Furanosyl Nucleoside Analogues Embodying Triazole or Theobromine Units as Potential Lead Molecules for Alzheimer's Disease. Issue 20 (17th May 2018)

• Record Type: Journal Article
• Authors: Gonçalves‐Pereira, Rita; Pereira, Margarida P.; Serra, Sofia G.; Loesche, Anne; Csuk, René; Silvestre, Samuel; Costa, Paulo J.; Oliveira, M. Conceição; Xavier, Nuno M.
• Is Part Of: European journal of organic chemistry. Issue 20/21(2018)
• Page Start: 2667
• Page End: 2681
• Publication Date: 2018-05-17
• Subjects: Nucleosides -- Carbohydrates -- Cycloaddition -- Biological activity -- Medicinal chemistry; Chemistry, Organic -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Bioorganic chemistry -- Periodicals; Chemistry, Physical organic -- Periodicals; 547
• DOI: 10.1002/ejoc.201800245
• Languages: English
• ISSNs: 1434-193X

Abstract

Abstract : The synthesis of novel types of furanosyl nucleoside analogues, namely N ‐(benzyltriazolyl)methyl glucuronamide derivatives, N ‐dodecyl glucuronamide‐based phenyltriazole nucleosides, and theobromine xylosyl 5′‐isonucleosides, as potential cholinesterase inhibitors is described herein. O ‐Substituted and partially O ‐substituted N ‐propargyl glucuronamides, accessed from glucofuranurono‐6, 3‐lactone, were engaged in Cu I ‐catalyzed cycloaddition with benzyl azide, whereas their N ‐dodecyl uronamide counterparts were converted in three steps into glycosyl azides, which were subjected to cycloaddition with phenylacetylene. A xylofuranose derivative having a free 5‐OH group was coupled with theobromine by Mitsunobu reaction and the obtained isonucleoside was functionalized at C‐1′ with a sulfonamide moiety, leading to a prospective nucleotide mimetic. Five compounds displayed selective inhibition of acetylcholinesterase in the micromolar concentration range, with an α‐glycosyl triazole ( K i = 3.53 µm) and its 1‐azido‐uronamide precursor ( K i = 1.73 µm) being the most active. Docking studies were performed to give insights into the different inhibitory behavior within glycosyl azide anomers. Two of the best inhibitors showed low toxicity in both a neural cell line and human fibroblasts, rendering them promising lead compounds and supporting further investigations. Abstract : The synthesis of glucuronamide‐based triazole nucleoside analogues and theobromine xylosyl 5′‐isonucleosides is reported. Key synthetic steps include alkyne–azide cycloaddition, MW‐assisted anomeric azidation, Mitsunobu reaction and N ‐glycosylation. Some of these novel molecules display potent and selective inhibition of acetylcholinesterase and low toxicity in both neuronal cells and human fibroblasts.