Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

We report the design, synthesis, and biological evaluation of the first macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors. The compounds selectively inhibit human class I HDAC isoforms in vitro, with no inhibition of the tubulin deacetylase activity associated with class IIb HDAC6 in cultured Jurkat cells. Compared to the natural product apicidin (<b>1</b>), one inhibitor (compound <b>10</b>) showed equivalent potency against K-562 cells, but was more cytoselective across a panel of cancer cell lines

Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

We report the design, synthesis, and biological evaluation of the first macrocyclic peptoid-containing histone deacetylase (HDAC) inhibitors. The compounds selectively inhibit human class I HDAC isoforms in vitro, with no inhibition of the tubulin deacetylase activity associated with class IIb HDAC6 in cultured Jurkat cells. Compared to the natural product apicidin (<b>1</b>), one inhibitor (compound <b>10</b>) showed equivalent potency against K-562 cells, but was more cytoselective across a panel of cancer cell lines

Synthesis and Structure–Activity Relationship Study of a New Series of Selective σ₁ Receptor Ligands for the Treatment of Pain: 4‑Aminotriazoles

The synthesis and pharmacological activity of a new series of 4-aminotriazoles as potent σ₁ receptor (σ₁R) ligands are reported. The compounds were prepared using a 4–5-step process, involving as a key step a click chemistry reaction between ynamides and azides. The most active compounds exhibited nanomolar potency for the σ₁R, and the selectivity over the σ₂R was improved on decreasing the central amine basicity. It was concluded that in order to achieve good σ₁R potency a minimum lipophilicity was required, while limiting to a defined range of cLog<i>P</i> avoided human ether-a-go-go-related gene channel inhibition. This made the most interesting derivatives to be concentrated in a narrow margin of lipophilicity. Among them, compound <b>13g</b> exhibited the most potent in vivo antinociceptive properties, which are indicative of its antagonist character