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

Abstract

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.