Synthesis of HDAC Substrate Peptidomimetic Inhibitors Using Fmoc Amino Acids Incorporating Zinc-Binding Groups

Amit Mahindra; Christopher J Millard; Iona Black; Lewis J Archibald; John W R Schwabe; Andrew G Jamieson

doi:10.1021/acs.orglett.9b00885

Synthesis of HDAC Substrate Peptidomimetic Inhibitors Using Fmoc Amino Acids Incorporating Zinc-Binding Groups

Org Lett. 2019 May 3;21(9):3178-3182. doi: 10.1021/acs.orglett.9b00885. Epub 2019 Apr 18.

Authors

Amit Mahindra¹, Christopher J Millard², Iona Black¹, Lewis J Archibald¹, John W R Schwabe², Andrew G Jamieson¹

Affiliations

¹ School of Chemistry , University of Glasgow , Joseph Black Building, University Avenue , Glasgow G12 8QQ , U.K.
² Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology , University of Leicester , Leicester LE1 7RH , U.K.

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(NHO^tBu)-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / chemistry*
Chelating Agents / chemistry
Coordination Complexes / chemistry
Fluorenes / chemistry*
Histone Deacetylase Inhibitors / chemical synthesis*
Nickel / chemistry
Peptidomimetics / chemical synthesis*
Solid-Phase Synthesis Techniques
Stereoisomerism
Zinc / chemistry*

Substances

Amino Acids
Chelating Agents
Coordination Complexes
Fluorenes
Histone Deacetylase Inhibitors
N(alpha)-fluorenylmethyloxycarbonylamino acids
Peptidomimetics
Nickel
Zinc

Grants and funding

Wellcome Trust/United Kingdom