"合成3,3'-雙取代的六號脫氧硫代二半乳糖苷作為具選擇性的半乳糖凝集素-3抑制劑"

Abstract

半乳糖凝集素是一種能結合β-半乳糖苷的蛋白，目前發現人類有11種半乳糖凝集素。由於參與多種病理活動，部分半乳糖凝集素被認為是數種疾病的治療標的物，例如乳癌、卵巢癌、心血管疾病以及特發性肺纖維化。然而，因為不同的半乳糖凝集素仍具有高度相似的醣識別區，所以發展具高選擇性的抑制劑是長期必須面臨的挑戰。在這份論文中，我們合成六號脫氧的硫代二半乳糖苷 (deTDG) 衍生物作為半乳糖凝集素的小分子抑制劑，並結合組合化學和結構上的合理設計。其中，我們利用有機錫催化的選擇性醯化和醚鍵生成，在deTDG的三號氫氧基上作衍生。目前已成功鑑定出數種對半乳糖凝集素-3具有良好選擇性及親和力的抑制劑。在這些分子中，選擇性最好的是化合物i，它對半乳糖凝集素-3的親和力比對半乳糖凝集素-1的親和力高54倍。而化合物ii為目前我們發現對半乳糖凝集素-3具有最佳親和力的抑制劑 (Kd = 70 nM)。半乳糖凝集素-1/ii複合體和半乳糖凝集素-3的X射線結構的疊圖中顯示，化合物ii上的羧酸根和半乳糖凝集素-3的精胺酸-144之間存在靜電作用力，進而解釋了其對半乳糖凝集素-3的高親合力。

Galectins represent a class of β-galactoside-binding proteins. There are eleven galectins identified in human. Participating in a variety of pathological activities, several galectin members have been considered as potential therapeutic targets of several diseases, such as breast/ovarian cancer, cardiovascular disease, and idiopathic pulmonary fibrosis. However, the development of highly selective inhibitors is a long-standing challenge since all galectins share a highly similar carbohydrate recognition domain. In this work, we synthesized 6-deoxy thiodigalactoside (deTDG) derivatives as galectin inhibitors and combined the approaches of combinatorial synthesis and structure-based design. Particularly, organotin-catalyzed regioselective acylation or ether formation was established at 3-hydroxyl group of deTDG. Several inhibitors were identified to display satisfying selectivity and affinity for galectin-3. Among them, compound i was the most selective inhibitor, showing 54-fold higher affinity with galectin-3 than with galectin-1. Compound ii was the most potent inhibitor of galectin-3 (Kd = 70 nM). Superimposition of galectin-1/ii and galectin-3 x-ray structures indicated the electrostatic interactions between the carboxylate of compound ii and Arg144 of galectin-3, explaining the extraordinary binding affinity.