| 10'-Fluorovinblastine and 10'-Fluorovincristine: Synthesis of a Key Series of Modified Vinca Alkaloids. | |
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MedLine Citation:
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PMID: 22247789 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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A study on the impact of catharanthine C10 and C12 indole substituents on the biomimetic Fe(III)-mediated coupling with vindoline led to the discovery and characterization of two new and substantially more potent derivatives, 10'-fluorovinblastine and 10'-fluorovincristine. In addition to defining a pronounced and unanticipated substituent effect on the biomimetic coupling, fluorine substitution at C10', which minimally alters the natural products, was found to uniquely enhance the activity 8-fold against both sensitive (IC(50) = 800 pM, HCT116) and vinblastine-resistant tumor cell lines (IC(50) = 80 nM, HCT166/VM46). As depicted in the X-ray structure of vinblastine bound to tubulin, this site resides at one end of the upper portion of the T-shaped conformation of the tubulin-bound molecule, suggesting the 10'-fluorine substituent makes critical contacts with the protein at a hydrophobic site uniquely sensitive to steric interactions. |
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Authors:
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Hiroaki Gotoh; Katharine K Duncan; William M Robertson; Dale L Boger |
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Publication Detail:
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Type: JOURNAL ARTICLE |
Journal Detail:
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Title: ACS medicinal chemistry letters Volume: 2 ISSN: 1948-5875 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2012-1-16 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101521073 Medline TA: ACS Med Chem Lett Country: - |
Other Details:
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Languages: ENG Pagination: 948-952 Citation Subset: - |
Affiliation:
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Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037. |
Export Citation:
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Descriptor/Qualifier:
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| Grant Support | |
ID/Acronym/Agency:
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R01 CA042056-29//NCI NIH HHS; R01 CA115526-06//NCI NIH HHS |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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