships. described herein thought act so-called multitarget drugs, being special interest area multidrug resistance.