Synthesis and Investigation of Therapeutic Potential of Isoform Specific HDAC8 Inhibitors for The Treatment of Cutaneous T Cell Lymphoma.

In recent times, we have reported the design and in silico studies of 52 hydroxamic acid derivatives bearing multi-substituent heteroaromatic rings with chiral amine linker as isoform selective histone deacetylase 8 inhibitors (HDAC8i). Wherein, the report suggested that the presence of chiral amine is a prerequisite to occupy the second binding site of HDAC8. Based on these preliminary results, five compounds were shortlisted and synthesized by microwave assisted approach and high yielding synthetic protocol. A series of in vitro assays were used to evaluate the synthesised compounds. Probes/inhibitors 1e, 2e, 3e, 4e and 5e exerted the anti-proliferative activities against cutaneous T cell lymphoma (CTCL) cell lines at 20-100 µM concentrations. Both the pyrimidine- and pyridine-based probes exhibited nM inhibitory activity against HDAC8. The pyrimidine-based probe 1e displayed remarkable HDAC8 selectivity superior to that of the standard drug, SAHA with an IC50 at 0.1 µM. This in silico oriented in vitro study demonstrated that simple modifications at different portions of pharmacophore in the hydroxamic acid analogues is effective for improving both HDAC8 inhibitory activity and isoform selectivity. Potent and highly isoform-selective HDAC8 inhibitors were identified. These findings would be expedient for further development of HDAC8-selective inhibitors.