Peterson Kristoffer, Collins Patrick M, Huang Xiaoli, Kahl-Knutsson Barbro, Essén Sofia, Zetterberg Fredrik R, Oredsson Stina, Leffler Hakon, Blanchard Helen, Nilsson Ulf J
Centre for Analysis and Synthesis, Department of Chemistry, Lund University POB 124 SE-221 00 Lund Sweden
Institute for Glycomics, Griffith University Gold Coast Campus Queensland 4222 Australia.
RSC Adv. 2018 Jul 11;8(44):24913-24922. doi: 10.1039/c8ra04389b. eCollection 2018 Jul 9.
A series of 3-triazole-thiogalactosides and 3,3'-triazole-thiodigalactosides substituted with different five-membered heterocycles at the C-4 triazole position were found to have high selectivity for galectin-1. Initial studies on the 3-triazole-thiogalactosides indicated that five membered heterocycles in general gave increased affinity for galectin-1 and improved selectivity over galectin-3. The selectivity profile was similar for thiodigalactosides exemplified by 3,3' substituted thien-3-yltriazole and thiazol-2-yltriazole, both having single-digit nM galectin-1 affinity and almost 10-fold galectin-1 selectivity. The binding interactions of a thiodigalactoside based galectin-1 inhibitor with two thien-3-yltriazole moieties were studied with X-ray crystallography. One of the thiophene moieties was positioned deeper into the pocket than previously reported phenyltriazoles and formed close contacts with Val31, Ser29, Gly124, and Asp123. The affinity and structural analysis thus revealed that steric and electronic optimization of five-membered aromatic heterocycle binding in a narrow galectin-1 subsite confers high affinity and selectivity.
一系列在C-4三唑位置被不同五元杂环取代的3-三唑-硫代半乳糖苷和3,3'-三唑-硫代二半乳糖苷被发现对半乳糖凝集素-1具有高选择性。对3-三唑-硫代半乳糖苷的初步研究表明，一般来说五元杂环会增加对半乳糖凝集素-1的亲和力，并提高相对于半乳糖凝集素-3的选择性。以3,3'-取代的噻吩-3-基三唑和噻唑-2-基三唑为例的硫代二半乳糖苷的选择性概况相似，二者对半乳糖凝集素-1的亲和力均在个位数纳摩尔级别，且对半乳糖凝集素-1的选择性几乎为10倍。利用X射线晶体学研究了一种基于硫代二半乳糖苷的半乳糖凝集素-1抑制剂与两个噻吩-3-基三唑部分的结合相互作用。其中一个噻吩部分比先前报道的苯基三唑更深地位于口袋中，并与Val31、Ser29、Gly124和Asp123形成紧密接触。亲和力和结构分析因此揭示，在狭窄的半乳糖凝集素-1亚位点中五元芳香杂环结合的空间和电子优化赋予了高亲和力和选择性。
