Design, synthesis, structure?activity relationship studies, and evaluation of novel GLS1 inhibitors
Design, synthesis, structure?activity relationship studies, and evaluation of novel GLS1 inhibitors
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新型GLS1抑制剂的设计、合成、构效关系研究和评价
DOI：
10.1016/j.bmcl.2023.129266
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Okada Takuya
中科院分区：
文献类型：
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作者：
Jo Michiko;Koizumi Keiichi;Suzuki Mizuho;Kanayama Daisuke;Watanabe Yurie;Gouda Hiroaki;Mori Hisashi;Mizuguchi Mineyuki;Obita Takayuki;Nabeshima Yuko;Toyooka Naoki;Okada Takuya
谷氨酰胺酶将谷氨酰胺转化为谷氨酸，并有两种亚型：谷氨酰胺酶1（GLS 1）和谷氨酰胺酶2（GLS 2）。GLS 1在几种肿瘤中过表达，目前正在研究开发转氨酶抑制剂作为抗肿瘤药物。本研究使用计算机筛选检测候选GLS 1抑制剂，并尝试合成新型GLS 1抑制剂，并评估其在小鼠肾脏提取物中以及对重组小鼠和人GLS 1的GLS 1抑制活性。以化合物C1为先导化合物合成了新化合物，并以小鼠肾提取物评价了其GLS 1抑制活性。在所测试的衍生物中，反式-4-羟基环己基酰胺衍生物2 j表现出最强的抑制活性。我们还评估了衍生物2 j、5i和8a对重组小鼠和人GLS 1的GLS 1抑制活性。衍生物5i和8a在10 mM下显著降低谷氨酸的产生。总之，我们在此鉴定了两种化合物，其表现出与已知的GLS 1抑制剂具有相同效力的GLS 1抑制活性。这些结果将有助于开发具有更强抑制活性的有效新型GLS 1抑制剂。
Glutaminase converts glutamine into glutamic acid and has two isoforms: glutaminase 1 (GLS1) and glutaminase 2 (GLS2). GLS1 is overexpressed in several tumors, and research to develop glutaminase inhibitors as antitumor drugs is currently underway. The present study examined candidate GLS1 inhibitors usingin silicoscreening and attempted to synthesize novel GLS1 inhibitors and assess their GLS1 inhibitory activities in a mouse kidney extract and against recombinant mouse and human GLS1. Novel compounds were synthesized using compoundCas the lead compound, and their GLS1 inhibitory activities were evaluated using the mouse kidney extract. Among the derivatives tested, thetrans-4-hydroxycyclohexylamide derivative2jexhibited the strongest inhibitory activity. We also assessed the GLS1 inhibitory activities of the derivatives2j,5i, and8aagainst recombinant mouse and human GLS1. The derivatives5iand8asignificantly decreased the production of glutamic acid at 10 mM. In conclusion, we herein identified two compounds that exhibited GLS1 inhibitory activities with equal potencies as known GLS1 inhibitors. These results will contribute to the development of effective novel GLS1 inhibitors with more potent inhibitory activity.