Hydroxamates of para-aminobenzoic acid as selective inhibitors of HDAC8

Umasankar Kulandaivelu; Laxmi Manasa Chilakamari; Surender Singh Jadav; Tadikonda Rama Rao; K N Jayaveera; Boyapati Shireesha; Alexander-Thomas Hauser; Johanna Senger; Martin Marek; Christophe Romier; Manfred Jung; Venkatesan Jayaprakash

doi:10.1016/j.bioorg.2014.08.005

Hydroxamates of para-aminobenzoic acid as selective inhibitors of HDAC8

Bioorg Chem. 2014 Dec:57:116-120. doi: 10.1016/j.bioorg.2014.08.005. Epub 2014 Sep 3.

Affiliations

¹ Medicinal Chemistry Research Division, Vaagdevi College of Pharmacy, Hanamkonda, Warangal 506 001, Andhra Pradesh, India.
² Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835 215, Jharkhand, India.
³ Blue Birds College Of Pharmacy, Hanamkonda, Warangal 506 015, Andhra Pradesh, India.
⁴ Department of Chemistry, Jawaharlal Nehru Technological University Anantapur, College of Engineering, Anantapur 515 002, Andhra Pradesh, India.
⁵ Institute of Pharmaceutical Sciences, Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany.
⁶ Integrated Structural Biology Department, IGBMC, 1 rue Laurent Fries, 67404 Illkirch, France.
⁷ Institute of Pharmaceutical Sciences, Universität Freiburg, Albertstr. 25, 79104 Freiburg, Germany. Electronic address: [email protected].
⁸ Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835 215, Jharkhand, India; Valens Pharma Services, Regus Citi Centre, Level 6, Chennai Citi Centre, 10/11, Dr. Radhakrishnan Salai, Chennai 600 004, Tamil Nadu, India. Electronic address: [email protected].

PMID: 25462986
DOI: 10.1016/j.bioorg.2014.08.005

Abstract

A series of hydroxamates (4a-4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f &4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20μM.

Keywords: HDAC8; Hydroxamates; Inhibitors; Molecular docking; p-Aminobenzoic acid derivatives.

Publication types

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

MeSH terms

4-Aminobenzoic Acid / chemistry*
4-Aminobenzoic Acid / pharmacology*
Crystallography, X-Ray
Drug Design
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / chemistry
Histone Deacetylases / metabolism
Humans
Hydroxamic Acids / chemistry*
Hydroxamic Acids / pharmacology*
Molecular Docking Simulation
Protein Binding
Repressor Proteins / antagonists & inhibitors*
Repressor Proteins / chemistry
Repressor Proteins / metabolism
Structure-Activity Relationship

Substances

Histone Deacetylase Inhibitors
Hydroxamic Acids
Repressor Proteins
HDAC8 protein, human
Histone Deacetylases
4-Aminobenzoic Acid