Effects of the antitumor drugs 3-nitrobenzothiazolo[3,2-alpha]quinolinium and fagaronine on nucleic acid and protein synthesis.

ABSTRACT

3-Nitrobenzothiazolo[3,2-alpha]quinolinium perchlorate (NBQ) has been shown to be active against in vivo experimental tumors of P388 and Ehrlich ascites cells. Furthermore, it has been established that NBQ binds to DNA by intercalation. In this work we describe its effects on DNA, RNA and protein syntheses both in KB cells and in cell-free synthesizing systems. Fagaronine, an alkaloid structurally related to NBQ, was studied also in an attempt to establish the basis for future studies on structure-activity relationships. Both NBQ and fagaronine inhibited DNA, RNA and protein syntheses in KB cells, with essentially equal effectiveness. Exposure of KB cells to NBQ for 2 hr caused irreversible inhibition of DNA, RNA and protein syntheses. Studies in cell-free systems showed that NBQ strongly inhibited Escherichia coli DNA polymerase I, whereas RNA polymerase activities were moderately affected. Furthermore, both drugs inhibited protein synthesis in cell-free systems derived from rabbit reticulocytes and Saccharomyces cerevisiae. Our results indicate that NBQ and fagaronine exert their cytotoxic activity by at least two independent mechanisms inhibition of DNA activity by binding to this molecule, and inhibition of protein synthesis probably by interacting with the ribosomal system.