Part I: Phosphorus analogs of arylsulfonylhydrazones, Part II: Aldophosphamide substrate-like inhibitors



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A new class of anticancer agents, arylsulfonylhydrazones of 2-formyl pyridine N-oxide, has previously been reported. Trace metal chelation by these hydrazones had been proposed as the mode of action in their antitumor activity. Four new phosphorus analogs of these hydrazones, two of which were cupric chelates, were synthesized and tested against Ehrlich carcinoma Sarcoma 180, and P388 lymphocytic leukemia. Additionally, the concurrent administration of these compounds with a solution of cupric chloride was investigated to determine the possibility of a potentiating effect of cupric chloride. A chelation study of these phosphorus analogs was also undertaken. [...] A key metabolite in the activation pathway of cyclophosphamide, a potent oncolytic agent, has been identified to be aldophosphamide [2-formyl ethyl-N,N-bis-(2-chloroethyl)phosphorodiamidate]. Through hepatic enzymatic action, aldophosphamide is rendered inactive by being oxidized to carboxyphosphamide, a non-cytotoxic metabolite. To act as potential substrates for the enzymes responsible for the degradation of aldophosphamide, several structural modifications of the basic nucleus were attempted. One potential substrate-like inhibitor was isolated as a 2,4-dinitrophenyl hydrazone. The precursor to this potential inhibitor was also isolated.