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Synthesis, DNA cross-linking activity, and cytotoxicity of dimeric mitomycins.

Abstract
Dimeric DNA cross-linking compounds have emerged as important new antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric mitomycins in which the two mitomycin units are tethered at either the mitomycin C(7) amino or the aziridine N(1a) positions. Significantly, mitomycin C (1) itself is the prototypical bioreductive DNA cross-linking agent. DNA cross-linking experiments using a denaturing-gel-electrophoresis-based assay showed that the extent of DNA cross-linking for select dimeric mitomycins can exceed that of the parent compound, mitomycin C, and that the reaction proceeds, in part, at the two distal C(1) sites in the mitomycins. The efficiency of DNA cross-linking depended on the nature of the linker and the position of linker unit's attachment. When we compared the efficiency of DNA cross-linking for the dimeric mitomycins with their in vitro cytotoxicities in cultured human tumor cells, we observed a poor correlation. The mitomycins that gave the highest levels of DNA cross-linked adducts displayed the weakest cytotoxicities. These findings determined that the denaturing-gel-electrophoresis-based assay was a poor predictor of cytotoxic activity.
AuthorsY Na, V S Li, Y Nakanishi, K F Bastow, H Kohn
JournalJournal of medicinal chemistry (J Med Chem) Vol. 44 Issue 21 Pg. 3453-62 (Oct 11 2001) ISSN: 0022-2623 [Print] United States
PMID11585450 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antibiotics, Antineoplastic
  • Cross-Linking Reagents
  • Mitomycin
  • DNA
Topics
  • Antibiotics, Antineoplastic (chemical synthesis, chemistry, pharmacology)
  • Cross-Linking Reagents (chemical synthesis, chemistry, pharmacology)
  • DNA (chemistry)
  • Dimerization
  • Drug Screening Assays, Antitumor
  • Electrophoresis, Agar Gel
  • Humans
  • Mitomycin (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

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