二氢恶唑并[2,3 - ]异喹啉鎓作为人羧酸酯酶2（hCE2）高度特异性抑制剂的发现
Discovery of dihydrooxazolo[2,3-]isoquinoliniums as highly specific inhibitors of hCE2.
作者信息
Ding Lixia, Wang Lu, Zou Kun, Li Bo, Song Yunqing, Zhang Qihua, Zhao Yitian, Xu Zhijian, Ge Guangbo, Zhao Bo, Zhu Weiliang
机构信息
Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences 555 Zuchongzhi Road Shanghai 201203 China
College of Chemistry and Materials Science, Nanjing Normal University 1 Wenyuan Road Nanjing 210097 China
出版信息
RSC Adv. 2019 Nov 4;9(61):35904-35912. doi: 10.1039/c9ra07457k. eCollection 2019 Oct 31.
Human carboxylesterase 2 (hCE2) is one of the most abundant esterases distributed in human small intestine and colon, which participates in the hydrolysis of a variety of ester-bearing drugs and thereby affects the efficacy of these drugs. Herein, a new compound (23o) with a novel skeleton of dihydrooxazolo[2,3-]isoquinolinium has been discovered with strong inhibition on hCE2 (IC = 1.19 μM, = 0.84 μM) and more than 83.89 fold selectivity over hCE1 (IC > 100 μM). Furthermore, 23o can inhibit hCE2 activity in living HepG2 cells with the IC value of 2.29 μM, indicating that this compound has remarkable cell-membrane permeability and is capable for inhibiting intracellular hCE2. The SAR (structure-activity relationship) analysis and molecular docking results demonstrate that the novel skeleton of oxazolinium is essential for hCEs inhibitory activity and the benzyloxy moiety mainly contributes to the selectivity of hCE2 over hCE1.
人羧酸酯酶2（hCE2）是分布于人类小肠和结肠中最丰富的酯酶之一，它参与多种含酯药物的水解，从而影响这些药物的疗效。在此，发现了一种具有新型二氢恶唑并[2,3 -]异喹啉鎓骨架的新化合物（23o），它对hCE2具有强烈抑制作用（IC = 1.19 μM， = 0.84 μM），对hCE1的选择性超过83.89倍（IC > 100 μM）。此外，23o能够在活的HepG2细胞中抑制hCE2活性，IC值为2.29 μM，表明该化合物具有显著的细胞膜通透性，能够抑制细胞内的hCE2。构效关系（SAR）分析和分子对接结果表明，恶唑啉鎓的新型骨架对于hCEs抑制活性至关重要，苄氧基部分主要有助于hCE2对hCE1的选择性。
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