Substituted dibenzo[c,h]cinnolines: topoisomerase I-targeting anticancer agents

Abstract

Several substituted dibenzo[c,h]cinnolines were synthesized and evaluated for their potential to target topoisomerase I and for their relative cytotoxic activity. Select benzo[i]phenanthridines are capable of stabilizing the cleavable complex formed with topoisomerase I and DNA. This study was initiated to examine whether dibenzo[c,h]cinnolines, which are in essence aza analogues of benzo[i]phenanthridines, possess similar pharmacological properties. 2,3-Dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine is one of the more potent benzo[i]phenanthridine derivatives in regard to topoisomerase I-targeting activity and cytotoxicity. The structure–activity relationship observed with these substituted dibenzo[c,h]cinnolines parallels that observed for benzo[i]phenanthridine derivatives. Compared to similarly substituted benzo[i]phenanthridines, the dibenzo[c,h]cinnoline analogues exhibit more potent topoisomerase I-targeting activity and cytotoxicity. The relative IC50 values obtained in assessing the cytotoxicity of 2,3-dimethoxy-8,9-methylenedioxydibenzo[c,h]cinnoline and 2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine in the human lymphoblastma cell line, RPMI8402, are 70 and 400 nM, respectively. In tumor cell lines selected for resistance to camptothecin and known to express mutant topoisomerase I, benzo[i]phenanthridine derivatives were not cross-resistant. In contrast, similarly substituted dibenzo[c,h]cinnolines with significant topoisomerase I-targeting activity did exhibit cross-resistance in these camptothecin-resistant cell lines. The cytotoxicity of these dibenzo[c,h]cinnolines was not diminished in cells overexpressing the efflux transporter, MDR1. These data indicate that substituted dibenzo[c,h]cinnolines can exhibit potent topoisomerase I-targeting activity and are capable of overcoming the multi-drug resistance associated with this efflux transporter.