title: Modification of the length and structure of the linker of N(6)-benzyladenosine modulates its selective antiviral activity against enterovirus 71.
abstract: Very recently, we demonstrated that N(6)-isopentenyladenosine, a cytokinin nucleoside, exerts a potent and selective antiviral effect on the replication of human enterovirus 71. The present study is devoted to the structure optimization of another natural compound: N(6)-benzyladenosine. We mainly focused on the exploration of the size and nature of the linker between the adenine and the phenyl ring, as well as on the necessity of the D-ribose residue. More than 30 analogues of N(6)-benzyladenosine were prepared and their antiviral properties were evaluated. Two main methodologies were used for preparation: N(6)-acetyl-2',3',5'-tri-O-acetyladenosine can be regioselectively alkylated either by alkyl halides under base promoted conditions or by alcohols in Mitsunobu reactions. After deacylation with 4 M PrNH2 in MeOH at room temperature for one day, the desired products were obtained in overall high yields. Analysis of the structure-activity relationship clearly shows that the optimal size of the linker is limited to 2 or 3 atoms (compounds 4-7). 2'-Deoxyadenosine derivatives did not elicit any inhibitory or cytotoxic effect, while 5'-deoxynucleosides still induced some cell protective antiviral activity. Based on these observations, it can be hypothesized that there may be another mechanism that is at the base of the antiviral activity of these compounds against enterovirus 71 besides a possible 5'-triphosphorylation followed by a putative inhibitory effect on RNA synthesis.
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow 119991, Russian Federation.
authors: Mikhail S
authors: MS
authors: Drenichev
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow 119991, Russian Federation.
authors: Vladimir E
authors: VE
authors: Oslovsky
authors: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Liang
authors: L
authors: Sun
authors: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Aloys
authors: A
authors: Tijsma
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow 119991, Russian Federation.
authors: Nikolay N
authors: NN
authors: Kurochkin
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow 119991, Russian Federation.
authors: Vitali I
authors: VI
authors: Tararov
authors: Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky pr., 47, Moscow 119991, Russian Federation.
authors: Alexander O
authors: AO
authors: Chizhov
authors: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Johan
authors: J
authors: Neyts
authors: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Christophe
authors: C
authors: Pannecouque
authors: KU Leuven - University of Leuven, Department of Microbiology and Immunology, Laboratory for Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Pieter
authors: P
authors: Leyssen
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Str. 32, Moscow 119991, Russian Federation. Electronic address: smikh@eimb.ru.
authors: Sergey N
authors: SN
authors: Mikhailov
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D029821:Enterovirus A, Human / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; C017061:N(6)-benzyladenosine; D000241:Adenosine
keywords: Enterovirus 71; N(6)-benzyladenosine derivatives; SAR; Synthesis and antiviral activity