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Development of Fluorinated Peptoid-Based Histone Deacetylase (HDAC) Inhibitors for Therapy-Resistant Acute Leukemia
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-11-09 , DOI: 10.1021/acs.jmedchem.2c01418
Nina Reßing 1, 2 , Julian Schliehe-Diecks 3 , Paris R Watson 4 , Melf Sönnichsen 3 , Abigail D Cragin 4 , Andrea Schöler 2 , Jing Yang 3, 5 , Linda Schäker-Hübner 1 , Arndt Borkhardt 3 , David W Christianson 4 , Sanil Bhatia 3 , Finn K Hansen 1
Affiliation  

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p, which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.

中文翻译:

开发基于氟化肽的组蛋白脱乙酰酶 (HDAC) 抑制剂,用于治疗耐药性急性白血病

使用微波辅助方案,我们合成了 16 种带有氟化连接子的类肽封端的 HDAC 抑制剂 (HDACi),并鉴定了两种命中化合物。在生化和细胞测定中,10h作为一种有效的非选择性 HDACi 脱颖而出,对不同的耐药性白血病细胞系具有显着的细胞毒性潜力。10h表现出显着的抗白血病活性,对健康细胞具有低细胞毒活性。此外,10h在 AML 细胞系中表现出与 DNA 甲基转移酶抑制剂地西他滨的协同相互作用。HDAC6 复合物与10h及其非氟化对应物的晶体结构的比较揭示了 L1 环袋的相似占据,但锌配位略有差异。酰基残基的取代模式对于异构体选择性而言至关重要。在苯环上引入异丙基提供了高度 HDAC6 选择性抑制剂10p,它与地西他滨表现出适度的协同作用,并超过了图巴他汀 A 的 HDAC6 选择性。
更新日期:2022-11-09
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