On the role of E-ring oxygen atoms in the binding of camptothecin to the topoisomerase I-DNA covalent binary complex

Nicolas J. Rahier, Brian M. Eisenhauer, Rong Gao, Shannon J. Thomas, Sidney M. Hecht

Research output: Contribution to journalArticle

12 Scopus citations


A recent X-ray crystallographic analysis of the binding of a water soluble camptothecin analogue to the human topoisomerase I-DNA covalent binary complex has suggested the existence of some novel features in the way that camptothecin is bound to the binary complex. Four additional models based on chemical and biochemical data have also been proposed. Presently we describe S-containing analogues of camptothecin prepared on the basis of these models, and report their ability to form stable ternary complexes with human topoisomerase I, and to mediate cytotoxicity at the locus of topoisomerase I. The results indicate that replacement of the 20-OH group of CPT with a SH functionality results in diminution of the potency of CPT as a topoisomerase I poison, while replacement of the O atoms at positions 20 and 21 with S atoms results in essentially complete loss of topoisomerase I inhibitory activity.

Original languageEnglish (US)
Pages (from-to)1381-1386
Number of pages6
JournalBioorganic and Medicinal Chemistry
Issue number4
StatePublished - Feb 15 2005
Externally publishedYes



  • Antitumor agents
  • Camptothecin
  • DNA cleavage
  • Topoisomerase I poisons

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this