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

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cell line screening data based on the results of in vitro tumor cell growth inhibition, including about 40 hitherto unpublished compound test results with up to 60 cancer cell lines.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

Synthesis and biological evaluation of 11-substituted 6-aminobenzo[c]phenanthridine derivatives, a new class of antitumor agents.

The synthesis of 11-substituted 6-amino-11,12-dihydrobenzo[c]phenanthridines and 11-substituted 6-aminobenzo[c]phenanthridines through an efficient method is described. The antiproliferative activity of selected compounds against a wide panel of tumor cell lines was tested in the in vitro anticancer screening and the in vivo hollow fiber assay of the National Cancer Institute. Several compounds turned out to exhibit considerable cytotoxicity for tumor cells. For the study of structure-activity relationships different substituents were introduced in the 11-position. Compounds with methoxyphenyl substituents tended to show the highest potency. Several compounds exhibited noteworthy antitumor activity with GI(50) values across all cell lines <1 microM. 6-Amino-11-(3,4,5-trimethoxyphenyl)benzo[c]phenanthridine perchlorate was the most potent agent in the NCI's in vivo hollow fiber assay. Most of the tested compounds showed a remarkable selectivity for leukemia, breast cancer, and prostate cancer.