Discovery of Pyrazolo[1, 5‐a]pyrimidine‐Based Selective HDAC6 Inhibitors with Broad‐Spectrum Antiproliferative Activity

Privileged pyrazolo[1, 5-a]pyrimidine scaffold is introduced as the cap moiety of selective histone deacetylase 6 inhibitors. Compound 8e demonstrated the most potent activity with IC₅₀ of 3.84 nM, anda 412-fold selectivity to histone deacetylase 1.8e also exhibited good antiproliferative activity against HL-60 and SK-MEL-2 cell lines.

Selective histone deacetylase 6 inhibitors show distinctive advantages for cancer treatment. In this paper, phenylhydroxamic acid group, a key pharmacophore of histone deacetylase 6 inhibitor, is introduced on common active pyrazolo[1,5-a]pyrimidine scaffold. Among all thirteen analogs, N-hydroxy-4-(((7-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)benzamide (8e) emerged as the most potent compound. Enzymatic assay showed that it potently inhibited histone deacetylase 6 with IC₅₀ of 3.84 nM, and demonstrated a 412-fold selectivity relative to the inhibition of histone deacetylase 1. In antiproliferative study, 8e also exhibited good antiproliferative activity against HL-60 and SK-MEL-2 cell lines with IC₅₀ of 0.2 and 0.35 nM, respectively. Molecular docking simulation indicated the binding site of histone deacetylase 6 could well accommodate pyrazolo[1,5-a]pyrimidine core, yielding a variety of interactions.

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