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

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

doi:10.1021/acs.orglett.9b00885

Amit Mahindra, Iona Black + Show 4 more

Open Access

https://doi.org/10.1021/acs.orglett.9b00885

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Journal: Organic letters	Publication Date: Apr 18, 2019
Citations: 11	License type: cc-by

Affiliation: University of Glasgow, University of Leicester

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.

Highlights

Enzymes have been found to deacetylate other nonhistone proteins and in this context can be referred to as KDACs.[3]
There are 18 human histone deacetylases (HDACs) enzymes, which have been subdivided into four different classes, based on their sequence homology with yeast proteins.[5]
Understanding the regulation of HDAC activity in the context of corepressor complexes presents a promising strategy to understand the specific role of each complex on gene expression

Summary

Organic Letters

Based on the histone H4 sequence (H4K16Asu) which inhibits the HDAC1−MTA1 complex with IC50 366 nM (Figure 1).[12]. The chiral NiII Schiff base complex (S)-Ni-Gly-2FBPB 1 was prepared by a modified version of our previously reported route (Supporting Information Scheme S1).[23,24] Alkylation of (S)-Ni-Gly-2FBPB 1 required orthogonally protected electrophiles compatible with basic conditions for the amino acid synthesis and Fmoc/tBu SPPS (Figure 2).[25] The alkylation reaction was initially attempted using electrophiles 6-bromo-N-. Heptapeptide SPI 11 based on residues 23−29 of the unstructured tail region of histone H3 and incorporating the non-native amino acid L-Asu(NHOtBu)-OH in place of K27Ac was prepared by microwave-assisted Fmoc/tBu SPPS on Rink Amide resin (Scheme 3). Experimental procedures and characterization data for all compounds, copies of 1H,13C, COSY, HSQC, and 19F NMR spectra for building blocks, and analytical HPLC traces for peptides (PDF)

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