Fortuna_2022_ChemMedChem__

The synthesis and biological evaluation of novel guanidino sugars as isonucleoside analogs is described. 5-Guanidino xylofuranoses containing 3- O -saturated/unsaturated hydrocarbon or aromatic-containing moieties were accessed from 5-azido xylofuranoses via reduction followed by guanidinylation with N , N '-bis( tert -butoxycarbonyl)- N ''-triflylguanidine. Molecules comprising novel types of isonucleosidic structures including 5-guanidino 3- O -methyl-branched N -benzyltriazole isonucleosides and a guanidinomethyltriazole 3'- O -dodecyl xylofuranos-5'-yl isonucleoside were accessed. The guanidinomethyltriazole derivative and a 3- O -dodecyl ( N -Boc)guanidino xylofuranose were revealed as selective inhibitors of acetylcholinesterase ( K i = 22.87 and 7.49 microM, respectively). The latter also showed moderate antiproliferative effects in chronic myeloid leukemia (K562) and breast cancer (MCF-7) cells. An aminomethyltriazole 5'-isonucleoside was the most potent molecule with low micromolar GI 50 values in both cells (GI 50 = 6.33 microM, 8.45 microM), similar to that of the drug 5-fluorouracil in MCF-7 cells. Moreover, the most bioactive compounds showed low toxicity in human fibroblasts, further indicating their interest as promising lead molecules.