Synthesis of N6 -Substituted Adenosines as Cytokinin Nucleosides.

This unit describes preparation of N6 -substituted adenosines (cytokinin nucleosides), a unique class of compounds with a wide spectrum of biological activities. Regioselective alkylation of N6 -acetyl-2',3',5'-tri-O-acetyladenosine with alkyl halides under basic conditions or alcohols under Mitsunobu conditions followed by deprotection are the methods of choice for the preparation of the cytokinin nucleosides. The attractive feature of this strategy is the possibility of using a broad library of commercially available alkyl halides and alcohols under mild reaction conditions. © 2018 by John Wiley & Sons, Inc.

Modification of the length and structure of the linker of N(6)-benzyladenosine modulates its selective antiviral activity against enterovirus 71.

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.

Chemical modification of the plant isoprenoid cytokinin N(6)-isopentenyladenosine yields a selective inhibitor of human enterovirus 71 replication.

In this study, we demonstrate that N(6)-isopentenyladenosine, which essentially is a plant cytokinin-like compound, exerts a potent and selective antiviral effect on the replication of human enterovirus 71 with an EC50 of 1.0 ± 0.2 µM and a selectivity index (SI) of 5.7. The synthesis of analogs with modification of the N(6)-position did not result in a lower EC50 value. However, in particular with the synthesis of N(6)-(5-hexene-2-yne-1-yl)adenosine (EC50 = 4.3 ± 1.5 µM), the selectivity index was significantly increased: because of a reduction in the adverse effect of this compound on the host cells, an SI > 101 could be calculated. With this study, we for the first time provide proof that a compound class that is based on the plant cytokinin skeleton offers an interesting starting point for the development of novel antivirals against mammalian viruses, in the present context in particular against enterovirus 71.

Facile synthesis of 8-azido-6-benzylaminopurine.

Bromination of 6-benzylaminopurine (1) with Br(2) in AcOH in the presence of AcONa afforded 6-benzylamino-8-bromopurine (2) in 59% yield. The position of bromination was confirmed by direct transformation of bromide 2 by reaction with NaN(3) in dimethyl sulfoxide to 8-azido-6-benzylaminopurine (3) in a yield of 70% and comparison of its properties with the known compound 2-azido-6-benzylaminopurine (11). Compounds 3 and 11 were checked for their biological activity in specific biotests based on the primary cytokinin effects in living plants. Both synthesized compounds displayed effects similar to the typical cytokinin 6-benzylaminopurine (1).

Convenient and efficient reduction of 1,1'-binaphthyls to H8-1,1'-binaphthyl derivatives with Pd and Ru catalysts on solid support.

Hydrogenation of chiral 2,2'-functionalized 1,1'-binaphthyls with Pd and Ru solid-supported metal catalysts was found to be a clean and convenient pathway to 5,5',6,6',7,7',8,8'-octahydro-1,1'-dinaphthyl derivatives. In most cases no racemization was observed in the course of the reaction.