PRODUCT ANALYSES IN DNA STRAND SCISSION BY ANTITUMOR ANTIBIOTIC ELSAMICIN-A

Elsamicin A is an antitumor antibiotic with fascinating chemical structure and a good candidate for pharmaceutical development. Molecular mechanism of DNA backbone cleavage mediated by Fe(II)-elsamicin A has been examined. Product analysis using DNA sequencing gels and HPLC reveals the production of damaged DNA fragments bearing 3′-/5′-phosphate and 3′-phosphoglycolate termini associated with formation of free base. In addition, hydrazine-trapping experiments indicate that C-4′ hydroxylated abasic sites are formed concomitant with DNA degradation by Fe(II)-elsamicin A. The results lead to the conclusion that the hydroxyl radical formed in Fe(II)-elsamicin A plus dithiothreitol system oxidizes the deoxyribose moiety via hydrogen abstraction predominantly at the C-4′ carbon of the deoxyribose backbone and ultimately produces strand breakage of DNA. © 1992 Academic Press, Inc.