5′-guanidino xylofuranosyl nucleosides as novel types of 5′-functionalized nucleosides with biological potential

Abstract

Background/Objectives: While various nucleoside and nucleotide analogs have been approved as anticancer and antiviral drugs, their limitations, including low bioavailability and chemotherapeutic resistance, encourage the development of novel structures. In this context, and motivated by our previous findings on bioactive 3′-O-substituted xylofuranosyl nucleosides and 5-guanidine xylofuranose derivatives, we present herein the synthesis and biological evaluation of 5′-guanidino furanosyl nucleosides comprising 6-chloropurine and uracil moieties and a 3-O-benzyl xylofuranosyl unit. Methods: The synthetic methodology 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. The molecules were evaluated for their anticancer and anti-neurodegenerative diseases potential. Results: 5′-Guanidino 6-chloropurine nucleosides revealed dual anticancer and butyrylcholinesterase (BChE)-inhibitory effects. Both N9/N7-linked nucleosides exhibited mixed-type and selective submicromolar/micromolar BChE inhibiton. The N9 regioisomer was the best inhibitor (Ki/Ki′ = 0.89 μM/2.96 μM), while showing low cytotoxicity to FL83B hepatocytes and no cytotoxicity to human neuroblastoma cells (SH-SY5Y). Moreover, the N9-linked nucleoside exhibited selective cytotoxicity 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 also showed neuroprotective potential in a Parkinson’s disease SH-SY5Y cells’ damage model. The active molecules exhibited IC50 values close to or lower than those of standard drugs, and comparable, or not significant, neuro- and hepatotoxicity. Conclusions: These findings demonstrate the interest of combining guanidine moieties with nucleoside frameworks towards the search for new therapeutic agents.