| Acid mediated formation of an N-acyliminium ion from tubulysins: A new methodology for the synthesis of natural tubulysins and their analogs. | |
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MedLine Citation:
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PMID: 21974954 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Tubuylsins are extremely potent cytotoxic agents which inhibit tubulin polymerization and lead to cell cycle arrest and apoptosis. Tubulysins have been isolated from fermentation mixtures and have been chemically synthesized; however, these efforts have been hampered by poor yields and arduous purifications. In contrast, treatment of a mixture of natural tubulysins A, B, C, G, and I, obtained from a fermentation batch with trifluoroacetic acid results in the formation of a single N-acyliminium ion. Subsequent addition of butyric, isopentyl, or acetic acid results in the formation of tubulysin B, A, or I, respectively, as a single species. New tubulysin analogs can be formed upon treatment of the acyliminium ion with other nucleophiles such as alcohols, thiols, and nitriles, resulting in corresponding N-acyl-N,O-acetals, N-acyl-N,S-thioacetals, and N,N'-diacyl-aminals. Carbon-carbon bond formation is also possible with a modification of this protocol. The cytotoxicies of the natural tubulysins and tubulysin analogs synthesized by this method were evaluated on KB cells. |
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Authors:
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Iontcho R Vlahov; Yu Wang; Marilynn Vetzel; Spencer Hahn; Paul J Kleindl; Joseph A Reddy; Christopher P Leamon |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-17 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: - ISSN: 1464-3405 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-10-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Ltd. All rights reserved. |
Affiliation:
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Endocyte, Inc., 3000 Kent Ave., W. Lafayette, IN 47906, United States. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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