Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove.
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.
Zewail-Foote
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Department of Chemistry and Biochemistry and College of Pharmacy, Drug Dynamics Institute, The University of Texas at Austin, Austin, Texas 78712, USA.
Hurley
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D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D001345:Autoradiography; D004247:DNA / Q000737:chemistry*; D004149:Dioxoles / Q000737:chemistry*; D007546:Isoquinolines / Q000737:chemistry*; D009287:Naphthyridines / Q000737:chemistry; D009841:Oligonucleotides / Q000737:chemistry; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D007546:Isoquinolines; D009287:Naphthyridines; D009841:Oligonucleotides; D044005:Tetrahydroisoquinolines; C010752:naphthyridinomycin; D004247:DNA; D000077606:Trabectedin; C026925:saframycin A