Cyclopropamitosenes, Novel Bioreductive Anticancer Agents. Synthesis, Electrochemistry, and Biological Activity of 7-Substituted Cyclopropamitosenes and Related Indolequinones

The synthesis of the indolequinones 8 and 9 starting from methyl 4-(benzyloxy)-5-methoxy-indole-2-carboxylate (10) is described. The methoxy group in the indolequinones 1, 2, 4, 5, and 7-9 can be displaced by various nitrogen nucleophiles (ammonia, 2-methoxyethylamine, aziridine, 2-methylaziridine,...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-10, Vol.37 (22), p.3834-3843
Main Authors: Cotterill, Ann S, Moody, Christopher J, Mortimer, Roger J, Norton, Claire L, O'Sullivan, Noeleen, Stephens, Miriam A, Stradiotto, Nelson R, Swann, Elizabeth, Stratford, Ian J
Format: Article
Language:English
Subjects:
Animals
Cell Division - drug effects
Cells, Cultured
Cricetinae
Cricetulus
Electrochemistry
Indoles - chemistry
Mitomycins - chemical synthesis
Mitomycins - pharmacology
Oxidation-Reduction
Quinones - chemical synthesis
Quinones - pharmacology
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Summary:The synthesis of the indolequinones 8 and 9 starting from methyl 4-(benzyloxy)-5-methoxy-indole-2-carboxylate (10) is described. The methoxy group in the indolequinones 1, 2, 4, 5, and 7-9 can be displaced by various nitrogen nucleophiles (ammonia, 2-methoxyethylamine, aziridine, 2-methylaziridine, pyrrolidine) in 22-88% yield. The resulting amino-substituted quinones, together with their methoxy precursors, were studied by cyclic voltammetry to determine their reduction potentials, which, in DMF solution, lie in the range -1.355 to -1.597 V (vs ferrocene). The cytotoxicity of the compounds towards aerobic and hypoxic mammalian cells was also determined; in general, under aerobic conditions, the cyclopropamitosenes are more toxic than the corresponding pyrrolo[1,2-a]indolequinones, which are in turn more toxic than the simple 1,2-dimethylindolequinones, with many of the compounds in each series showing greater toxicity toward hypoxic cells.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00048a019