Authors: Don L. Warner, Jamie
Montgomery, Katherine M. McHail, Emma L. McInturff, and Alina M. Schimpf
Affiliation:
Title: Evaluation of DNA Cross-Linking by Aziridinomitosenes
Abstract: We have synthesized several aziridinomitosenes, compounds structurally related to the mitomycin family of antitumoral antibiotics, using a silver cation/oxazolium salt/azomethine ylide/cycloaddition sequence. Our studies show that these analogs alkylate DNA under non-reductive conditions, and that interstrand DNA cross-linking and DNA/protein cross-linking may be occurring. It is hypothesized that at least one of the C6 and C7 sites on the quinone ring is partially responsible for the formation of DNA interstrand cross-links and DNA protein cross-links. Molecular modeling studies demonstrate that both sites are accessible when bound to DNA. Additional cell-killing experiments demonstrate that while C6-methyl and C7-methyl analogs display remarkable cytotoxicity against human leukemia (HL-60) cancer cells, the C6/C7 unsubstituted analog is less potent, underscoring the significance of these sites. We report herein our biological and synthetic efforts that seek to understand the unique reactivity of the C6/C7 unsubstituted aziridinomitosenes. Support by NIH/1R15CA113464-01.