Ecteinascidin 743: A minor groove alkylator that bends DNA toward the major groove

Maha Zewail-Foote, Laurence H. Hurley

Research output: Contribution to journalArticle

202 Scopus citations

Abstract

The ecteinascidins (Ets), which are natural products derived from marine tunicates, exhibit potent antitumor activity. Of the numerous Ets isolated, Et 743 is presently being evaluated in phase II clinical trials. Et 743 binds in the minor groove of DNA and alkylates N2 of guanine. Although structurally similar to saframycin, which exhibits poor activity in cellular assays, Et 743 has shown good efficacy as an antitumor agent. In this study, DNA structural distortions induced by Et 743 were examined to provide insight into the molecular basis for the antitumor activity of Et 743. Electrophoretic mobility shifts of ligated oligomers containing site-directed adducts were used to examine the extent and direction of the Et 743-induced bend. Surprisingly, we find that Et 743 bends DNA toward the major groove, which is a unique feature among DNA-interactive agents that occupy the minor groove.

Original languageEnglish (US)
Pages (from-to)2493-2497
Number of pages5
JournalJournal of Medicinal Chemistry
Volume42
Issue number14
DOIs
StatePublished - Jul 15 1999
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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