5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential
<b>Background/Objectives:</b> 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 motiva...
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2025-05-01
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| author | Jennifer Szilagyi Tânia Moreira Rafael Santana Nunes Joana Silva Celso Alves Alice Martins Rebeca Alvariño Niels V. Heise René Csuk Nuno M. Xavier |
| author_facet | Jennifer Szilagyi Tânia Moreira Rafael Santana Nunes Joana Silva Celso Alves Alice Martins Rebeca Alvariño Niels V. Heise René Csuk Nuno M. Xavier |
| author_sort | Jennifer Szilagyi |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> 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′-<i>O</i>-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-<i>O</i>-benzyl xylofuranosyl unit. <b>Methods:</b> The synthetic methodology was based on the <i>N-</i>glycosylation of a 5-azido 3-<i>O</i>-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<sup>7</sup>/N<sup>9</sup>-linked purine nucleosides followed by guanidinylation with <i>N</i>,<i>N</i>′-bis(<i>tert</i>-butoxycarbonyl)-<i>N</i>′′-triflylguanidine. The molecules were evaluated for their anticancer and anti-neurodegenerative diseases potential. <b>Results:</b> 5′-Guanidino 6-chloropurine nucleosides revealed dual anticancer and butyrylcholinesterase (BChE)-inhibitory effects. Both N<sup>9</sup>/N<sup>7</sup>-linked nucleosides exhibited mixed-type and selective submicromolar/micromolar BChE inhibiton. The N<sup>9</sup> regioisomer was the best inhibitor (<i>K</i><sub>i</sub>/<i>K</i><sub>i</sub>′ = 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<sup>9</sup>-linked nucleoside exhibited selective cytotoxicity to prostate cancer cells (DU-145; IC<sub>50</sub> = 27.63 μM), while its N<sup>7</sup> regioisomer was active against all cancer cells tested [DU-145, IC<sub>50</sub> = 24.48 μM; colorectal adenocarcinoma (HCT-15, IC<sub>50</sub> = 64.07 μM); and breast adenocarcinoma (MCF-7, IC<sub>50</sub> = 43.67 μM)]. In turn, the 5′-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC<sub>50</sub> = 76.02 μM) and also showed neuroprotective potential in a Parkinson’s disease SH-SY5Y cells’ damage model. The active molecules exhibited IC<sub>50</sub> values close to or lower than those of standard drugs, and comparable, or not significant, neuro- and hepatotoxicity. <b>Conclusions</b>: These findings demonstrate the interest of combining guanidine moieties with nucleoside frameworks towards the search for new therapeutic agents. |
| format | Article |
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| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-3e03cc0e9c2140b4bcb0f15688aa25052025-08-20T03:47:58ZengMDPI AGPharmaceuticals1424-82472025-05-0118573410.3390/ph180507345′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological PotentialJennifer Szilagyi0Tânia Moreira1Rafael Santana Nunes2Joana Silva3Celso Alves4Alice Martins5Rebeca Alvariño6Niels V. Heise7René Csuk8Nuno M. Xavier9Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, PortugalCentro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, PortugalCentro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, PortugalMARE—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, PortugalMARE—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, PortugalMARE—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, PortugalDepartamento de Fisiología, Facultade de Veterinaria, IDIS, Universidade de Santiago de Compostela, 27002 Lugo, SpainBereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), GermanyBereich Organische Chemie, Martin-Luther-Universität Halle-Wittenberg, Kurt-Mothes-Str. 2, D-06120 Halle (Saale), GermanyCentro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal<b>Background/Objectives:</b> 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′-<i>O</i>-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-<i>O</i>-benzyl xylofuranosyl unit. <b>Methods:</b> The synthetic methodology was based on the <i>N-</i>glycosylation of a 5-azido 3-<i>O</i>-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<sup>7</sup>/N<sup>9</sup>-linked purine nucleosides followed by guanidinylation with <i>N</i>,<i>N</i>′-bis(<i>tert</i>-butoxycarbonyl)-<i>N</i>′′-triflylguanidine. The molecules were evaluated for their anticancer and anti-neurodegenerative diseases potential. <b>Results:</b> 5′-Guanidino 6-chloropurine nucleosides revealed dual anticancer and butyrylcholinesterase (BChE)-inhibitory effects. Both N<sup>9</sup>/N<sup>7</sup>-linked nucleosides exhibited mixed-type and selective submicromolar/micromolar BChE inhibiton. The N<sup>9</sup> regioisomer was the best inhibitor (<i>K</i><sub>i</sub>/<i>K</i><sub>i</sub>′ = 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<sup>9</sup>-linked nucleoside exhibited selective cytotoxicity to prostate cancer cells (DU-145; IC<sub>50</sub> = 27.63 μM), while its N<sup>7</sup> regioisomer was active against all cancer cells tested [DU-145, IC<sub>50</sub> = 24.48 μM; colorectal adenocarcinoma (HCT-15, IC<sub>50</sub> = 64.07 μM); and breast adenocarcinoma (MCF-7, IC<sub>50</sub> = 43.67 μM)]. In turn, the 5′-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC<sub>50</sub> = 76.02 μM) and also showed neuroprotective potential in a Parkinson’s disease SH-SY5Y cells’ damage model. The active molecules exhibited IC<sub>50</sub> values close to or lower than those of standard drugs, and comparable, or not significant, neuro- and hepatotoxicity. <b>Conclusions</b>: These findings demonstrate the interest of combining guanidine moieties with nucleoside frameworks towards the search for new therapeutic agents.https://www.mdpi.com/1424-8247/18/5/734nucleos(t)ide analogsanticancer agentscholinesterase inhibitorsneuroprotective compoundsguanidine moietyN-glycosylatiom |
| spellingShingle | Jennifer Szilagyi Tânia Moreira Rafael Santana Nunes Joana Silva Celso Alves Alice Martins Rebeca Alvariño Niels V. Heise René Csuk Nuno M. Xavier 5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential Pharmaceuticals nucleos(t)ide analogs anticancer agents cholinesterase inhibitors neuroprotective compounds guanidine moiety N-glycosylatiom |
| title | 5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential |
| title_full | 5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential |
| title_fullStr | 5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential |
| title_full_unstemmed | 5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential |
| title_short | 5′-Guanidino Xylofuranosyl Nucleosides as Novel Types of 5′-Functionalized Nucleosides with Biological Potential |
| title_sort | 5 guanidino xylofuranosyl nucleosides as novel types of 5 functionalized nucleosides with biological potential |
| topic | nucleos(t)ide analogs anticancer agents cholinesterase inhibitors neuroprotective compounds guanidine moiety N-glycosylatiom |
| url | https://www.mdpi.com/1424-8247/18/5/734 |
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