Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Eur J Med Chem. 2020 Feb 15;188:111991. doi: 10.1016/j.ejmech.2019.111991. Epub 2019 Dec 20.
Semisynthetic 18β-glycyrrhetinic acid (GA) analogues bearing 1-en-2-cyano-3-oxo substitution on ring A have enhanced antitumor effects with reduced levels of HDAC3 and HDAC6 proteins. Aiming to inhibit both HDAC protein and activity, we developed a hybrid molecule by tethering active GA analogue methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate (CDODA-Me) and Vorinostat (SAHA). We tested the proper hybrid approaches of GA with hydroxamic acid and turned out that GA conjugated with SAHA by a piperazine linker was the best. The conjugate (15) of CDODA-Me and SAHA linked through a piperazine group was a potent cytotoxic agent against cancer cells with apoptosis induction. Compound 15 was more effective than the simple combination of CDODA-Me and SAHA to induce apoptosis. Mechanistic studies revealed that 15 was less effective than SAHA to inhibit HDAC activity, but was more effective than CDODA-Me to decrease the levels of HDAC3 and HDAC6 proteins with upregulated levels of acetylated H3 and acetylated α-tubulin. Compound 15 represents a new HDAC3 and HDAC6 inhibitor by reducing protein levels.
具有 A 环 1-烯-2-氰基-3-氧取代的半合成 18β-甘草次酸（GA）类似物具有增强的抗肿瘤作用，同时降低 HDAC3 和 HDAC6 蛋白水平。为了抑制 HDAC 蛋白和活性，我们通过连接活性 GA 类似物甲基 2-氰基-3,11-二氧代-18β-齐墩果-1,12-二烯-30-酸酯（CDODA-Me）和伏立诺他（SAHA）开发了一种杂合分子。我们测试了 GA 与羟肟酸的合适杂合方法，结果表明，通过哌嗪连接子将 GA 与 SAHA 连接的缀合物是最好的。通过哌嗪基团连接的 CDODA-Me 和 SAHA 的缀合物（15）是一种有效的细胞毒性剂，可诱导癌细胞凋亡。与 CDODA-Me 和 SAHA 的简单组合相比，化合物 15 更有效地诱导细胞凋亡。机制研究表明，与 SAHA 相比，15 抑制 HDAC 活性的效果较差，但与 CDODA-Me 相比，它降低 HDAC3 和 HDAC6 蛋白水平的效果更好，同时乙酰化 H3 和乙酰化α-微管蛋白水平升高。化合物 15 通过降低蛋白水平代表了一种新的 HDAC3 和 HDAC6 抑制剂。
