Enzyme inhibition by hydroamination: design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor.

Autor:	Trivella DB; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA; Institute of Chemistry, University of Campinas, Campinas SP 13083-970, Brazil; Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas SP 13083-970, Brazil., Pereira AR; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA., Stein ML; Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching 85747, Germany., Kasai Y; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA., Byrum T; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA., Valeriote FA; Henry Ford Health System, Department of Internal Medicine, Josephine Ford Cancer Center, 440 Burroughs, Detroit, MI 48202, USA., Tantillo DJ; Department of Chemistry, University of California at Davis, 1 Shields Avenue, Davis, CA 95616, USA., Groll M; Center for Integrated Protein Science, Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Garching 85747, Germany. Electronic address: michael.groll@tum.de., Gerwick WH; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093-0736, USA. Electronic address: wgerwick@ucsd.edu., Moore BS; Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0212, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093-0736, USA. Electronic address: bsmoore@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Chemistry & biology [Chem Biol] 2014 Jun 19; Vol. 21 (6), pp. 782-91. Date of Electronic Publication: 2014 Jun 12.
DOI:	10.1016/j.chembiol.2014.04.010
Abstrakt:	Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy. (Copyright © 2014 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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