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Mar. Drugs 2018, 16(7), 240; https://doi.org/10.3390/md16070240

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

1
Center for Integrated Protein Science Munich at the Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany
2
Department of Chemistry, Texas A&M University, College Station, TX 77843, USA
3
Department of Chemistry & Biochemistry, Baylor University, Waco, TX 76798, USA
Current address: Chemical and Industrial Services, BHGE, Sugar Land, TX 77478, USA.
*
Authors to whom correspondence should be addressed.
Received: 15 June 2018 / Revised: 5 July 2018 / Accepted: 11 July 2018 / Published: 19 July 2018
(This article belongs to the Special Issue Marine Drugs Interact with Functional Proteins)
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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. View Full-Text
Keywords: beta-lactone; anticancer natural products; yeast 20S proteasome; aldol-lactonization beta-lactone; anticancer natural products; yeast 20S proteasome; aldol-lactonization
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Groll, M.; Nguyen, H.; Vellalath, S.; Romo, D. (−)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study. Mar. Drugs 2018, 16, 240.

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