Abstract
To develop novel CNS penetrant HDAC inhibitors, a new series of HDAC inhibitors having benzoheterocycle were designed, synthesized, and biologically evaluated. Among the synthesized compounds, benzothiazole derivative 9b exhibited a remarkable anti-proliferative activity (GI50 = 2.01 μM) against SH-SY5Y cancer cell line in a dose and time-dependent manner, better than the reference drug SAHA (GI50 = 2.90 μM). Moreover, compound 9b effectively promoted the accumulation of acetylated Histone H3 and α-tubulin through inhibition of HDAC1 and HDAC6 enzymes, respectively. HDAC enzyme assay also confirmed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM. Furthermore, compound 9b inhibited colony formation capacity of SH-SY5Y cells, which is considered a hallmark of cell carcinogenesis and metastatic potential. The theoretical prediction, in vitro PAMPA-BBB assay, and in vivo brain pharmacokinetic studies confirmed that compound 9b had much higher BBB permeability than SAHA. In silico docking study demonstrated that compound 9b fitted in the substrate binding pocket of HDAC1 and HDAC6. Taken together, compound 9b provided a novel scaffold for developing CNS penetrant HDAC inhibitors and therapeutic potential for CNS-related diseases.
Highlights
Histone deacetylase (HDACs) and histone acetyltransferases (HATs) control the dynamic status of histone acetylation, which plays an important role in the regulation of gene expression
We designed and synthesized a new series of central nervous system (CNS) penetrant HDAC inhibitors. Biological evaluation of these HDAC inhibitors indicated that benzothiazole analogue 9b exerted the most potent anti-proliferative activity (IC50 = 2.01 μM) against human neuroblastoma SH-SY5Y cell line, slightly better than the clinically approved HDAC inhibitor, SAHA (IC50 = 2.90 μM)
HDACs enzyme assay further disclosed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM, respectively
Summary
Histone deacetylase (HDACs) and histone acetyltransferases (HATs) control the dynamic status of histone acetylation, which plays an important role in the regulation of gene expression. HDACs remove the acetyl groups from hyper-acetylated histones, resulting in a closed chromatin configuration that blocks the access of the transcription machinery to DNA, and suppress gene expression[1]. HATs acetylate the lysine residues of histones, opposing the effect of HDACs and that leads to a relaxed chromatin structure, which enhances gene transcription. In addition to their roles in the transcriptional gene regulation, HDACs are involved in the acetylation of various non-histone proteins such as Hsp[90], α-tubulin, p53, Foxp[3], E2F1, and NF-κB2,3. Despite the challenges and difficulties in the drug discovery of CNS therapeutics, the potential therapeutic benefits of HDAC inhibitors in CNS diseases prompted us to develop CNS penetrant HDAC inhibitors structurally distinct from the previous reported CNS-penetrant HDAC inhibitors
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