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5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential

Affiliation
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal;(J.S.);(T.M.);(R.S.N.)
Szilagyi, Jennifer;
Affiliation
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal;(J.S.);(T.M.);(R.S.N.)
Moreira, Tânia;
ORCID
0000-0002-9014-0570
Affiliation
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal;(J.S.);(T.M.);(R.S.N.)
Nunes, Rafael Santana;
ORCID
0000-0003-1224-1699
Affiliation
MARE—Marine and Environmental Sciences Centre & ARNET—Aquatic Research Network Associated Laboratory, ESTM, Polytechnic University of Leiria, Av. Porto de Pesca, Edifício Cetemares, 1749-016 Lisboa, Portugal;(J.S.);(C.A.);(A.M.)
Silva, Joana;
ORCID
0000-0003-1581-2127
Affiliation
MARE—Marine and Environmental Sciences Centre & ARNET—Aquatic Research Network Associated Laboratory, ESTM, Polytechnic University of Leiria, Av. Porto de Pesca, Edifício Cetemares, 1749-016 Lisboa, Portugal;(J.S.);(C.A.);(A.M.)
Alves, Celso;
Affiliation
MARE—Marine and Environmental Sciences Centre & ARNET—Aquatic Research Network Associated Laboratory, ESTM, Polytechnic University of Leiria, Av. Porto de Pesca, Edifício Cetemares, 1749-016 Lisboa, Portugal;(J.S.);(C.A.);(A.M.)
Martins, Alice;
ORCID
0000-0001-8796-1389
Affiliation
Departamento de Fisiología, Facultade de Veterinaria, IDIS, Universidade de Santiago de Compostela, 27002 Lugo, Spain;
Alvariño, Rebeca;
ORCID
0000-0002-6540-6357
Affiliation
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany;(N.V.H.);(R.C.)
Heise, Niels V.;
ORCID
0000-0001-7911-290X
Affiliation
Bereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany;(N.V.H.);(R.C.)
Csuk, René;
ORCID
0000-0001-8739-8768
Affiliation
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal;(J.S.);(T.M.);(R.S.N.)
Xavier, Nuno M.

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 N 7 /N 9 -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 N 9 /N 7 -linked nucleosides exhibited mixed-type and selective submicromolar/micromolar BChE inhibiton. The N 9 regioisomer was the best inhibitor ( K i / K i ′ = 0.89 μM/2.96 μM), while showing low cytotoxicity to FL83B hepatocytes and no cytotoxicity to human neuroblastoma cells (SH-SY5Y). Moreover, the N 9 -linked nucleoside exhibited selective cytotoxicity to prostate cancer cells (DU-145; IC 50 = 27.63 μM), while its N 7 regioisomer was active against all cancer cells tested [DU-145, IC 50 = 24.48 μM; colorectal adenocarcinoma (HCT-15, IC 50 = 64.07 μM); and breast adenocarcinoma (MCF-7, IC 50 = 43.67 μM)]. In turn, the 5′-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC 50 = 76.02 μM) and also showed neuroprotective potential in a Parkinson’s disease SH-SY5Y cells’ damage model. The active molecules exhibited IC 50 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.

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