Bicyclic tetrapeptides as potent HDAC inhibitors: effect of aliphatic loop position and hydrophobicity on inhibitory activity

Md Nurul Islam; Md Shahidul Islam; Md Ashraful Hoque; Tamaki Kato; Norikazu Nishino; Akihiro Ito; Minoru Yoshida

doi:10.1016/j.bmc.2014.06.031

Bicyclic tetrapeptides as potent HDAC inhibitors: effect of aliphatic loop position and hydrophobicity on inhibitory activity

Bioorg Med Chem. 2014 Aug 1;22(15):3862-70. doi: 10.1016/j.bmc.2014.06.031. Epub 2014 Jun 26.

Authors

Md Nurul Islam¹, Md Shahidul Islam², Md Ashraful Hoque³, Tamaki Kato⁴, Norikazu Nishino⁴, Akihiro Ito⁵, Minoru Yoshida⁵

Affiliations

¹ Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan; Department of Chemistry, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh. Electronic address: mnurulchem@gmail.com.
² Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan; Department of Chemistry, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh.
³ Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan; Department of Biochemistry and Molecular Biology, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh.
⁴ Graduate School of Life Science and Systems Engineering, Kyushu Institute of Technology, Kitakyushu 808-0196, Japan.
⁵ Chemical Genetics Laboratory/Chemical Genomics Research Group, RIKEN Advanced Science Institute, Saitama 351-0198, Japan.

PMID: 25022972
DOI: 10.1016/j.bmc.2014.06.031

Abstract

Several histone deacetylase (HDAC) inhibiting bicyclic tetrapeptides have been designed and synthesized through intramolecular ring-closing metathesis (RCM) reaction and peptide cyclization. We designed bicyclic tetrapeptides based on CHAP31, trapoxin B and HC-toxin I. The HDAC inhibitory and p21 promoter assay results showed that the aliphatic loop position as well as the hydrophobicity plays an important role toward the activity of the bicyclic tetrapeptide HDAC inhibitors.

Keywords: Aliphatic loop position; Bicyclic tetrapeptides; Histone deacetylase inhibitors; Ring-closing metathesis.

Publication types

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

MeSH terms

Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylases / chemistry
Histone Deacetylases / metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Intercellular Signaling Peptides and Proteins
Oligopeptides / chemical synthesis
Oligopeptides / chemistry*
Peptides / chemistry
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / chemistry*
Peptides, Cyclic / metabolism
Protein Binding

Substances

Histone Deacetylase Inhibitors
Intercellular Signaling Peptides and Proteins
Oligopeptides
Peptides
Peptides, Cyclic
cyclic hydroxamic acid-containing peptide 31
trapoxin B
HC toxin
Histone Deacetylases