Design, Synthesis, and Biological Evaluation of HDAC Inhibitors Containing Natural Product-Inspired N-Linked 2-Acetylpyrrole Cap

Drawing inspiration from the structural resemblance between a natural product <i>N</i>-(3-carboxypropyl)-2-acetylpyrrole and phenylbutyric acid, a pioneer HDAC inhibitor evaluated in clinical trials, we embarked on the design and synthesis of a novel array of HDAC inhibitors containing an <i>N</i>-linked 2-acetylpyrrole cap by utilizing the pharmacophore fusion strategy. Among them, compound <b>20</b> exhibited potential inhibitory activity on HDAC1, and demonstrated notable potency against RPMI-8226 cells with an IC₅₀ value of 2.89 ± 0.43 μM, which was better than chidamide (IC₅₀ = 10.23 ± 1.02 μM). Western blot analysis and Annexin V-FTIC/propidium iodide (PI) staining showed that <b>20</b> could enhance the acetylation of histone H3, as well as remarkably induce apoptosis of RPMI-8226 cancer cells. The docking study highlighted the presence of a hydrogen bond between the carbonyl oxygen of the 2-acetylpyrrole cap group and Phe198 of the HDAC1 enzyme in <b>20</b>, emphasizing the crucial role of introducing this natural product-inspired cap group. Molecular dynamics simulations showed that the docked complex had good conformational stability. The ADME parameters calculation showed that <b>20</b> possesses remarkable theoretical drug-likeness properties. Taken together, these results suggested that <b>20</b> is worthy of further exploration as a potential HDAC-targeted anticancer drug candidate.