Effect of E-ring modifications in camptothecin on topoisomerase I inhibition: A quantum mechanics treatment

Xiangshu Xiao, Mark Cushman

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Camptothecins (CPTs) are the prototypical class of topoisomerase I (Top1) inhibitors with significant anticancer activities. Structure-activity relationship studies have demonstrated that inverting the stereochemistry at C-20 (R-CPT) or changing the E-ring lactone to a lactam (CPT-lactam) abolishes the Topi inhibitory activity. The explanations that have been advanced for these effects are that there is either a failure of hydrogen bond formation involving the C-20 hydroxyl group of R-CPT or a failure of E-ring opening of the lactam, which have been proposed to be required for Top1 inhibition. We demonstrate here that the preferred conformation for the CPTs has the 20-Et pseudoaxial, while the 20-OH is pseudoequatorial, and therefore, the 20-OH groups in all the three CPT analogues (S-CPT, R-CPT, and CPT-lactam) are able to hydrogen bond with Asp533. The loss of the Top1 inhibitory activity by the latter two CPT analogues is attributed to the decreased π-π stacking interaction energy with the neighboring base pairs compared to the natural S-CPT. The differences in π-π stacking interaction energies are derived from the differential electrostatics on the E-ring.

Original languageEnglish (US)
Pages (from-to)9584-9587
Number of pages4
JournalJournal of Organic Chemistry
Volume70
Issue number23
DOIs
StatePublished - Nov 11 2005

    Fingerprint

ASJC Scopus subject areas

  • Organic Chemistry

Cite this