Investigations on the mechanism of action of the novel antitumor agents 2-benzothiazolyl, 2-benzoxazolyl, and 2-benzimidazolyl hydrazones derived from 2-acetylpyridine

2-Acetylpyridine hydrazone derivatives of benzothiazole, benzoxazole. and b enzimidazole were found to exhibit potent cytotoxic activity against the gr owth of suspended leukemia and lymphomas. They were also active in a number of solid tumor screens, e.g. HeLa uterine carcinoma, SOS bone osteosarcoma , lung MB9812, lung A549, Mcf-7 breast growth. In L1210 lymphoid leukemia c ells the compounds preferentially inhibited RNA synthesis followed by DNA s ynthesis at 100 mu M after 60 min. The reduction of de novo purine synthesi s by the compounds at the regulatory sites PRPP-amido transferase, IMP dehy drogenase and dihydrofolate reductase was responsible for the suppression o f nucleic synthesis. Other minor sites where the agents have metabolic effe cts were thymidylate synthetase and thymidine kinase which would be additiv e with the overall inhibition of cell growth. The ct-DNA studies suggest th at the compounds also interacted with the DNA molecule itself, probably aff ecting template activity,