60599-10-2Relevant academic research and scientific papers
Synthesis and evaluation of 2′-dihalo ribonucleotide prodrugs with activity against hepatitis C virus
Chris Krueger,Chen, Hui-Ju,Randolph, John T.,Brown, Brian S.,Halvorsen, Geoff T.,Heyman, Howard R.,Li, Tongmei,Marvin, Christopher C.,Shanley, Jason P.,Voight, Eric A.,Bow, Daniel A.J.,Van Handel, Cecilia,Peterkin, Vincent,Carr, Robert A.,Stolarik, DeAnne,Dekhtyar, Tatyana,Irvin, Michelle L.,Krishnan, Preethi,Henry, Rodger F.,Wagner, Rolf,DeGoey, David A.
supporting information, (2019/11/26)
[Figure presented] Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2′-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2′-deoxy-2′-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.
Synthesis of isotopically labeled D-[1′-13C]ribonucleoside phosphoramidites
Saito, Yoshio,Nyilas, Agnes,Agrofoglio, Luigi A.
, p. 83 - 90 (2007/10/03)
The preparation of fully protected labeled diisopropylamino-β-cyanoethyl-[1′-13C]ribonucleoside phosphoramidites with regioisomeric purity is described. We demonstrated in this paper that a regioselective 2′-O-silylation, through a 3′,5′-O-di-tert-butylsilanediyl protection, has been applied for the synthesis of [1′-13C]ribonucleoside phosphoramidite units. This method allowed us to obtain only the desired 2′-O-silyl-3′-O-phosphoramidites avoiding the undesired 3′-O-silyl-2′-O-phosphoramidite nucleosides isolated by standard procedures. This is a suitable procedure to RNA precursors with respect to the isotope-containing precursors.
Synthesis and antiviral activity of oxaselenolane nucleosides
Chu,Ma,Olgen,Pierra,Du,Gumina,Gullen,Cheng,Schinazi
, p. 3906 - 3912 (2007/10/03)
As dioxolane and oxathiolane nucleosides have exhibited promising antiviral and anticancer activities, it was of interest to synthesize isoelectronically substituted oxaselenolane nucleosides, in which the 3'-CH2 is replaced by a selenium atom. To study structure-activity relationships, various pyrimidine and purine oxaselenolane nucleosides were synthesized from the key intermediate, (±)-2-benzoyloxymethyl-1,2-oxaselenolane 5-acetate (6). Among the synthesized racemic nucleosides, cytosine and 5-fluorocytosine analogues exhibited potent anti-HIV and anti-HBV activities. It was of interest to obtain the enantiomerically pure isomers to determine if they have differential antiviral activities. However, due to the difficult and time-consuming nature of enantiomeric synthesis, a chiral HPLC separation was performed to obtain optical isomers from the corresponding racemic mixtures. Each pair of enantiomers of Se-ddC and Se-FddC was separated by an amylose chiral column using a mobile phase of 100% 2-propanol. The results indicate that most of the anti-HIV activity of both cytosine and fluorocytosine nucleosides resides with the (-)-isomers.
