Mechanism for the Catalytic Activation of Ecteinascidin 743 and Its Subsequent Alkylation of Guanine N2

• Published in: Journal of the American Chemical Society Vol. 120; no. 10; pp. 2490 - 2491
• Main Authors: Moore, Bob M, Seaman, Frederick C, Wheelhouse, Richard T, Hurley, Laurence H
• Format: Journal Article
• Language: English
• Published: American Chemical Society 18.03.1998
• Subjects: anthramycin; carbinolamine; Ecteinascidin 743; naphthyridinomycin; saframycin S
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja974109r

Ecteinascidin 743 (1), the first of a novel class of therapeutically significant marine alkaloids, has shown good activity against a variety of solid tumor types in phase 1 clinical trials. For the design of novel synthetic ecteinascidins, it is important to identify the chemical and structural elements essential for activity. We have recently reported an NMR-based model of a 1 guanine N2 (GN2)-DNA adduct, and herein we report the results of studies to determine the protonation state of the 1-DNA adduct. Together, these data provide evidence for a specific mechanism for the catalytic activation of 1 in the minor groove of DNA and subsequent alkylation of GN2. The alkylation of GN2 in duplex DNA is well established for a variety of carbinolamine-containing antibiotics, such as 1, anthramycin (2), saframycin S (3), and naphthyridinomycin (4). The chemical reactivity of these agents has been proposed to reside in the iminium intermediate generated by the general acid-mediated dehydration of the carbinolamine moiety. While the mechanism for the formation of the iminium intermediate in bulk solution is a general chemical reaction, both the source of general acid in the minor groove of DNA and the protonation state of the adduct remain unidentified. Examination of the carbinolamine antibiotic structures 1-4 shows that basic nitrogens, which should bear a proton at physiological pH, are in close proximity to the hydroxyl group and therefore could serve as a proton source when buried in the minor groove of DNA. Our approach to defining the mechanism of activation for 1 was to determine the protonation state of the drug and DNA in the covalent adduct and then utilize mass and charge balance to propose a mechanism leading to alkylation.