Discovery of Potent HDAC6-Selective Inhibitors Based on Artemisinin: Design, Synthesis, and Antitumor Evaluation

Beyond their well-established antimalarial effects, artemisinin and its derivatives have demonstrated promising antitumor activity. Herein, a series of novel artemisinin-based histone deacetylase inhibitors were rationally designed and synthesized using a pharmacophore hybridization strategy. Among them, compound G25 exhibited the most potent in vitro antiproliferative activity, particularly against hematologic malignancies, including MV4–11 (IC50 = 28 nM), MOLM-13 (IC50 = 89 nM), and HL60 cells (IC50 = 92 nM). Mechanism studies revealed that G25 induced autophagy and apoptosis in a p53-dependent manner. HDAC isoform profiling demonstrated that G25 was a potent and selective HDAC6 inhibitor (IC50 = 12 nM). Importantly, G25 showed in vivo antileukemic activity in a MOLM-13-Luc acute myeloid leukemia xenograft model, as evidenced by suppressed tumor progression and a trend toward prolonged survival. Pharmacokinetic evaluation indicated rapid metabolic clearance, suggesting the need for further optimization. Collectively, G25 represents a promising lead scaffold for developing artemisinin-derived HDAC6-selective antitumor agents.

青蒿素（artemisinin）及其衍生物除了拥有已被广泛验证的抗疟活性外，还展现出颇具潜力的抗肿瘤活性。本研究采用药效团杂交策略，理性设计并合成了一系列基于青蒿素的新型组蛋白去乙酰化酶（histone deacetylase, HDAC）抑制剂。其中化合物G25展现出最强的体外抗增殖活性，对血液系统恶性肿瘤尤为有效，涉及的细胞系包括MV4–11（半数抑制浓度IC50=28 nM）、MOLM-13（IC50=89 nM）与HL60细胞（IC50=92 nM）。机制研究表明，G25以p53依赖的方式诱导细胞自噬与细胞凋亡。组蛋白去乙酰化酶亚型谱分析实验显示，G25是一种强效且高选择性的HDAC6抑制剂（IC50=12 nM）。尤为关键的是，G25在MOLM-13-Luc急性髓系白血病异种移植模型中展现出体内抗白血病活性，具体体现为肿瘤进展受到抑制以及生存期延长的趋势。药代动力学评价结果显示其代谢清除速率较快，提示仍需对其进行进一步优化。综上，G25是开发青蒿素类HDAC6选择性抗肿瘤药物的极具潜力的先导骨架。