Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

29 June 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


The synthesis of novel guanidino sugars as potential mimetics of nucleosides and their biological evaluation is described. 5-Guanidino xylofuranoses containing different O-substituents at C-3, including saturated/unsaturated hydrocarbon chains and aromatic-containing moieties, were accessed from 5-azido xylofuranose precursors through reduction followed by guanidinylation of the obtained amines with N,N′-bis(tert-butoxycarbonyl)-N′′-triflylguanidine. A 5-azido 3-O-methyl-branched N-benzyltriazole isonucleoside was converted into the corresponding 5-guanidino-containing isonucleoside, whose structure includes both the guanidine and triazole moieties as nucleobase-like motifs connected to the xylofuranose template. In alternative, this structurally new type of compound was synthesized via cycloaddition between a 5-guanidino-3-O-propargyl xylofuranose derivative and benzyl azide in the presence of a CuI/Amberlyst A-21 catalytic system, along with the 5-iodotriazole derivative as a secondary product, which, in turn was the sole product when using equimolar CuI and a catalytic amount of 4-dimethylaminopyridine. A guanidinomethyltriazole 3′-O-dodecyl xylofuranos-5′-yl isonucleoside, which comprise a novel isonucleosidic framework having a guanidine system appended on the sugar-linked triazole motif, was obtained from the related aminomethyltriazole 5’-isonucleoside via guanidinylation. Bioactivity screening revealed 2 compounds as selective inhibitors of acetylcholinesterase (AChE), namely the guanidinomethyltriazole derivative, with moderate inhibition (Ki = 22.87 µM) and the 3-O-dodecyl (N-Boc)guanidino xylofuranose, which was the most active compound (Ki = 7.49 µM) acting as a non-competitive inhibitor. The latter also displayed moderate antiproliferative effects in chronic myeloid leukemia (K562, GI50 =31.02 μM) and in breast cancer (MCF-7, GI50 = 26.89 μM) cells. The aminomethyltriazole 5’-isonucleoside was the most potent molecule with single-digit micromolar GI50 values against both cells (GI50 = 6.33 μM and 8.45 μM), similar to that of the standard drug 5-fluorouracil against MCF-7 cells.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.