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-(N)-Heterocyclic Carboxaldehyde Thiosemicarbazone Inhibitors of Ribonucleoside Diphosphate Reductase¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 [B. A. B., K. C. A., A. C. S.], and Department of Biochemistry, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77025 [E. C. M.]

The antineoplastic activity and some biochemical effects of 5-ethoxycarbonyloxy-1-formylisoquinoline thiosemicarbazone, 5-phenoxycarbonyloxy-1-formylisoquinoline thiosemicarbazone, and 5-phenoxycarbonyloxy-2-formylpyridine thiosemicarbazone were compared with those of 1-formylisoquinoline thiosemicarbazone to determine whether the 5-substituted derivatives were irreversible inhibitors of ribonucleoside diphosphate reductase. All of the compounds tested caused significant prolongation of the survival time of mice bearing Sarcoma 180 ascites cells. 1-Formylisoquinoline thiosemicarbazone at 1.8 x 10^-8 M produced 50% inhibition of a partially purified ribonucleoside diphosphate reductase from the Novikoff rat tumor. To achieve the same degree of inhibition, 4 and 20 times more 5-ethoxycarbonyloxy-1-formylisoquinoline thiosemicarbazone and 5-phenoxycarbonyloxy-1-formylisoquinoline thiosemicarbazone, respectively, and 55 times more 5-phenoxycarbonyloxy-2-formylpyridine thiosemicarbazone were required in the standard assay. Ackermann-Potter plots of activity versus varying amounts of enzyme in the presence of fixed concentrations of inhibitors indicated that both 1-formylisoquinoline thiosemicarbazone and 5-substituted derivatives caused some degree of irreversible inhibition, as well as reversible inhibition. The duration of blockade of thymidine-³H incorporation into DNA of Sarcoma 180 ascites cells by single doses of -(N)-heterocyclic carboxaldehyde thiosemicarbazones was considerably longer for 5-substituted derivatives. The incorporation of cytidine-5-³H into acid-soluble ribonucleotides and RNA was generally not inhibited by these agents; however, significant interference with the incorporation of cytidine into both acid-soluble deoxyribonucleotides and DNA was produced by 1-formylisoquinoline thiosemicarbazone and 5-ethoxycarbonyloxy-1-formylisoquinoline thiosemicarbazone. 5-Phenoxycarbonyloxy-1-formylisoquinoline thiosemicarbazone and 5-phenoxycarbonyloxy-2-formylpyridine thiosemicarbazone did not inhibit the conversion of cytidine-5-³H to acid-soluble deoxyribonucleotides at the levels tested but did interfere with the subsequent progression of radioactivity into DNA. The findings with these latter agents suggested that these compounds did not inhibit ribonucleoside diphosphate reductase in situ, but created a second unknown lesion on the pathways involved in the biosynthesis of DNA.

¹ Support was provided by Grants CA-02817 and CA-04464 from the National Cancer Institute, USPHS, and Grant BC-53 from the American Cancer Society.

Received 10/23/73. Accepted 2/19/74.