School of Pharmacy, Fudan University, Shanghai 201203, China.
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
Bioorg Chem. 2022 Nov;128:106112. doi: 10.1016/j.bioorg.2022.106112. Epub 2022 Aug 28.
Herein, two series of HDAC/tubulin dual inhibitors via introducing the key pharmacophore of HDAC inhibitor into the skeletons of 2,6-diarylpyridine and 2'-arylchalcone were synthesized. Among them, 2,6-diarylpyridine-based hydroxamic acid 10a exhibited good inhibitory activity against HDAC8 (IC = 117 nM) with 50-fold and 42-fold high selectivity relative to HDAC1 and HDAC6, respectively. Meanwhile, 10a disrupted tubulin polymerization effectively and exhibited potent antiproliferative activity against BE-(2)-C cell line, with IC value of 17 nM. Mechanism studies revealed that 10a blocked cell cycle, induced cellular apoptosis and suppressed colony formation. Moreover, 10a possessed good physicochemical properties and metabolic stability. Importantly, 10a exhibited better antitumor effects in human neuroblastoma xenograft mice model than those of clinical HDAC inhibitor and tubulin inhibitor, whether used alone or in combination. These results highlighted the advantages of the HDAC8/tubulin dual inhibitor 10a as an outstanding antitumor agent.
本文通过将 HDAC 抑制剂的关键药效团引入 2,6-二芳基吡啶和 2'-芳基查耳酮骨架中，合成了两类 HDAC/微管双抑制剂。其中，基于 2,6-二芳基吡啶的羟肟酸 10a 对 HDAC8 的抑制活性（IC = 117 nM）较好，与 HDAC1 和 HDAC6 相比，选择性分别提高了 50 倍和 42 倍。同时，10a 有效破坏了微管聚合，并对 BE-(2)-C 细胞系表现出很强的抗增殖活性，IC 值为 17 nM。机制研究表明，10a 能阻断细胞周期，诱导细胞凋亡，抑制集落形成。此外，10a 具有良好的理化性质和代谢稳定性。重要的是，10a 在人神经母细胞瘤异种移植小鼠模型中表现出比临床使用的 HDAC 抑制剂和微管抑制剂更好的抗肿瘤效果，无论是单独使用还是联合使用。这些结果突出了 HDAC8/微管双抑制剂 10a 作为一种优秀的抗肿瘤药物的优势。
