Tearing Down to Rebuild

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Science  02 May 2003:
Vol. 300, Issue 5620, pp. 705
DOI: 10.1126/science.300.5620.705b

Biologically active natural products combine the specificity that is characteristic of biological molecules with the reactivity of short-lived, in situ-generated intermediates. In the case of neocarzinostatin, the enediyne core is encapsulated within a stabilizing protein; on exposure to thiol, it becomes a potent DNA-cleaving agent with antitumor potential. Chatterji et al. describe the deconstruction of leinamycin, which can be activated by glutathione under intracellular conditions. The core component is a 1,2-dithiolan-3-one 1-oxide heterocycle with a distant, unconjugated C=C bond. Ring opening by thiol leads to the formation of an episulfonium ion (the sulfur analog of an epoxide) and facile alkylation of guanosine. By stripping away the bells and whistles (and thus losing specificity toward DNA), these authors demonstrate that the heterocycle core is indeed the chemically sufficient moiety.—GJC

J. Am. Chem. Soc. 10.1021/ja029169y (2003).

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