Role of the 20-hydroxyl group in camptothecin binding by the topoisomerase I-DNA binary complex

Xiangyang Wang, Xiang Zhou, Sidney M. Hecht

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Recent findings concerning the structure of the covalent binary complex formed by DNA topisomerase I and its DNA substrate, as well as the nature of interactions with inhibitors that bind reversibly to this binary complex, have led to two proposed models for the binding of the prototype inhibitor camptothecin to the DNA - topisomerase I binary complex. While these models differ in many regards, they both suggest the involvement of the 20-OH group of camptothecin in a donor hydrogen bond with an enzyme side chain functional group. Presently, five analogues of camptothecin that differ only at C-20 have been evaluated for their ability to bind to the topoisomerase I-DNA binary complex and thereby inhibit enzyme function. Both 20-chloro- and 20- bromocamptothecin bound as well to the enzyme-. DNA binary complex as 20- aminoCPT despite the absence of a substituent at C-20 capable of contributing a donor hydrogen bond.

Original languageEnglish (US)
Pages (from-to)4374-4381
Number of pages8
JournalBiochemistry
Volume38
Issue number14
DOIs
StatePublished - Apr 6 1999

ASJC Scopus subject areas

  • Biochemistry

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