Route exploration and synthesis of the reported pyridone-based PDI inhibitor STK076545.
Route exploration and synthesis of the reported pyridone-based PDI inhibitor STK076545.
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DOI：
10.1039/d0ob01205j
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发表时间：
2020-09-14
影响因子：
3.2
通讯作者：
Dockendorff C
中科院分区：
文献类型：
--
作者：
Greve E;Lindeman SV;Scartelli C;Lin L;Flaumenhaft R;Dockendorff C
蛋白质二硫异构酶（PDI）对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一个有希望的靶点。先前的高通量筛选鉴定出商业化合物STK076545是一种有前途的PDI抑制剂。为了证实其活性并支持进一步的生物学研究，研究人员在α-位置用n -烷基化吡啶酮重新合成了已报道的β-酮酰胺。许多传统的方法由于不希望的碎片或重排而变得复杂。然而，以α-吡啶酮烯丙基酯与醛醇反应为关键步骤，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STK076545的结构，但其缺乏PDI活性和不一致的光谱数据表明其商业结构是错误的。
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.
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