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.
Uesugi
M
M
Institute for Chemical Research, Kyoto University, Japan.
Sugiura
Y
Y
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D001483:Base Sequence; D002240:Carbohydrate Sequence; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004269:DNA, Bacterial / Q000737:chemistry*; D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D007501:Iron; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides; D010957:Plasmids; D011089:Polydeoxyribonucleotides / Q000737:chemistry; D015183:Restriction Mapping
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D004269:DNA, Bacterial; D005609:Free Radicals; D006878:Hydroxides; D009838:Oligodeoxyribonucleotides; D011089:Polydeoxyribonucleotides; C019530:poly(dC-dG); D017665:Hydroxyl Radical; D004247:DNA; D007501:Iron; C049904:elsamicin A