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Design, Synthesis, and Biological Evaluation of Novel C5-Modified Pyrimidine Ribofuranonucleosides as Potential Antitumor or/and Antiviral Agents

Author(s):

Nikolaos Kollatos, Christos Mitsos, Stella Manta, Niki Tzioumaki, Christos Giannakas, Tania Alexouli, Aggeliki Panagiotopoulou, Dominique Schols, Graciela Andrei and Dimitri Komioti*   Pages 1 - 17 ( 17 )

Abstract:


Background: Nucleoside analogues are well-known antitumor, antiviral, and chemotherapeutic agents. Alterations on both their sugar and the heterocyclic parts may lead to significant changes in the spectrum of their biological activity and the degree of selective toxicity, as well as in their physicochemical properties.

Method: C5-arylalkynyl-β-D-ribofuranonucleosides 3-6, 3΄-deoxy 12-15, 3΄-deoxy-3΄-C-methyl- β-D-ribofurananucleosides 18-21 and 2΄-deoxy-β-D-ribofuranonucleosides 23-26 of uracil, were synthesized using a one-step Sonogashira reaction under microwave irradiation and subsequent deprotection.

Results: All newly synthesized nucleosides were tested for their antitumor or antiviral activity. Moderate cytostatic activity against cervix carcinoma (HeLa), murine leukemia (L1210) and human lymphocyte (CEM) tumor cell lines was displayed by the protected 3΄-deoxy derivatives 12b, 12c, 12d, and the 3΄-deoxy-3΄-methyl 18a, 18b, 18c. The antiviral evaluation revealed appreciable activity against Coxsackie virus B4, Respiratory syncytial virus, Yellow Fever Virus and Human Coronavirus (229E) for the 3΄-deoxy compounds 12b, 14, and the 3΄-deoxy-3΄-methyl 18a, 18c, 18d, accompanied by low cytotoxicity.

Conclusion: This report describes the total and facile synthesis of modified furanononucleosides of uracil, with alterations on both the sugar and the heterocyclic portions. Compounds 12b, 14 and 18a,c,d showed noticeable antiviral activity against a series of RNA viruses and merit further biological and structural optimization investigations.

Keywords:

Sonogashira reaction, C5-pyrimidine ribofurano nucleosides, microwave irradiation, cytotoxic activity, antiviral activity.

Affiliation:

Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa, Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa, Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa, Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa, Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa, Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa, Institute of Biosciences and Applications National Centre for Scientific Research “Demokritos”, Athens, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Department of Biochemistry and Biotechnology, Laboratory of Bioorganic Chemistry, University of Thessaly, Larissa



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