Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies
Abstract
Guided by the structural optimization principle and the promising anticancer effect of the quinoxaline nucleus, a new series of novel HDAC inhibitors were designed and synthesized. The synthesized compounds were designed to bear the reported pharmacophoric features of the HDAC inhibitors in addition to an extra moiety to occupy the non-used vacant deep pocket of the HDAC receptor. The newly prepared compounds were evaluated for theirin vitroanti-proliferative activities against HepG-2 and HuH-7 liver cancer cell lines. The tested compounds showed promising anti-proliferative activities against both cell lines. The most active ten candidates (6c,6d,6f,6g,6k,6l,7b,8,10h, and12) were further evaluated for their effect on the gene expression levels of Bax as an apoptotic marker and Bcl-2 as an anti-apoptotic one. Moreover, they were evaluated for their ability to inhibit histone deacetylase (HDAC1, HDAC4, and HDAC6) activities. Compound6cachieved the best cytotoxic activities on both HepG-2 and HuH-7 cell lines with IC50values of 1.53 and 3.06 µM, respectively, and also it showed the most inhibitory activities on HDAC1, HDAC4, and HDAC6 with IC50values of 1.76, 1.39, and 3.46 µM, respectively, compared to suberoylanilide hydroxamic acid (SAHA) as a reference drug (IC50= 0.86, 0.97, and 0.93 µM, respectively). Furthermore, it achieved a more characteristic arrest in the growth of cell population of HepG-2 at both G0/G1 and S phases with 1.23-, and 1.18-fold, respectively,…
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