Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety

Abstract

Introduction

Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates.

Methods

This work describes design and synthesis of a new set of HDAC inhibitors ( 7a-c and 8a, b) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition.

Results

The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC ₅₀ range: 53.7–205.4 nM) than HDAC1 (IC ₅₀ range: 114.3–2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors ( 7a-c and 8a,b) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O).

Discussion

Compound 7a was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC ₅₀ values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC ₅₀ = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC ₅₀ = 7.63 µM) against SH-SY5Y cells. Whereas, compound 8a (IC ₅₀ = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC ₅₀ = 4.99 µM). Collectively, these results suggest that 7a merits further optimization and development as an effective new HDACI lead compound.