{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T02:55:55Z","timestamp":1788576955323,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T00:00:00Z","timestamp":1676505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"5RO1-MH-116695","award":["5P30-AI-50409"],"award-info":[{"award-number":["5P30-AI-50409"]}]},{"name":"Emory\u2019s WSC 2020 Covid-19 (CURE Award)","award":["5P30-AI-50409"],"award-info":[{"award-number":["5P30-AI-50409"]}]},{"name":"WSC 2020 Covid-19 (CURE Award)","award":["5P30-AI-50409"],"award-info":[{"award-number":["5P30-AI-50409"]}]},{"name":"NIH","award":["5P30-AI-50409"],"award-info":[{"award-number":["5P30-AI-50409"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Over the past decades, both 4\u2032-modified nucleoside and carbocyclic nucleoside analogs have been under the spotlight as several compounds from either family showed anti-HIV, HCV, RSV or SARS-CoV-2 activity. Herein, we designed compounds combining these two features and report the synthesis of a series of novel 4\u2032-substituted carbocyclic uracil derivatives along with their corresponding monophosphate prodrugs. These compounds were successfully prepared in 19 to 22 steps from the commercially available (-)-Vince lactam and were evaluated against a panel of RNA viruses including SARS-CoV-2, influenza A\/B viruses and norovirus.<\/jats:p>","DOI":"10.3390\/v15020544","type":"journal-article","created":{"date-parts":[[2023,2,16]],"date-time":"2023-02-16T02:28:27Z","timestamp":1676514507000},"page":"544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synthesis of 4\u2032-Substituted Carbocyclic Uracil Derivatives and Their Monophosphate Prodrugs as Potential Antiviral Agents"],"prefix":"10.3390","volume":"15","author":[{"given":"Nicolas","family":"Biteau","sequence":"first","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Amichai","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niloufar","family":"Azadi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramyani","family":"De","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7472-033X","authenticated-orcid":false,"given":"Jessica","family":"Downs-Bowen","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0056-176X","authenticated-orcid":false,"given":"Julia","family":"Lecher","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"MacBrayer","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-3614","authenticated-orcid":false,"given":"Raymond","family":"Schinazi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Amblard","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine, and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.antiviral.2018.04.004","article-title":"The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold","volume":"154","author":"Yates","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113233","DOI":"10.1016\/j.ejmech.2021.113233","article-title":"Advance of structural modification of nucleosides scaffold","volume":"214","author":"Lin","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9291","DOI":"10.1039\/C4OB01449A","article-title":"A review of methods to synthesise 4\u2032-substituted nucleosides","volume":"12","author":"Betson","year":"2014","journal-title":"Org. Biomol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.1016\/j.bmcl.2007.02.004","article-title":"Design, synthesis, and antiviral properties of 4\u2032-substituted ribonucleosides as inhibitors of hepatitis C virus replication: The discovery of R1479. Bioorg","volume":"17","author":"Smith","year":"2007","journal-title":"Med. Chem. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.antiviral.2013.11.008","article-title":"Chutes and ladders in hepatitis C nucleoside drug development","volume":"102","author":"Coats","year":"2014","journal-title":"Antivir. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1021\/jm5017279","article-title":"Discovery of 4\u2032-chloromethyl-2\u2032-deoxy-3\u2032,5\u2032-di-O-isobutyryl-2\u2032-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection","volume":"58","author":"Wang","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1093\/jac\/dky415","article-title":"Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans","volume":"74","author":"Patel","year":"2019","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1097\/COH.0000000000000467","article-title":"4\u2032-Ethynyl-2-fluoro-2\u2032-deoxyadenosine, MK-8591: A novel HIV-1 reverse transcriptase translocation inhibitor","volume":"4","author":"Markowitz","year":"2018","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tips.2021.10.004","article-title":"Update and latest advances in antiretroviral therapy","volume":"43","author":"Delgad","year":"2022","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1097\/COH.0000000000000740","article-title":"Role of islatravir in HIV treatment and prevention: An update","volume":"17","author":"Derbalah","year":"2022","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_11","first-page":"706","article-title":"Islatravir implant as HIV-1 pre-exposure treatment","volume":"18","author":"Masone","year":"2021","journal-title":"Nat. Rev. Urol."},{"key":"ref_12","unstructured":"Painter, G.R., Perryman, D., and Bluemling, G.R. (2019). Preparation of 4\u2032-halogen containing nucleotide and nucleoside therapeutics and uses related thereto. (WO2019173602 A1)."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1126\/science.abj5508","article-title":"4\u2032-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication","volume":"375","author":"Sourimant","year":"2022","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7067","DOI":"10.1016\/j.tet.2005.04.040","article-title":"Metathesis strategy in nucleoside chemistry","volume":"61","author":"Amblard","year":"2005","journal-title":"Tetrahedron"},{"key":"ref_15","first-page":"1809","article-title":"Recent progress for the synthesis of selected carbocyclic nucleosides","volume":"13","author":"Chevrier","year":"2015","journal-title":"Fut. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e202100307","DOI":"10.1002\/tcr.202100307","article-title":"Chemical approaches to carbocyclic nucleosides","volume":"22","author":"Roy","year":"2022","journal-title":"Chem. Rec."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5056","DOI":"10.1039\/c3cs00003f","article-title":"Advances in the enantioselective synthesis of carbocyclic nucleosides","volume":"42","author":"Boutureira","year":"2013","journal-title":"Chem. Soc. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3304","DOI":"10.1016\/j.tetasy.2006.12.007","article-title":"Enantiomeric synthesis of carbocyclic D-4\u2032-C-methylribonucleosides as potential antiviral agents","volume":"17","author":"Liu","year":"2006","journal-title":"Tet. Asymm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9218","DOI":"10.1021\/acs.jmedchem.8b00141","article-title":"Synthesis and antiviral evaluation of carbocyclic nucleoside analogs of nucleoside reverse transcriptase translocation inhibitor MK-8591 (4\u2032-ethynyl-2-fluoro-2\u2032-deoxyadenosine)","volume":"61","author":"Alexandre","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e01652-20","DOI":"10.1128\/AAC.01652-20","article-title":"Repurposing nucleoside analogs for human coronaviruses","volume":"6","author":"Zandi","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3851\/IMP2229","article-title":"Antiviral activity of nucleoside analogues against norovirus","volume":"17","author":"Costantini","year":"2012","journal-title":"Antivir. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1021\/acs.biochem.8b01063","article-title":"Structural and antiviral studies of the human norovirus GII.4 protease","volume":"58","author":"Muzzarelli","year":"2019","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"126639","DOI":"10.1016\/j.bmcl.2019.126639","article-title":"Novel influenza polymerase PB2 inhibitors for the treatment of influenza A infection","volume":"29","author":"Zhang","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1021\/acs.jmedchem.8b01300","article-title":"Discovery of a series of 2\u2032-\u03b1-fluoro,2\u2032-\u03b2-bromo-ribonucleosides and their phosphoramidate prodrugs as potent pan-genotypic inhibitors of hepatitis C virus","volume":"62","author":"Mengshetti","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1080\/15257770.2012.658131","article-title":"A 2\u2032-deoxy-2\u2032-fluoro-2\u2032-C-methyl uridine cyclopentyl carbocyclic analog and its phosphoramidate prodrug as inhibitors of HCV NS5B polymerase","volume":"31","author":"Liu","year":"2012","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1016\/j.tet.2015.05.084","article-title":"Construction of a chiral quaternary carbon center by a radical cyclization\/ring-enlargement reaction: Synthesis of 4\u03b1-azidoethyl carbocyclic ribose, a key unit for the synthesis of cyclic ADP-ribose derivatives of biological importance","volume":"71","author":"Sato","year":"2015","journal-title":"Tetrahedron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1021\/acs.orglett.1c03936","article-title":"RNAs containing carbocyclic ribonucleotides","volume":"24","author":"Chickering","year":"2022","journal-title":"Org. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9154","DOI":"10.1021\/cr5002035","article-title":"Synthesis of nucleoside phosphate and phosphonate prodrugs","volume":"114","author":"Pradere","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8311","DOI":"10.1021\/jo201492m","article-title":"Synthesis of diastereomerically pure nucleotide phosphoramidates","volume":"76","author":"Ross","year":"2011","journal-title":"J. Org. Chem."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/544\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:37:19Z","timestamp":1760121439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/544"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,16]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["v15020544"],"URL":"https:\/\/doi.org\/10.3390\/v15020544","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,16]]}}}