By J. Skoda, Peter Langen
Read Online or Download Antimetabolites in Biochemistry, Biology and Medicine. Proceedings of a Symposium on Antimetabolites in Biochemistry, Biology and Medicine, Held in Prague, Czechoslovakia, July 10–12, 1978 PDF
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Additional info for Antimetabolites in Biochemistry, Biology and Medicine. Proceedings of a Symposium on Antimetabolites in Biochemistry, Biology and Medicine, Held in Prague, Czechoslovakia, July 10–12, 1978
Aull, J. A. Lyon, J. W. Reinsch, and R. B. Dunlap, Formation of ternary complexes of thymidylate synthetase as followed by absorbance, fluorescence, and circular dichroic spectra and gel electrophoresis, J^. Biol. Chem. 251, 1303 (1976). R. K. Sharma, and R. L. Kisliuk, Quenching of thymidylate synthetase fluorescence by substrate analogs, Biochem. Biophys. Res. Commun. 64, 648 (1975). J. H. Galivan, G. F. Maley, and F. Maley, The effect of substrate analogs on the circular dichroic spectra of thymidylate synthetase from Lactobacillus casei, Biochemistry 14, 3338 (1975).
Kinetic studies are consistent with the concept that the active inhibitory form of the heteroaromatic carboxaldehyde thiosemicarbazones is an iron chelate which consists of 2 molecules of the drug per atom of iron. The site of interaction of the inhibitors with ribonucleotide reductase is distinct from that of the nucleotide substrate and the aliosteric effector, but would appear to be at or near the area occupied by the dithiol substrate. Measurement of the effects of 2-formylpyridine thiosemicarbazone, 1-formylisoquinoline thiosemicarbazone, and methyl- and benzo-substituted derivatives thereof, on ribonucleotide reductase have led to the postulation of a hypothetical zone of hydrophobic interaction between the enzyme and inhibitor.
INTRODUCTION Brockman et_ al. (1) published the initial report of the antineoplastic activity of a member of the α-(N)-heterocyclic carboxaldehyde thiosemicarbazone series, demonstrating the antileukemic activity of 2-formylpyridine thiosemicarbazone against the L1210 murine leukemia; this compound was abandoned as a potential clinically useful cancer chemotherapeutic agent, however, because of its low therapeutic index. C. Sartorelli the design and synthesis of 1-formylisoquinoline thiosemicarbazone (IQ-1) and a number of other heteroaromatic carboxaldehyde thiosemicarbazones.