Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Amine-based Histone Deacetylase Inhibitors

Hazem Abdelkarim, Raghupathi Neelarapu, Antonett Madriaga, Aditya S. Vaidya, Irida Kastrati, Bhargava Karumudi, Yue Ting Wang, Taha Y. Taha, Gregory R.J. Thatcher, Jonna Frasor, Pavel A. Petukhov

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biological evaluation in cellular models of cancer, and preliminary drug metabolism and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-aminoheptanohydroxamic acid-based HDAC inhibitors. Introduction of an amino group with one or two surface binding groups (SBGs) yielded a successful strategy to develop novel and potent HDAC inhibitors. The secondary amines were found to be generally more potent than the corresponding tertiary amines. Docking studies suggested that the SBGs of tertiary amines cannot be favorably accommodated at the gorge region of the binding site. The secondary amines with naphthalen-2-ylmethyl, 5-phenylthiophen-2-ylmethyl, and 1H-indol-2-ylmethyl (2 j) substituents exhibited the highest potency against class I HDACs: HDAC1 IC50 39–61 nm, HDAC2 IC50 260–690 nm, HDAC3 IC50 25–68 nm, and HDAC8 IC50 320–620 nm. The cytotoxicity of a representative set of secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors against HT-29, SH-SY5Y, and MCF-7 cancer cells correlated with their inhibition of HDAC1, 2, and 3 and was found to be similar to or better than that of suberoylanilide hydroxamic acid (SAHA). Compounds in this series increased the acetylation of histones H3 and H4 in a time-dependent manner. DMPK studies indicated that secondary amine 2 j is metabolically stable and has plasma and brain concentrations >23- and >1.6-fold higher than the IC50 value for class I HDACs, respectively. Overall, the secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors exhibit excellent lead- and drug-like properties and therapeutic capacity for cancer applications.

Original languageEnglish (US)
Pages (from-to)2030-2043
Number of pages14
JournalChemMedChem
Volume12
Issue number24
DOIs
StatePublished - Dec 19 2017
Externally publishedYes

Keywords

  • amines
  • antitumor agents
  • epigenetics
  • histone deacetylases
  • inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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