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Mutasynthesis of Fluorosalinosporamide, a Potent and Reversible Inhibitor of the Proteasome

Authors

  • Alessandra S. Eustáquio Dr.,

    1. Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0204, USA, Fax: (+1) 858-534-1305
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  • Bradley S. Moore Prof. Dr.

    1. Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0204, USA, Fax: (+1) 858-534-1305
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  • This work was supported by a grant from the National Institutes of Health (grant no.: CA127622 to B.S.M.). A.S.E. is a Tularik postdoctoral fellow of the Life Sciences Research Foundation. We thank M. Onega and D. O'Hagan (University of St. Andrews, UK) for kindly providing 5′-fluoro-5′-deoxyadenosine and 5-fluoro-5-deoxyribose and J. Haerle, S. Kelly, and J. Kalaitzis (University of California at San Diego, USA) for technical help with fermentation, cytotoxicity assays, and NMR analysis, respectively.

Abstract

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A knockout result: Fluorine substituents give drugs beneficial properties. By using a rational combination of genetic engineering and precursor-directed biosynthesis, fluorosalinosporamide (see scheme) was generated in a fermentation-based approach. The anticancer lead compound and marine natural product salinosporamide A is chlorinated. A comparison of the biological activity of these proteasome inhibitors is presented.

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