Synthesis and evaluation of new 6-amino-substituted benzo[c]phenanthridine derivatives

Abstract

Different 7,8,9,10-tetrahydrobenzo[c]phenanthridin-6(5H)-ones (10a-e) were prepared by using a one-pot procedure which includes the preparation of various 6- and 7-alkoxy-1-naphthylisocyanates from 1-naphthylamines and triphosgene, followed by addition of 1-N-morpholino-1-cyclohexenes, and cyclization of the resulting amides upon heating in the presence of hydrogen chloride. Subsequent aromatization, chlorination, and substitution with (dimethylamino)alkylamines, followed by a demethylation or a selective desisopropylation, allowed us to synthesize the derivatives 6a-i and 7a-h bearing a [(dimethylamino)alkyl]amino side chain at their 6-position. These compounds, as the other analogs 5a-b, were devised to further study the structure-activity relationships in the benzo[c]phenanthridine family of antitumor alkaloids led by fagaronine (1a) and nitidine (1b). Topoisomerases I and II cleavable complex assay and evaluation of the cytotoxicity and antitumor properties were performed. In vitro cytotoxicity (L1210 and Calc 18) shows a relationship between the cytotoxicity of these compounds and their topoisomerase poisoning properties. However, all these compounds were devoid of significant antitumor effect on the P388 murine leukemia system.