Some characteristics of DNA strand scission by macromolecular antitumor antibiotic C-1027 containing a novel enediyne chromophore.
A new macromolecular antitumor antibiotic, C-1027, shows potent cytotoxic effects and DNA cutting activity. The DNA cleaving properties of C-1027 are compared with those of other enediyne compounds such as neocarzinostatin, esperamicin A1, and calicheamicin gamma 1. Even in the absence of thiols or reductants, the antibiotic C-1027 has high DNA breakage ability. Of special interest is the fact that C-1027 causes strand breaks two base pairs apart at specific sites such as 5'-TAT/3'-ATA and 5'-AGA/3'-TCT (cleavage sites in italics) in the two strands. This novel double-stranded cleavage fashion is different from that of calicheamicin gamma 1, which is found to have a 3-bp separation between cleavage sites on the two strands. The asymmetric cleavage pattern to the 3'-side and a competitive experiment with distamycin A reveal minor-groove interaction of double-helical DNA with C-1027. This antibiotic appears to oxidize DNA through hydrogen abstraction predominantly at the C-4' carbon of deoxyribose. The activation mechanism of C-1027, which contains an enediyne chromophore of the esperamicin/calicheamicin type, has been proposed.
Institute for Chemical Research, Kyoto University, Japan.
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Sugiura
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Matsumoto
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D004278:DNA, Superhelical / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D053281:Enediynes; D006834:Hydrazines / Q000494:pharmacology; D008969:Molecular Sequence Data; D011506:Proteins / Q000494:pharmacology; D009353:Zinostatin / Q000494:pharmacology
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D004278:DNA, Superhelical; D053281:Enediynes; D006834:Hydrazines; D011506:Proteins; C055955:calicheamicin gamma(1)I; C058024:C 1027; C029424:hydrazine; D004247:DNA; D009353:Zinostatin; C047543:esperamicin A1