Click Glycosylation for the Synthesis of 1,2,3-Triazole-Linked Picropodophyllotoxin Glycoconjugates and Their Anticancer Activity

摘要

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was employed successfully to prepare a series 4β-triazole-linked picropodophyllotoxin glycoconjugates (25 – 34). Maltose residue, 1,6-β-D-diglucose residue, and several triazole-linked disaccharide and trisaccharide residues were coupled to 4β- azido-podophyllotoxin derivatives through click glycosylation strategy. The initial click glycosylation products were treated with catalytic amount of NaOCH_3 to facilitate global deacylation and epimerization at C-2 position to yield the cis-γ-lactone moiety in the picropodophyllotoxin glycoconjugates. Most of these picropodophyllotoxin glycoconjugates show weak cyto- toxicity (IC_(50) > 40 μM) against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) as indicated by in vitro MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazo- lium bromide] assay. However, compound 27 that contains a 1,6-β-D-di-glucose residue displays strong anticancer activity against all cancer cell lines tested, with IC_(50) values ranging from 0.67 to 7.41 μM, which is significantly more potent than the control drug etoposide against four of the five cancer cells tested. Structure activity relationship analysis suggests that the 4’-O-methyl group on the E ring of podophyllotoxin scaffold is perhaps important for the anticancer activity of glycosylated picropodophyllotoxin derivatives with a cis-γ-lactone moiety.