From norbornane-based nucleotide analogs locked in South conformation to novel inhibitors of feline herpes virus Milan Dejmek a , Hubert Hr ˇebabecky ´ a , Michal Šála a , Martin Drac ˇínsky ´ a , Eliška Procházková a , Pieter Leyssen b , Johan Neyts b , Jan Balzarini b , Radim Nencka a,⇑ a 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 b Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium article info Article history: Received 17 January 2014 Revised 31 March 2014 Accepted 3 April 2014 Available online 13 April 2014 Keywords: Carbocyclic nucleosides Nucleoside phosphonates Purine Norbornane Feline herpes virus 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 bicy- clo[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. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Modern antiviral treatment relies on nucleoside and nucleotide derivatives, a fundamental element of so-called ‘cocktail therapy’, which is the most successful in the current therapy of HIV infec- tion. The development of anti-HIV therapeutics has brought nucle- oside phosphonates to the spotlight and allowed their full recognition as the most effective class of nucleoside and nucleotide reverse-transcriptase inhibitors (NRTIs). 1 Although the acyclic nucleoside phosphonates (ANPs), represented by tenofovir 1, have obtained most of the fame, there is a number of other interesting cyclic nucleoside phosphonates being developed including GS- 9148 (2) and its carbocyclic derivatives (e.g., 3), which combine the strengths of the nucleoside phosphonates, the didanosine or abacavir-like skeleton and rational design-based optimization, leading to their significant anti-HIV potency and favorable resis- tance profile. 2 Another cyclic nucleoside phosphonate that has gained considerable attention in the literature is PMDTA (4), reported by Herdewijn and co-workers (Fig. 1). 3 Although conformational constriction has proven to be a vital modification of nucleosides leading to an enhancement of desired antiviral properties, conformationally locked derivatives of cyclic nucleoside phosphonate have been reported rather rarely so far. Saneyoshi et al. have prepared several locked derivatives of PMDTA, 4 whereas Gilead Sciences, Inc. has filed a patent concern- ing various conformationally locked phosphonate analogs as anti- viral agents. 5 In both of these cases, however, the conformation was locked using bicycle[3.1.0]hexane as a substitute of the natural tetrahy- dofuran sugar ring. Recently, we have introduced bicy- clo[2.2.1]heptane (norbornane) 6 as a potentially attractive surrogate of the sugar moiety and shown that some derivatives bearing the 6-chloropurine nucleobase can possess significant anti- viral activities against (+)ssRNA viruses from the Picornaviridae http://dx.doi.org/10.1016/j.bmc.2014.04.004 0968-0896/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +420 220 183 265; fax: +420 220 183 560. E-mail address: nencka@uochb.cas.cz (R. Nencka). N N N N NH 2 X O P O HO HO F N N N N NH 2 P O HO HO O N N N N NH 2 O O P HO O HO 1 2 X=O 3 X=CH 2 4 Figure 1. The structures of important acyclic and cyclic nucleoside phosphonates. Bioorganic & Medicinal Chemistry 22 (2014) 2974–2983 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc