Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II.
A series of substituted 2-phenylbenzimidazole-4-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. These compounds represent the logical conclusion to our search for "minimal" DNA-intercalating agents with the lowest possible DNA-binding constants. Such "2-1" tricyclic chromophores, of lower aromaticity than the structurally similar 2-phenylquinolines, have the lowest DNA binding affinity yet seen in the broad series of tricyclic carboxamide intercalating agents. Despite very low in vitro cytotoxicities, several of the compounds had moderate levels of in vivo antileukemic effects. However, the most interesting aspect of their biological activity was the lack of cross-resistance shown to an amsacrine-resistant P388 cell line, suggesting that these compounds may not express their cytotoxicity via interaction with topoisomerase II.
Denny
W A
WA
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Rewcastle
G W
GW
Baguley
B C
BC
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004247:DNA / Q000378:metabolism; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA