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.