(-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study

Marine Drugs
Michael GrollD Romo

Abstract

Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (⁻)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition.

References

Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
May 20, 2004·Journal of the American Chemical Society·Leleti Rajender ReddyE J Corey
May 27, 2005·Journal of Medicinal Chemistry·Venkat R MacherlaBarbara C M Potts
Jun 9, 2005·Journal of the American Chemical Society·Atsushi Endo, Samuel J Danishefsky
Nov 3, 2005·Journal of the American Chemical Society·Philip C Hogan, E J Corey
Nov 9, 2005·Methods in Enzymology·Michael Groll, Robert Huber
Apr 15, 2008·Angewandte Chemie·Alessandra S Eustáquio, Bradley S Moore
Sep 4, 2008·Organic Letters·Takeo FukudaSatoshi Omura
Oct 22, 2008·Journal of the American Chemical Society·Michael GrollEric N Jacobsen
Oct 23, 2008·Journal of Medicinal Chemistry·Rama Rao ManamBarbara C M Potts
Nov 22, 2008·Bioorganic & Medicinal Chemistry·William FenicalBarbara C Potts
Jul 11, 2009·Proceedings of the National Academy of Sciences of the United States of America·Alessandra S EustáquioBradley S Moore
Sep 15, 2009·Journal of Medicinal Chemistry·Markus NettBradley S Moore
Mar 3, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Shirin Arastu-KapurChristopher J Kirk
May 20, 2011·Organic Letters·Nobuhiro SatohTohru Fukuyama
Aug 10, 2011·Current Topics in Medicinal Chemistry·Michael Groll, Barbara C Potts
Nov 1, 2011·Chemical Communications : Chem Comm·Melissa Ann Gräwert, Michael Groll
Feb 22, 2012·Methods in Molecular Biology·Nerea Gallastegui, Michael Groll
Jul 31, 2013·Acta Crystallographica. Section D, Biological Crystallography·Dušan Turk
Mar 12, 2016·Nature Communications·Eva M HuberMichael Groll
Feb 27, 2018·Expert Opinion on Pharmacotherapy·Emilia ScalzulliMaria Teresa Petrucci

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Methods Mentioned

BETA
X-ray
acylation
deacylation

Software Mentioned

XDS
MAIN
CNS

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