Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells
Discovery of pyrazolones as novel carboxylesterase 2 inhibitors that potently inhibit the adipogenesis in cells
复制标题
发现吡唑啉酮作为新型羧酸酯酶 2 抑制剂，可有效抑制细胞中的脂肪生成
DOI：
10.1016/j.bmc.2021.116187
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发表时间：
2021-05-06
影响因子：
3.5
通讯作者：
Zou, Li-Wei
中科院分区：
文献类型：
--
作者：
Qian, Xing-Kai;Zhang, Jing;Zou, Li-Wei
羧酸酯酶2（Carboxylesterase 2，CES 2）是羧酸酯酶家族中最重要的I相药物代谢酶之一。它在口服酯类前药的生物利用度和一些抗癌药物如伊立替康（CPT 11）和卡培他滨的治疗效果中起着至关重要的作用。除了已知的CES 2在异生物质代谢中的作用外，该酶还参与内源性代谢和脂质的产生。本研究合成了一系列吡唑啉酮类化合物，并研究了它们对CES 2的体外抑制作用。构效关系分析表明，4-甲基苯基（R1）、4-甲基苄基（R-2）和环己基（R-3）结构单元的引入有利于抑制CES 2。在这些SAR结果的指导下，设计并合成了1-环己基-4-（4-甲基苄基）-3-对甲苯基-1H-吡唑-5（4 H）-酮（27）。进一步的研究表明，化合物27显示出较强的CES 2抑制活性，具有较低的IC 50值（0.13 μ M）。抑制动力学研究表明，化合物27通过非竞争性抑制作用抑制CES 2-荧光素二乙酸酯（FD）的水解。此外，分子对接结果表明，化合物27中吡唑啉酮的核心、环己烷结构、4-甲基苄基和4-甲基苯基均与CSE 2的氨基酸残基起重要作用。此外，化合物27可以抑制小鼠前脂肪细胞诱导的脂肪细胞脂肪生成。综上所述，我们设计并合成了一种新的吡唑啉酮类化合物，该化合物对CES 2具有较强的抑制能力，能够抑制小鼠前脂肪细胞诱导的脂肪形成，为开发更有效的吡唑啉酮类CES 2抑制剂提供了一个很有前景的先导化合物，也为探索CES 2在人体中的生物学功能提供了一个潜在的工具。
Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R-2) and cyclohexyl (R-3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H-pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 mu M). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.