5'-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5'-Functionalized Nucleosides with Therapeutic Potential

The synthesis and biological evaluation of 5′-guanidino furanosyl nucleosides comprising 6-chloropurine and uracil moieties and a 3-O-benzyl xylofuranosyl unit is presented. Their access was based on the N-glycosylation of a 5-azido 3-O-benzyl xylofuranosyl acetate donor with the silylated nucleobase and a subsequent one-pot sequential two-step protocol involving Staudinger reduction of the thus obtained 5-azido uracil and N7/N9-linked purine nucleosides followed by guanidinylation with N,N’-bis(tert-butoxycarbonyl)-N’’-triflylguanidine. Bioactivity screening revealed the significant activities exhibited among the synthesized compounds, namely abilities to inhibit butyrylcholinesterase (BChE), a therapeutic target for the symptomatic treatment of latter stages of Alzheimer’s disease, cytotoxic activities against cancer cells, and/or neuroprotective effects. 5′-Guanidino 6-chloropurine nucleosides were shown to act as mixed-type and selective submicromolar or micromolar BChE inhibitors, from which the N9 nucleoside was the most prominent compound with inhibition constants Ki / Ki' of 0.89 μM / 2.96 μM, besides showing low cytotoxicity to FL83B hepatocytes and no significant cytotoxicity to human neuroblastoma cells (SH-SY5Y). Moreover, the N9-linked nucleoside exhibited selective cytotoxic activity to prostate cancer cells (DU-145, IC50 = 27.63 μM), while its N7 regioisomer was active against all cancer cells tested [DU-145, IC50 = 24.48 μM; colorectal adenocarcinoma (HCT-15, IC50 = 64.07 μM); and breast adenocarcinoma (MCF-7, IC50 = 43.67 μM)]. In turn, the 5'-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC50 = 76.02 μM) and showed also neuroprotective potential in a Parkinson’s disease SH-SY5Y cells’ damage model. The active molecules exhibited IC50 values to the affected cancer cells close or lower than those of standard drugs, and comparable or not significant neuro- and hepatotoxicity.