School of Chemistry and Bio21 Institute , University of Melbourne , Parkville , Australia 3010.
J Org Chem. 2019 Jun 7;84(11):6788-6797. doi: 10.1021/acs.joc.9b00544. Epub 2019 May 14.
Mincle is a C-type lectin receptor of the innate immune system with the ability to sense pathogens and commensals through lipidic metabolites. While a growing number of bacterial glycolipids have been discovered that can signal through human Mincle, no fungal metabolites are known that can signal through the human form of this receptor. We report the total synthesis of a complex β-1,2-mannosyloxymannitol glycolipid from Malassezia pachydermatis 44-2, which was reported to signal through the murine Mincle receptor. Assembly of 44-2 was achieved through a highly convergent route that exploits symmetry elements inherent within this molecule and delineation of conditions that maintain the delicate l-mannitol triester-triol array. We show that 44-2 is a potent agonist of human Mincle signaling and constitutes the first fungal metabolite identified that can signal through the human Mincle receptor, providing new insights into antifungal immunity.
Mincle 是先天免疫系统中的一种 C 型凝集素受体，能够通过脂类代谢物感知病原体和共生菌。虽然已经发现越来越多的细菌糖脂可以通过人类 Mincle 发出信号，但目前还不知道真菌代谢物可以通过人类形式的这种受体发出信号。我们报告了从厚皮马拉色菌 44-2 中合成一种复杂的 β-1,2-甘露糖氧甘露糖醇糖脂，据报道，该糖脂可以通过鼠类 Mincle 受体发出信号。通过高度收敛的路线实现了 44-2 的组装，该路线利用了该分子固有的对称元素，并确定了保持精细 l-甘露糖醇三酯-三醇阵列的条件。我们表明 44-2 是人类 Mincle 信号的有效激动剂，并且构成了第一个被鉴定为可以通过人类 Mincle 受体发出信号的真菌代谢物，为抗真菌免疫提供了新的见解。
