Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives. (31st May 2022)

• Record Type: Journal Article
• Authors: Fortuna, Andreia; Gonçalves‐Pereira, Rita; Costa, Paulo J.; Jorda, Radek; Vojáčková, Veronika; Gonzalez, Gabriel; Heise, Niels V.; Csuk, René; Oliveira, M. Conceição; Xavier, Nuno M.
• Is Part Of: ChemMedChem. Volume 17:Number 14(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-31
• Subjects: guanidino sugars -- nucleoside analogs -- guanidinylation -- antiproliferative activity -- cholinesterase inhibitors; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200180
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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 μM, 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 GI50 values in both cells (GI50 =6.33 μM, 8.45 μM), 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. Abstract : Promising leads : The synthesis and biological evaluation of novel guanidino sugars as nucleoside analogs, including 3‐ O ‐substituted guanidino xylofuranoses, a 3‐ O ‐methyl‐branched N ‐benzyltriazole isonucleoside and a guanidinomethyltriazole 5′‐isonucleoside, is described. Two compounds were demonstrated to inhibit selectively acetylcholinesterase or to display antiproliferative effects in K562 and MCF‐7 cells with single‐digit micromolar K i or GI50 values.