2′-Fluorosugar analogues of the highly potent anti-varicella-zoster virus bicyclic nucleoside analogue (BCNA) Cf 1743

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 22, 2009, Pages 6264-6267

  McGuigan, Christopher ^a   Derudas, Marco ^a   Quintiliani, Maurizio ^a   Andrei, Graciela ^b   Snoeck, Robert ^b   Henson, Geoffrey ^c   Balzarini, Jan ^b  

^a CARDIFF UNIVERSITY   (United Kingdom)

^b REGA INSTITUTE FOR MEDICAL RESEARCH   (Belgium)

^c Inhibitex   (United States)

Author keywords

BCNAs; Cf 1743; Fluorosugars; Herpes; Nucleosides; Shingles; Thymidine kinase; VZV; Zoster

Indexed keywords

ANTIVIRUS AGENT; CARBOHYDRATE DERIVATIVE; CF 1743; NUCLEOSIDE ANALOG; THYMIDINE KINASE; UNCLASSIFIED DRUG; BICYCLO COMPOUND; BROXURIDINE; FLUORIDE; NUCLEOSIDE; PYRIMIDINE NUCLEOSIDE;

ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; EMBRYO; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; VARICELLA ZOSTER VIRUS; CELL LINE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; DRUG EFFECT; DRUG INTERACTION; ENZYME SPECIFICITY; HELA CELL; METABOLISM; MICROBIOLOGICAL EXAMINATION; PHYSIOLOGY; STRUCTURE ACTIVITY RELATION; VIRUS REPLICATION;

HERPES; HUMAN HERPESVIRUS 3;

ANTIVIRAL AGENTS; BICYCLO COMPOUNDS; BROMODEOXYURIDINE; CELL LINE; DRUG DESIGN; DRUG INTERACTIONS; FLUORIDES; HELA CELLS; HERPESVIRUS 3, HUMAN; HUMANS; MICROBIAL SENSITIVITY TESTS; MODELS, MOLECULAR; NUCLEOSIDES; PYRIMIDINE NUCLEOSIDES; STRUCTURE-ACTIVITY RELATIONSHIP; SUBSTRATE SPECIFICITY; THYMIDINE KINASE; VIRUS REPLICATION;

EID: 71249091875     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.09.116     Document Type: Article

References (13)

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10. 3J = 8.20), 7.23 (1H, s, H-5), 6.35 (1H, d, J = 6.50, H-1′), 6.33-6.30 (1H, m, 3′-OH), 5.43 (1H, t, J = 5.30, 5′-OH), 4.36-4.18 (1H, m, H-3′), 3.99-3.95 (1H, m, H-4′), 3.91-3.85 (1H, m, H-5′), 3.75-3.69 (1H, m, H-5′), 2.63 (2H, t, J = 7.6 α-CH
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12. 4 (Acros, New Yersey, USA) 50 mM + heptanesulfonic acid 5 mM pH 3.2 (buffer) (Sigma, St. Louis, MO) and 2% acetonitrile (ACN) (Biosolve, Valkenswaard, The Netherlands); 6 min linear gradient to 80% buffer and 20% ACN; 2 min linear gradient to 75% buffer and 25% ACN; 10 min linear gradient to 65% buffer and 35% ACN; 10 min linear gradient to 50% buffer and 50% ACN; 10 min isocratic flow; 5 min linear gradient to 98% buffer and 2% ACN; 5 min equilibration at the same conditions. Metabolites of the BCNAs were determined by fluorescence detection (excitation at 340 nm and emission at 415 nm). Retention times of BCNA nucleoside and 5′-monophosphate derivatives were as follows: 1 (Cf 1743): 30.2 and 22.0 min; 9 (Cf 2852): 31.8 and 24.0 min; 10 (Cf 2792): 31.3 and 22.7 min; 11 (Cf 2819): 32.8 and 24.5 min, respectively.
13. Procedure of the anti-VZV experiments in HEL cell cultures. The laboratory wild-type VZV strain OKA and the thymidine kinase-deficient VZV strain 07/1 were used. The OKA strain was supplied by Dr. M. Takahashi, Osaka University, Osaka, Japan. The YS strain was isolated from vesicular fluid of a patient with varicella and the TK-deficient 07/1 strain was isolated alter exposure of BVaraU to VZV (YS)-infected cell cultures (Sakuma, Antimicrob. Agents Chemother. 1984, 25, 742). Confluent HEL cell cultures grown in 96-well microtiter plates were inoculated with VZV at an input of 20 PFU per well. After a 2-h incubation period, residual virus was removed and varying concentrations of the test compounds were added (in duplicate). Antiviral activity was expressed as the 50%-effective concentration required to reduce viral plaque formation after 5 days by 50% as compared with untreated controls. Cytotoxicity was expressed as the minimum cytotoxic concentration (MCC) or the compound concentration that causes a microscopically detectable alteration of cell morphology.