Ten new beta-D-ribofuranosyl and 2'-beta-C-methyl-beta-D-ribofuranosyl triciribine derivatives 4-13 with various N4 and 6-N substituents on the tricyclic ring were synthesized from the corresponding toyocamycin and new 2'-beta-C-methyl toyocamycin derivatives. The inhibitory studies of these compounds in the HCV replicon assay reveal that some of them possess interesting anti-HCV properties with low cytotoxicity.
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http://dx.doi.org/10.1016/j.bmcl.2004.04.067 | DOI Listing |
J Am Chem Soc
August 2022
Alnylam Pharmaceuticals, 675 West Kendall, Cambridge, Massachusetts 02142, United States.
Although 2'-deoxy-2'-α-F-2'-β--methyl (2'-F/Me) uridine nucleoside derivatives are a successful class of antiviral drugs, this modification had not been studied in oligonucleotides. Herein, we demonstrate the facile synthesis of 2'-F/Me-modified pyrimidine phosphoramidites and their subsequent incorporation into oligonucleotides. Despite the C3'- preorganization of the parent nucleoside, a single incorporation into RNA or DNA resulted in significant thermal destabilization of a duplex due to unfavorable enthalpy, likely resulting from steric effects.
View Article and Find Full Text PDFBioorg Med Chem Lett
September 2017
IDENIX an MSD Company, Cap Gamma, 1682 rue de la Valsière, 34189 Montpellier Cedex 4, France.
Herein we describe the discovery of IDX21437 35b, a novel Rd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes.
View Article and Find Full Text PDFACS Med Chem Lett
June 2017
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, P. R. China.
A novel 2',3'-dideoxy-2'-α-fluoro-2'-β--methyl-6-methoxy guanosine () and its phosphoramidate prodrug () have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line.
View Article and Find Full Text PDFNucleosides Nucleotides Nucleic Acids
July 2015
a BK21 Project Team, College of Pharmacy , Chosun University, Kwangju , Republic of Korea.
Novel 4 'α-trifluoromethyl-2 'β-methyl carbocyclic nucleoside analogs have been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell cultures. Construction of cyclopentene intermediate 10a was achieved via sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis starting from the α-trifluoromethyl-α,β-unsaturated ester 5. Stereoselective dihydroxylation and desilylation yielded the target carbodine analogs.
View Article and Find Full Text PDFBioorg Med Chem Lett
June 2013
Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, GA 30033, USA.
The synthesis of new ribo and 2'-β-C-methyl ribo Janus type nucleosides J-AA, J-AG and J-AU is reported along with their ability to block HCV and HIV replication. Their toxicity was also assessed in Huh7, human lymphocytes, CEM and Vero cells.
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