A short synthesis of carbohydrate derived N-benzyl aminocyclopentitols through N-O bond cleavage of the corresponding isoxazolidine derivatives: Evaluation of their anticancer properties using in vitro and in silico studies

Abstract

A short synthesis of a potent glycosidase inhibitor N-benzyl-β-D-gluco aminocyclopentitol along with its 2-deoxy, and orthogonally protected 2-O-benzyl, 1,2,3-tri-O-benzyl and 1,2,3-tri-O-acetyl analogues through carbohydrate derived cyclopentane-fused isoxazolidine derivatives has been described herein. The key steps involve NaI mediated vinylation of D-glucose derived 5,6-di-O-mesylated compounds in sealed tube to produce 5,6-dideoxy-l,2-O-isopropylidene-α-D-xylo-hexo-5-enofuranos derivatives in very good yields. Subsequent acetonide deprotection and stereoselective intramolecular nitrone cycloaddition (INC) reaction involving C-4-vinyl functionalities and the latent aldehyde moiety at C-1 yielded various cyclopentano-isoxazolidines. The N-O bond cleavage of the isoxazolidine rings produced the targeted aminocyclopentitols. In vitro anticancer activities of the isoxazolidines and N-benzyl aminocyclopentitols were performed and found only 1,2,3-tri-O-benzyl analogue (20c) of N-benzyl-β-D-gluco aminocyclopentitols emerged as potent anticancer agent with IC₅₀ value 54.90 μM. Furthermore, the molecular docking study confirmed that 20c, compared with the other derivatives, scores higher binding affinity for all the targeted receptors, HSP90, PLK1, and TOP2A.