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

Citation
Yw. Na et al., Synthesis, DNA cross-linking activity, and cytotoxicity of dimeric mitomycins, J MED CHEM, 44(21), 2001, pp. 3453-3462
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
0022-2623 → ACNP
Volume
44
Issue
21
Year of publication
2001
Pages
3453 - 3462
Database
ISI
SICI code
0022-2623(20011011)44:21<3453:SDCAAC>2.0.ZU;2-2
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 eit her the mitomycin C(7) amino or the aziridine N(1a) positions. Significantl y, mitomycin C(1) itself is the prototypical bioreductive DNA cross-linking agent. DNA cross-linking experiments using a denaturing-gel-electrophoresi s-based assay showed that the extent of DNA cross-linking for select dimeri c mitomycins can exceed that of the parent compound, mitomycin C, and that the reaction proceeds, in part, at the two distal C(l) sites in the mitomyc ins. The efficiency of DNA cross-linking depended on the nature of the link er and the position of linker unit's attachment. When we compared the effic iency of DNA cross-linking for the dimeric mitomycins with their in vitro c ytotoxicities in cultured human tumor cells, we observed a poor correlation . The mitomycins that gave the highest levels of DNA cross-linked adducts d isplayed the weakest cytotoxicities. These findings determined that the den aturing-gel-electrophoresis-based assay was a poor predictor of cytotoxic a ctivity.