四氢-β-咔啉衍生物作为强效组蛋白去乙酰化酶 6 抑制剂，具有广谱的抗增殖活性。
Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity.
机构信息
Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, 712100, PR China.
出版信息
Eur J Med Chem. 2023 Nov 15;260:115776. doi: 10.1016/j.ejmech.2023.115776. Epub 2023 Aug 30.
A series of tetrahydro-β-carboline (THβC)-based hydroxamic acids were rationally designed and synthesized as novel selective HDAC6 inhibitors (sHDAC6is) by the application of scaffold hopping strategy. Several THβC analogues were highly potent (IC < 5 nM) and selective against HDAC6 enzyme and exhibited good antiproliferative activity against human multiple myeloma (MM) cell. Molecular docking interpreted the structure activity relationship (SAR). Target engagement of HDAC6 was confirmed in RPMI-8226 cells using the WB assay. In vitro, (1S, 3R)-1-(4-chlorophenyl)-N-(4-(hydroxycarbamoyl)benzyl)-2,3,4,9-tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxamide (14g) showed potent broad antiproliferative activity against various tumors including leukemia, colon cancer, melanoma, and breast cancer cell lines, better than ACY-1215. Moreover, 14g also showed good pharmacokinetics properties in mice via oral administration.
通过应用支架跳跃策略，设计并合成了一系列四氢-β-咔啉（THβC）为基础的羟肟酸，作为新型选择性 HDAC6 抑制剂（sHDAC6is）。几种 THβC 类似物对 HDAC6 酶具有很高的抑制活性（IC < 5 nM）和选择性，并对人多发性骨髓瘤（MM）细胞表现出良好的抗增殖活性。分子对接解释了构效关系（SAR）。使用 WB assay 证实了 RPMI-8226 细胞中 HDAC6 的靶标结合。在体外，（1S, 3R）-1-（4-氯苯基）-N-（4-（羟氨基甲酰基）苄基）-2,3,4,9-四氢-1H-吡啶并[3, 4-b]吲哚-3-甲酰胺（14g）对各种肿瘤包括白血病、结肠癌、黑色素瘤和乳腺癌细胞系具有很强的广谱抗增殖活性，优于 ACY-1215。此外，14g 经口服给药在小鼠体内也表现出良好的药代动力学特性。
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