Synthesis of HDAC substrate peptidomimetic inhibitors (SPIs) using Fmoc amino acids incorporating zinc-binding groups

Mahindra, A., Millard, C. J., Black, I., Archibald, L. J., Schwabe, J. W.R. and Jamieson, A. G. (2019) Synthesis of HDAC substrate peptidomimetic inhibitors (SPIs) using Fmoc amino acids incorporating zinc-binding groups. Organic Letters, 21(9), pp. 3178-3182. (doi: 10.1021/acs.orglett.9b00885) (PMID:30998366) (PMCID:PMC6503537)

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Abstract

Syntheses of Fmoc amino acids having zinc-binding groups were prepared and incorporated into substrate inhibitor H3K27 peptides using Fmoc/tBu solid-phase peptide synthesis (SPPS). Peptide 11, prepared using Fmoc-Asu(NHOtBu)-OH, is a potent inhibitor (IC50 = 390 nM) of the core NuRD corepressor complex (HDAC1–MTA1–RBBP4). The Fmoc amino acids have the potential to facilitate the rapid preparation of substrate peptidomimetic inhibitor (SPI) libraries in the search for selective HDAC inhibitors.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mahindra, Dr Amit and Archibald, Lewis and Jamieson, Dr Andrew
Authors: Mahindra, A., Millard, C. J., Black, I., Archibald, L. J., Schwabe, J. W.R., and Jamieson, A. G.
College/School:College of Science and Engineering
College of Science and Engineering > School of Chemistry
Journal Name:Organic Letters
Publisher:American Chemical Society
ISSN:1523-7060
ISSN (Online):1523-7052
Published Online:18 April 2019
Copyright Holders:Copyright © 2019 American Chemical Society
First Published:First published in Organic Letters 21(9):3178-3182
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
679091QT-EPSRC: QT DemonstratorGiles HammondEngineering and Physical Sciences Research Council (EPSRC)EP/M506539/1S&E P&A - PHYSICS & ASTRONOMY
738201EPSRC DTP 16/17 and 17/18Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/N509668/1R&I - RESEARCH STRATEGY & INNOVATION