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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-09, Vol.29 (19), p.4653
• Main Authors: Zhang, Han, Shen, Qianqian, Hu, Zhu, Wu, Pei-Qian, Chen, Yi, Zhao, Jin-Xin, Yue, Jian-Min
• Format: Article
• Language: English
• Subjects: Acids; anti-cancer activity; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological products; Biological Products - chemical synthesis; Biological Products - chemistry; Biological Products - pharmacology; Cancer therapies; Cell Line, Tumor; Drug Design; Drug resistance; Epigenetics; Flow cytometry; HDAC inhibitors; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase 1 - chemistry; Histone Deacetylase 1 - metabolism; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydrogen; molecular docking; Molecular Docking Simulation; Molecular dynamics; molecular dynamics simulation; Molecular Structure; Multiple myeloma; Natural products; Product introduction; pyrrole derivatives; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Structure-Activity Relationship
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29194653

Drawing inspiration from the structural resemblance between a natural product -(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 -linked 2-acetylpyrrole cap by utilizing the pharmacophore fusion strategy. Among them, compound exhibited potential inhibitory activity on HDAC1, and demonstrated notable potency against RPMI-8226 cells with an IC value of 2.89 ± 0.43 μM, which was better than chidamide (IC = 10.23 ± 1.02 μM). Western blot analysis and Annexin V-FTIC/propidium iodide (PI) staining showed that 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 , 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 possesses remarkable theoretical drug-likeness properties. Taken together, these results suggested that is worthy of further exploration as a potential HDAC-targeted anticancer drug candidate.