Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA.
Org Biomol Chem. 2020 Sep 14;18(34):6665-6681. doi: 10.1039/d0ob01205j. Epub 2020 Aug 19.
The enzyme protein disulfide isomerase (PDI) is essential for the correct folding of proteins and the activation of certain cell surface receptors, and is a promising target for the treatment of cancer and thrombotic conditions. A previous high-throughput screen identified the commercial compound STK076545 as a promising PDI inhibitor. To confirm its activity and support further biological studies, a resynthesis was pursued of the reported β-keto-amide with an N-alkylated pyridone at the α-position. Numerous conventional approaches were complicated by undesired fragmentations or rearrangements. However, a successful 5-step synthetic route was achieved using an aldol reaction with an α-pyridone allyl ester as a key step. An X-ray crystal structure of the final compound confirmed that the reported structure of STK076545 was achieved, however its lack of PDI activity and inconsistent spectral data suggest that the commercial structure was misassigned.
酶蛋白二硫键异构酶（PDI）对于蛋白质的正确折叠和某些细胞表面受体的激活至关重要，是治疗癌症和血栓形成疾病的有前途的靶点。先前的高通量筛选发现商业化合物 STK076545 是一种很有前途的 PDI 抑制剂。为了确认其活性并支持进一步的生物学研究，对报道的具有α-位 N-烷基化吡啶酮的β-酮酰胺进行了重新合成。许多常规方法因不需要的片段化或重排而变得复杂。然而，使用α-吡啶酮烯丙基酯作为关键步骤的醛醇反应成功地实现了 5 步合成路线。最终化合物的 X 射线晶体结构证实了报道的 STK076545 结构的实现，但其缺乏 PDI 活性和不一致的光谱数据表明商业结构被错误分配。
