ABSTRACT
A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.
Subject(s)
Antineoplastic Agents/chemical synthesis , Aziridines/chemical synthesis , Neoplasms, Experimental/drug therapy , Quinazolines/chemical synthesis , Animals , Aziridines/chemistry , Aziridines/pharmacology , Aziridines/therapeutic use , Breast Neoplasms , Cell Division/drug effects , Cell Line , Drug Screening Assays, Antitumor , Female , Humans , Leukemia L1210 , Leukemia, Experimental/drug therapy , Melanoma, Experimental/drug therapy , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Molecular Structure , Quinazolines/chemistry , Quinazolines/pharmacology , Quinazolines/therapeutic use , Sarcoma, Experimental/drug therapy , Structure-Activity RelationshipABSTRACT
The synthesis of 2,3-bis(2-pyridyl)-5,8-quinoxalinediones has been carried out in order to provide new antitumor drugs related to streptonigrin. Some derivatives have been found to possess significant cytotoxic properties and their mechanism of action has been studied. They were found to induce single-strand cleavage of covalently closed circular DNA (ccc-DNA). This biological activity requires an apparent in situ reduction (NADH activation) of the quinone to a hydroquinone or semiquinone radical, is facilitated by the presence of Cu(II), and involves activation of molecular oxygen to highly reactive radical species. Thus, although less active than the parent drugs, these molecules provide an attractive rationale for the observed cytotoxic and antitumor potency, as well as the cell-free single strand DNA cleavage efficacy of that family of drugs.