SYNTHESIS AND ANTITUMOR ACTIVITIES OF TETRACYCLIC QUINOLONE ANTINEOPLASTIC AGENTS

DNA topoisomerases, found in aii prokaryotic and eukaryotic cells, pla y a key role in controlling the topological state of DNA. They are inv olved in DNA replication, RNA transcription and recombination affectin g cell proliferation. Quinolone antibacterial agents have been shown t o be inhibitors of DNA gyrase, a bacterial topoisomerase II enzyme. Th e eukaryotic topoisomerase II is the target of Various cytotoxic agent s such as adriamycin and etoposide. Due to the mechanistic similaritie s and sequence homologies shared by both bacterial and mammalian DNA t opoisomerase II, we initiated a screening programme to search for quin olones as antitumour agents and reported the identification of a new c lass of quinolone, quinobenoxazines, having excellent in vitro cytotox ic activity comparable to adriamycin. In the continuation of this rese arch work, we synthesized a series of amino-substituted quinobenoxazin es and found that some of them possess more potent in vitro cytotoxici ty than the parent unsubstituted quinobenoxazines. The chemical synthe sis as well as biological properties of these tetracyclic quinolones a re described.