Department of Chemistry, University of Fribourg, 1700 Fribourg, Switzerland.
Chair of Pharmacology, Faculty of Science and Medicine University of Fribourg, 1700 Fribourg, Switzerland.
J Med Chem. 2021 May 13;64(9):6221-6240. doi: 10.1021/acs.jmedchem.1c00260. Epub 2021 Apr 15.
The enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is one of the more recently identified mammalian sources of HS. A recent study identified several novel 3-MST inhibitors with micromolar potency. Among those, (2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one) or HMPSNE was found to be the most potent and selective. We now took the central core of this compound and modified the pyrimidone and the arylketone sides independently. A 63-compound library was synthesized; compounds were tested for HS generation from recombinant 3-MST in vitro. Active compounds were subsequently tested to elucidate their potency and selectivity. Computer modeling studies have delineated some of the key structural features necessary for binding to the 3-MST's active site. Six novel 3-MST inhibitors were tested in cell-based assays: they exerted inhibitory effects in murine MC38 and CT26 colon cancer cell proliferation; the antiproliferative effect of the compound with the highest potency and best cell-based activity () was also confirmed on the growth of MC38 tumors in mice.
3-巯基丙酮酸硫转移酶（3-MST）是最近发现的哺乳动物来源的 HS 之一。最近的一项研究确定了几种具有毫摩尔效力的新型 3-MST 抑制剂。其中，（2-[(4-羟基-6-甲基嘧啶-2-基)硫基]-1-（萘-1-基）乙酮）或 HMPSNE 被发现是最有效和选择性的。我们现在以该化合物的核心部分为基础，分别修饰嘧啶酮和芳基酮侧链。合成了一个包含 63 个化合物的文库；这些化合物在体外重组 3-MST 中测试了 HS 的产生。随后测试了活性化合物以阐明其效力和选择性。计算机建模研究阐明了与 3-MST 的活性位点结合所需的一些关键结构特征。六种新型 3-MST 抑制剂在基于细胞的测定中进行了测试：它们在鼠 MC38 和 CT26 结肠癌细胞增殖中发挥抑制作用；具有最高效力和最佳基于细胞活性的化合物的抗增殖作用（）也在小鼠 MC38 肿瘤的生长中得到了证实。
