Duan Wenwen, Li Jin, Inks Elizabeth S, Chou C James, Jia Yuping, Chu Xiaojing, Li Xiaoyang, Xu Wenfang, Zhang Yingjie
†Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Ji'nan, Shandong 250012, People's Republic of China.
‡Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina 29425, United States.
J Med Chem. 2015 May 28;58(10):4325-38. doi: 10.1021/acs.jmedchem.5b00317. Epub 2015 May 7.
On the basis of the strategy of creating multifunctional drugs, a novel series of phenylsulfonylfuroxan-based hydroxamates with histone deacetylase (HDAC) inhibitory and nitric oxide (NO) donating activities were designed, synthesized, and evaluated. The most potent NO donor-HDAC inhibitor (HDACI) hybrid, 5c, exhibited a much greater in vitro antiproliferative activity against the human erythroleukemia (HEL) cell line than that of the approved drug SAHA (Vorinostat), and its antiproliferative activity was diminished by the NO scavenger hemoglobin in a dose-dependent manner. Further mechanism studies revealed that 5c strongly induced cellular apoptosis and G1 phase arrest in HEL cells. Animal experiment identified 5c as an orally active agent with potent antitumor activity in a HEL cell xenograft model. Interestingly, although compound 5c was remarkably HDAC6-selective at the molecular level, it exhibited pan-HDAC inhibition in a western blot assay, which is likely due to class I HDACs inhibition caused by NO release at the cellular level.
基于创制多功能药物的策略，设计、合成并评估了一系列新型的基于苯磺酰基呋咱的异羟肟酸酯，它们具有组蛋白去乙酰化酶（HDAC）抑制活性和一氧化氮（NO）释放活性。最具活性的NO供体-HDAC抑制剂（HDACI）杂合物5c，对人红白血病（HEL）细胞系的体外抗增殖活性比已获批药物SAHA（伏立诺他）更强，并且其抗增殖活性被NO清除剂血红蛋白以剂量依赖的方式减弱。进一步的机制研究表明，5c强烈诱导HEL细胞发生细胞凋亡和G1期阻滞。动物实验确定5c在HEL细胞异种移植模型中是一种具有强效抗肿瘤活性的口服活性药物。有趣的是，尽管化合物5c在分子水平上对HDAC6具有显著的选择性，但在蛋白质印迹分析中它表现出对所有HDAC的抑制作用，这可能是由于在细胞水平上NO释放导致I类HDAC受到抑制。
