Abstract
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 language | English (US) |
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Pages (from-to) | 1381-1386 |
Number of pages | 6 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 13 |
Issue number | 4 |
DOIs | |
State | Published - Feb 15 2005 |
Externally published | Yes |
Keywords
- 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