Total synthesis and bioactivity investigation of a chiral diacylglycerol

The total synthesis of compound 1, a chiral diglyceride metabolite present in both humans and fungi, was achieved via a seven-step route, affording the target molecule in 2.33% overall yield. The synthetic strategy involved: (1) selective protection of the terminal hydroxyl group of chiral ketal 2 with a sterically hindered benzyl group, followed by ketal deprotection to yield benzyl ether 4; (2) protection of the terminal hydroxyl group of benzyl ether 4 with a bulky silyl protecting group, and subsequent esterification of the remaining hydroxyl with erucic acid to generate ester 6; (3) removal of the silyl protecting group from ester 6, followed by esterification of the liberated hydroxyl group with pentadecanoic acid to afford ester 8; and (4) selective deprotection of the benzyl group of ester 8 to furnish compound 1. Network pharmacology and molecular docking studies identified 196 potential targets of compound 1, with AKT1, ALB, CASP3, EGFR, HSP90AA1, IGF1, and SRC highlighted as potential hub targets. In silico analysis suggested potential therapeutic applications in diabetes, neuro-systemic diseases, thyroid hormone disorders, lipid disorders, tumors, and gynaecological diseases. Furthermore, in silico screening using three databases identified 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) as a potential biological target. However, in vitro HMGCR inhibition assays failed to demonstrate a significant reduction in cholesterol levels in human blood upon treatment with compound 1. These findings contribute to the understanding of the chemical synthesis and biological activity of chiral diglycerides and provide a basis for future research in this area.