Biomaterial Database

Synthesis and anti-viral activity of a series of d- and l-2'-deoxy-2'-fluororibonucleosides in the subgenomic HCV replicon system. 2005

Junxing Shi, and Jinfa Du, and Tianwei Ma, and Krzysztof W Pankiewicz, and Steven E Patterson, and Phillip M Tharnish, and Tamara R McBrayer, and Lieven J Stuyver, and Michael J Otto, and Chung K Chu, and Raymond F Schinazi, and Kyoichi A Watanabe

Pharmasset, Inc., 1860 Montreal Rd., Tucker, GA 30084, USA. jshi@pharmasset.com

Based on the discovery of (2'R)-d-2'-deoxy-2'-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of d- and l-2'-deoxy-2'-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2'-fluoro group, was achieved by either fluorination of 2,2'-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2'R)-d-2'-deoxy-2',5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N(4)-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N(4)-hydroxyl and the 2'-fluoro into one molecule, resulting (2'R)-d-2'-deoxy-2'-fluoro-N(4)-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the l-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity.

UI	MeSH Term	Description	Entries
D009682	Magnetic Resonance Spectroscopy	Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING).	In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D012093	Replicon	Any DNA sequence capable of independent replication or a molecule that possesses a REPLICATION ORIGIN and which is therefore potentially capable of being replicated in a suitable cell. (Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)	Replication Unit,Replication Units,Replicons,Unit, Replication,Units, Replication
D002417	Cattle	Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.	Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
D003853	Deoxyribonucleosides	A purine or pyrimidine base bonded to DEOXYRIBOSE.
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000998	Antiviral Agents	Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.	Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D016174	Hepacivirus	A genus of FLAVIVIRIDAE causing parenterally-transmitted HEPATITIS C which is associated with transfusions and drug abuse. Hepatitis C virus is the type species.	Hepatitis C virus,Hepatitis C-Like Viruses,Hepaciviruses,Hepatitis C Like Viruses,Hepatitis C viruses,Hepatitis C-Like Virus
D016339	Spectrometry, Mass, Fast Atom Bombardment	A mass spectrometric technique that is used for the analysis of a wide range of biomolecules, such as glycoalkaloids, glycoproteins, polysaccharides, and peptides. Positive and negative fast atom bombardment spectra are recorded on a mass spectrometer fitted with an atom gun with xenon as the customary beam. The mass spectra obtained contain molecular weight recognition as well as sequence information.	Fast Atom Bombardment Mass Spectrometry,Fast Atom Bombardment Mass Spectroscopy,Mass Spectrometry, Fast Atom Bombardment,Mass Spectroscopy, Fast Atom Bombardment,Spectroscopy, Mass, Fast Atom Bombardment
D016679	Genome, Viral	The complete genetic complement contained in a DNA or RNA molecule in a virus.	Viral Genome,Genomes, Viral,Viral Genomes