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Fluoro-5'-Norcarbocyclic Nucleoside Phosphonates Bearing Uracil And molecules Article Synthesis and Antiviral Evaluation of 0 0 3 -Fluoro-5 -norcarbocyclic Nucleoside Phosphonates Bearing Uracil and Cytosine as Potential Antiviral Agents Pierre-Yves Geant, Jean-Pierre Uttaro, Christian Périgaud and Christophe Mathé * Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, Université de Montpellier, CNRS, ENSCM, cc 1705, Site Triolet, Place Eugène Bataillon, 34095 Montpellier CEDEX 5, France; [email protected] (P.-Y.G.); [email protected] (J.-P.U.); [email protected] (C.P.) * Correspondence: [email protected] Academic Editor: Katherine Seley-Radtke Received: 15 July 2020; Accepted: 12 August 2020; Published: 14 August 2020 Abstract: Carbocyclic nucleoside analogues are an essential class of antiviral agents and are commonly used in the treatment of viral diseases (hepatitis B, AIDS). Recently, we reported the racemic synthesis and the anti-human immunodeficiency virus activities (HIV) of 30-fluoro-50-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base. Based on these results, the corresponding racemic norcarbocyclic nucleoside phosphonates bearing pyrimidine bases were synthesized. The prepared compounds were evaluated against HIV, but none of them showed marked antiviral activity compared to their purine counterparts. Keywords: nucleoside analogues; carbocyclic; phosphonates; antiviral 1. Introduction Nucleoside analogues have been an important part of the therapeutic arsenal used in the treatment of viral diseases for several years [1]. Among them, a class of modified nucleoside analogues are carbocyclic nucleosides, in which the endocyclic oxygen of the furanose ring of the natural nucleosides is replaced by an isosteric methylene group. The mode of action of these compounds involves their intracellular phosphorylation to their 50-triphosphate form which can interact with virus-specific polymerases, acting as a competitive inhibitor or an alternate substrate for these target enzymes and finally preventing further viral nucleic acid chain elongation. As illustrated with the approval of carbocyclic nucleosides such as abacavir and entecavir as anti-HIV and anti-HBV drugs, respectively, the design and synthesis of novel carbocyclic scaffolds could lead to the discovery of new antiviral agents [2,3]. As a part of our ongoing research on 50-norcarbocyclic nucleoside phosphonates [4,5] as potential anti-viral agents, we have described the synthesis and the anti-HIV activities of 30-fluoro-50-norcarbocyclic nucleoside phosphonates bearing purines as heterocyclic base (Figure1)[6]. In such structures, the presence of a P-C bond instead of the hydrolysable P-O induces a metabolic stability of the linkage mimicking the phosphate moiety. Thus, these results prompted us to undertake the synthesis and the antiviral evaluation of the corresponding 30-fluoro-40-50-norcarbocyclic nucleoside phosphonates bearing uracil ( )-1 and cytosine ( )-2, respectively. ± ± Molecules 2020, 25, 3708; doi:10.3390/molecules25163708 www.mdpi.com/journal/molecules Molecules 2020, 25, 3708 2 of 9 MoleculesMolecules 2020 2020, ,24 24, ,x x 22 of of 9 9 FigureFigure 1. 1. Example Example of of antiviral antiviral carbocyclic carbocyclic nucleosides nucleosides and and structures structures of of the the target target compounds. compounds. 2.2. Results Results 2.1. Chemistry 2.1.2.1. Chemistry Chemistry TheThe strategystrategystrategy for forfor the thethe synthesis synthesissynthesis of the ofof target thethe target carbocyclictarget carbocycliccarbocyclic nucleosides nucleosidesnucleosides was based waswas upon basedbased the preparation uponupon thethe of compound ( )-7 as a common precursor (Scheme1). The latter was synthesized from alcohol preparationpreparation ofof compoundcompound± (±)-(±)-77 asas aa commoncommon precursorprecursor (Scheme(Scheme 1).1). TheThe latterlatter waswas synthesizedsynthesized fromfrom ( )-3 obtained according to our previously described procedure [6]. The azide with trans-configuration alcoholalcohol± (±)-(±)-33 obtainedobtained accordingaccording toto ourour previouslypreviously describeddescribed procedureprocedure [6].[6]. TheThe azideazide withwith trans-trans- configurationwasconfiguration obtained inwaswas good obtainedobtained yield using inin good agood Mitsunobu yieldyield using reactionusing aa [Mitsunobu7Mitsunobu] in the presence reactionreaction of diphenylphosphorylazide [7][7] inin thethe presencepresence ofof (DPPA), triphenylphosphine and diisopropyl azodicarboxylate (DIAD). From azido derivative ( )-4, diphenylphosphorylazidediphenylphosphorylazide (DPPA),(DPPA), triphenylphosphinetriphenylphosphine andand diisopropyldiisopropyl azodicarboxylateazodicarboxylate (DIAD).(DIAD).± the required amine ( )-5 was obtained after reduction with LiAlH4 in 84% yield. Finally, introduction FromFrom azidoazido derivativederivative± (±)-(±)-44, , thethe requiredrequired amineamine (±)-(±)-55 waswas obtainedobtained afterafter reductionreduction withwith LiAlHLiAlH44 inin of the uracil moiety of the common precursor ( )-7 was achieved through a two steps procedure [8] 84%84% yield.yield. Finally,Finally, introductionintroduction ofof thethe uraciluracil moietymoiety± ofof thethe commoncommon precursorprecursor (±)-(±)-77 waswas achievedachieved with 76% yield by treatment of ( )-5 with (E)-3-ethoxyacryloyl chloride followed by a cyclization throughthrough aa twotwo stepssteps procedureprocedure [8][8]± withwith 76%76% yieldyield byby treatmenttreatment ofof (±)-(±)-55 withwith ((EE)-3-ethoxyacryloyl)-3-ethoxyacryloyl chloridereactionchloride followed underfollowed acidic by by a a conditions. cyclization cyclization reaction reaction under under acidic acidic conditions. conditions. TBDPSOTBDPSO OHOH TBDPSOTBDPSO NN3 TBDPSOTBDPSO NHNH2 aa 3 bb 2 FF FF FF (( )-)-33 (±)-(±)-44 (±)-(±)-55 OO cc NHNH HH TBDPSO N HH NN d TBDPSO N N OO d N HOHO OEtOEt OO FF OO FF (±)-6 (±)-(±)-77 (±)-6 3 2 2 SchemeScheme 1. 1. ReagentsReagents and andand conditions: conditions:conditions: (a) (a)(a) DPPA, DPPA,DPPA, DIAD, DIAD,DIAD, PPh 3PPhPPh, THF3, , /THF/CHCHTHF/CH2Cl2,2 0ClCl◦2C,, , 0 300 °C,°C, min, 3030 67%. min,min, (b) 67%.67%. LiAlH (b)(b)4 , LiAlHTHF,LiAlH 044, ,◦ THF,THF,C to 0 RT,0 °C°C 30 toto min, RT,RT, 3030 84%. min, min, (c) 84%.84%. (E )-3-ethoxyacryloyl (c)(c) ((EE)-3-ethoxyacryloyl)-3-ethoxyacryloyl chloride, chloride,chloride, AgOCN, AgOCN, AgOCN, toluene, toluene,toluene, reflux, reflux,reflux, 30 min; 3030 min;thenmin; then (then)-5 ( ,(±± DMF,)-)-55, ,DMF, DMF,20 − −C2020 to °C °C RT, to to 5RT, RT, h, 98%.5 5 h, h, 98%. 98%. (d) HCl(d) (d) HCl (2N),HCl (2N), (2N), EtOH, EtOH, EtOH, reflux, reflux, reflux, 12 h, 12 12 78%. h, h, 78%. 78%. ± − ◦ SynthesisSynthesis of of 3 3′0-fluoro-5′-fluoro-5-fluoro-5′-norcarbocyclic′0-norcarbocyclic-norcarbocyclic nucleoside nucleoside phosphonates phosphonates bearing bearing uracil uracil was was carried carried out out in four stepssteps fromfrom compoundcompound ((±)-)-7 (Scheme 22).). Briefly,Briefly, thethe transtrans-(-(±)-)-7 isomerisomer was converted into the in four steps from compound (±)-± 7 (Scheme 2). Briefly, the trans-(±)-± 7 isomer was converted into the corresponding cis-isomer (±)- ( )-88 inin 93% 93% yield yield using using a a Mitsunobu reaction in the presence of benzoicbenzoic corresponding cis-isomer (±)-± 8 in 93% yield using a Mitsunobu reaction in the presence of benzoic acid,acid, triphenylphosphine triphenylphosphine andand DIAD,DIAD, thenthen followedfollowed byby thethe removalremoval ofof the the resulting resulting benzoate benzoate group group withwith potassiumpotassium carbonatecarbonate inin methanol.methanol. ThisThis inteintermediatermediate waswas transformedtransformed intointo thethe correspondingcorresponding phosphonatephosphonate (±)-(±)-99 inin thethe presencepresence ofof sodiumsodium hydridehydride andand diethyldiethyl pp-toluene-toluene sulfonyloxymethylsulfonyloxymethyl phosphonatephosphonate [9].[9]. FinaFinally,lly, thethe desireddesired 33′-fluoro-5′-fluoro-5′-norcarbocyclic′-norcarbocyclic nucleosidenucleoside phosphonatephosphonate (±)-(±)-11 Molecules 2020, 25, 3708 3 of 9 with potassium carbonate in methanol. This intermediate was transformed into the corresponding phosphonate ( )-9 in the presence of sodium hydride and diethyl p-toluene sulfonyloxymethyl Molecules 2020, 24, x± 3 of 9 phosphonate [9]. Finally, the desired 3 -fluoro-5 -norcarbocyclic nucleoside phosphonate ( )-1 bearing 0 0 ± bearinguracil was uracil obtained was obtained after deprotection after deprotection of the diethylphosphonoester of the diethylphosphonoester group of the group crude phosphonateof the crude phosphonate( )-9 by treatment (±)-9 withby treatment trimethylsilyl with trimethylsilyl bromide (TMSBr) brom inide anhydrous (TMSBr) DMF,in anhydrous followed DMF, by purification followed ± byusing purification reverse phase using column reverse chromatography. phase column chromatography. Scheme 2. Reagents and conditions: (a) (i) BzOH, DIAD, PPh3, THF, RT, 1 h; (ii) K2CO3, MeOH, RT, 4 Scheme 2. Reagents and conditions: (a) (i) BzOH, DIAD, PPh3, THF, RT, 1 h; (ii) K2CO3, MeOH, RT, 4 2 2 h, 93% over over two two steps. steps. (b) (b) (EtO) (EtO)2P(O)CHP(O)CHOTs,2OTs, NaH, NaH, DMF, DMF, RT, RT, 3 3 days. days. (c) (c) TMSBr, TMSBr, DMF, DMF, RT, RT, 24 24 h, h, 24% 24% fromfrom ( ±)-)-88.. ± Then, we planned the synthesissynthesis ofof 33′-fluoro-5-fluoro-5′-norcarbocyclic nucleoside phosphonatephosphonate ((±)-)-2 0 0 ± bearing cytosine cytosine as as
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