SPONTANEOUS GENERATION OF A BIRADICAL SPECIES OF NEOCARZINOSTATIN CHROMOPHORE - ROLE IN DNA BULGE-SPECIFIC CLEAVAGE

被引:46
作者
HENSENS, OD [1 ]
CHIN, DH [1 ]
STASSINOPOULOS, A [1 ]
ZINK, DL [1 ]
KAPPEN, LS [1 ]
GOLDBERG, IH [1 ]
机构
[1] HARVARD UNIV,SCH MED,DEPT BIOL CHEM & MOLEC PHARMACOL,BOSTON,MA 02115
关键词
ENEDIYNE; BERGMAN REARRANGEMENT; MECHANISM OF ACTIVATION; SPIROLACTONE; STEREOSELECTIVE MICHAEL ADDITION;
D O I
10.1073/pnas.91.10.4534
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Detailed structure determination of the major and minor base-catalyzed degradation products of the chromophore of the enediyne anticancer antibiotic neocarzinostatin in the absence of DNA demonstrates that the enolate Michael addition reaction leading to a spirolactone cumulene intermediate is a spontaneous, stereoselective process. The implications of these findings for the mechanism of the thiol-independent, site-specific cleavage by the so-generated radical species of the drug at a DNA bulge are described.
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页码:4534 / 4538
页数:5
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