From norbornane-based nucleotide analogs locked in South conformation to novel inhibitors of feline herpes virus |
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| Affiliation: | 1. Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, 166 10 Prague 6, Czech Republic;2. Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;1. I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, 620990 Ekaterinburg, Russian Federation;2. Institute of Chemical Engineering, Ural Federal University, 620002 Ekaterinburg, Russian Federation;3. National Medical Research Center for Phthisiopulmonology and Infectious Diseases, 620039 Ekaterinburg, Russian Federation;1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China;2. Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China;1. Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Selangor, Malaysia;2. Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia;1. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari A. Moro, via Orabona 4, 70125 Bari, Italy;2. Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark;3. Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark;4. PET and Cyclotron Unit, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark |
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| Abstract: | A synthetic route toward a series of unique cyclic nucleoside phosphonates locked in South conformation is described. The desired conformation is stabilized by a substitution of the sugar moiety by bicyclo[2.2.1]heptane (norbornane) bearing a purine or pyrimidine nucleobase in the bridgehead position. Although the final phosphonate derivatives are devoid of any significant antiviral activity probably due to the unfavorable conformational properties, several intermediates and their analogs exhibit surprising activity against feline herpes virus. Since these compounds do not possess an appropriate hydroxymethyl function allowing phosphorylation and subsequent incorporation into the polynucleotide chain, it seems to be likely that these compounds act by a novel unknown mechanism of action and may represent a new possible alternative for nucleoside and nucleotide therapeutics of this widely spread feline infection. A number of derivatives exerted also a significant antiviral activity against Coxsackievirus B3 and B4. |
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| Keywords: | Carbocyclic nucleosides Nucleoside phosphonates Purine Norbornane Feline herpes virus |
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