Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania.
Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania.
Bioorg Chem. 2018 Apr;77:534-541. doi: 10.1016/j.bioorg.2018.02.004. Epub 2018 Feb 10.
Four series of para or meta - substituted thiazolylbenzenesulfonamides bearing Cl substituents were designed, synthesized, and evaluated as inhibitors of all 12 catalytically active recombinant human carbonic anhydrase (CA) isoforms. Observed affinities were determined by the fluorescent thermal shift assay and the intrinsic affinities were calculated based on the fractions of binding-ready deprotonated sulfonamide and CA bearing protonated hydroxide bound to the catalytic Zn(II) in the active site. Several compounds exhibited selectivity towards CA IX, an anticancer target. Intrinsic affinities reached 30 pM, while the observed affinities - 70 nM. The structure-intrinsic affinity relationship map of the compounds showed the energetic contributions of the thiazole ring and its substituents.
设计、合成并评价了四个系列对位或间位取代的含 Cl 取代基的噻唑基苯磺酰胺类化合物，作为 12 种全人重组碳酸酐酶（CA）同工酶的抑制剂。通过荧光热迁移分析测定了观察到的亲和力，根据结合准备好的去质子化磺酰胺和带质子化氢氧化物的 CA 的分数计算了固有亲和力，这些物质与活性部位的催化 Zn(II)结合。一些化合物对癌症靶点 CAIX 具有选择性。固有亲和力达到 30 pM，而观察到的亲和力为 70 nM。化合物的结构固有亲和力关系图显示了噻唑环及其取代基的能量贡献。
