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      Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs.

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          Abstract

          The potent cytotoxins pederin and psymberin have been prepared through concise synthetic routes (10 and 14 steps in the longest linear sequences, respectively) that proceed via a late-stage multicomponent approach to construct the N-acyl aminal linkages. This route allowed for the facile preparation of a number of analogs that were designed to explore the importance of the alkoxy group in the N-acyl aminal and functional groups in the two major subunits on biological activity. These analogs, including a pederin/psymberin chimera, were analyzed for their growth inhibitory effects, revealing several new potent cytotoxins and leading to postulates regarding the molecular conformational and hydrogen bonding patterns that are required for biological activity. Second generation analogs have been prepared based on the results of the initial assays and a structure-based model for the binding of these compounds to the ribosome. The growth inhibitory properties of these compounds are reported. These studies show the profound role that organic chemistry in general and specifically late-stage multicomponent reactions can play in the development of unique and potent effectors for biological responses.

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          Author and article information

          Journal
          J. Am. Chem. Soc.
          Journal of the American Chemical Society
          1520-5126
          0002-7863
          Oct 19 2011
          : 133
          : 41
          Affiliations
          [1 ] Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
          Article
          10.1021/ja207331m
          21902245
          2b72e643-c5a6-459d-9abe-512156c952d2
          History

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