Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors.
Discovery of Carbono(di)thioates as Indoleamine 2,3-Dioxygenase 1 Inhibitors.
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发现二硫代碳酸酯作为吲哚胺 2,3-双加氧酶 1 抑制剂。
DOI：
10.1021/acsmedchemlett.0c00527
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发表时间：
2021
影响因子：
4.2
通讯作者：
Matsuno Kenji
中科院分区：
文献类型：
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作者：
Kumazawa Miyuki;Tejima Manabu;Fukuda Miwa;Takeda Shota;Suzuki Kenji;Mizumoto Yukiko;Sato Kakeru;Waki Minoru;Miyachi Hiroyuki;Asai Akira;Takikawa Osamu;Hashimoto Tomoko;Ohno Osamu;Matsuno Kenji
一项结构-活性关系研究意外地表明，分别由2-烷基硫代恶唑啉3a3b和3b独特的碱性水解得到的carbonothioates4a4b是吲哚胺2,3-双加氧酶1 （IDO1）抑制剂的新型支架。羰基硫代酸酯的衍生化增强了对IDO1和细胞犬尿氨酸生成的抑制活性，而没有细胞毒性，并导致相关支架羰基硫代酸酯5和氰基羰基硫代酸酯6作为IDO1抑制剂的发现。OH组的加入提供了最有效的类似物。Soret波段的紫外可见吸收光谱以及对接和肽图谱研究表明，这些分子在IDO1的活性位点与血红素结合。我们独特的IDO1抑制剂是未来发展的潜在先导。
A structure–activity relationship study unexpectedly showed that carbonothioates4aand4b, obtained by a unique alkaline hydrolysis of 2-alkylthio-oxazolines3aand3b, respectively, are a novel scaffold for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. Derivatization of the carbonothioates enhanced inhibitory activity against IDO1 and cellular kynurenine production without cytotoxicity and led to the discovery of the related scaffolds carbonodithioates5and cyanocarbonimidodithioates6as IDO1 inhibitors. Incorporation of an OH group provided the most potent analogue5i. UV–visible absorption spectroscopy of the Soret band, as well as docking and peptide mapping studies, suggested that these molecules bind to the heme in the active site of IDO1. Our unique IDO1 inhibitors are potential leads for future development.