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Eur J Med Chem ; 209: 112884, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-800277


A novel methodology to access alkynyl nucleoside analogues is elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their antiviral properties investigated in vitro. Regiochemistry of the functionalization was achieved with the aid of 5-endo-dig electrophilic halocyclization of acetyl 5-p-tolyl- or 5-p-pentylphenyl-2'-deoxyuridine. Structure of one of the resulting nucleosides, 6-p-tolyl-5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452-481 nm. High quantum yields of 0.53-0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, are potential tools for fluorescent tagging, studying nucleoside metabolism, 2'-deoxyribonucleoside kinase activity, and antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds posess antiviral activity (EC50 1.3-13.2 µM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p-pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p-pentylphenyl potency as a pharmacophore.

Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Fluorescence , Halogenation , Herpesvirus 3, Human/drug effects , Humans , Models, Molecular , Pyrimidine Nucleosides/chemical synthesis , Varicella Zoster Virus Infection/drug therapy , Varicella Zoster Virus Infection/virology
Med Chem ; 16(3): 368-384, 2020.
Article in English | MEDLINE | ID: covidwho-71681


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. METHODS: C5-arylalkynyl-ß-D-ribofuranonucleosides 3-6, 3΄-deoxy 12-15, 3΄-deoxy-3΄-C-methyl- ß-D-ribofurananucleosides 18-21 and 2΄-deoxy-ß-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.

Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Drug Design , Pyrimidine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antiviral Agents/chemistry , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , HeLa Cells , Humans , Mice , Pyrimidine Nucleosides/chemistry