23589-16-4Relevant articles and documents
A highly facile and efficient one-step synthesis of N6-adenosine and N6-2′-deoxyadenosine derivatives
Wan, Zhao-Kui,Binnun, Eva,Wilson, Douglas P.,Lee, Jinbo
, p. 5877 - 5880 (2005)
(Chemical Equation Presented) A highly facile and efficient one-step synthesis of N6-adenosine and N6-2′-deoxyadenosine derivatives has been developed. Treatment of inosine or 2′-deoxyinosine, without protection of sugar hydroxyl groups, with alkyl or arylamines, in the presence of BOP and DIPEA in DMF, led to the formation of N6- adenosine and N6-2′-deoxyadenosine derivatives in good to excellent yields. Carcinogenic polyaromatic hydrocarbon (PAH) N 6-2′-deoxyadenosine adduct 10 and a rare DNA constituent 11 were thus synthesized directly from 2′-deoxyinosine both in 98% yield.
Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases
Goswami, Manibarsha,Wilke, Kaelyn E.,Carlson, Erin E.
supporting information, p. 8170 - 8182 (2017/10/18)
Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from their regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure-activity relationship assessment of adenine-based inhibitors using biochemical and docking methods. These studies have resulted in several observations. First, interaction of an inhibitor's amine group with the conserved active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic electron-withdrawing groups at several positions in the adenine core enhance potency. The selectivity of these inhibitors was tested against heat shock protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.
Modification of the length and structure of the linker of N6-benzyladenosine modulates its selective antiviral activity against enterovirus 71
Drenichev, Mikhail S.,Oslovsky, Vladimir E.,Sun, Liang,Tijsma, Aloys,Kurochkin, Nikolay N.,Tararov, Vitali I.,Chizhov, Alexander O.,Neyts, Johan,Pannecouque, Christophe,Leyssen, Pieter,Mikhailov, Sergey N.
, p. 84 - 94 (2016/02/18)
Very recently, we demonstrated that N6-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: N6-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 N6-benzyladenosine were prepared and their antiviral properties were evaluated. Two main methodologies were used for preparation: N6-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.
α,β-Methylene-ADP (AOPCP) Derivatives and Analogues: Development of Potent and Selective ecto-5′-Nucleotidase (CD73) Inhibitors
Bhattarai, Sanjay,Freundlieb, Marianne,Pippel, Jan,Meyer, Anne,Abdelrahman, Aliaa,Fiene, Amelie,Lee, Sang-Yong,Zimmermann, Herbert,Yegutkin, Gennady G.,Str?ter, Norbert,El-Tayeb, Ali,Müller, Christa E.
, p. 6248 - 6263 (2015/08/24)
ecto-5′-Nucleotidase (eN, CD73) catalyzes the hydrolysis of extracellular AMP to adenosine. eN inhibitors have potential for use as cancer therapeutics. The eN inhibitor α,β-methylene-ADP (AOPCP, adenosine-5′-O-[(phosphonomethyl)phosphonic acid]) was used as a lead structure, and derivatives modified in various positions were prepared. Products were tested at rat recombinant eN. 6-(Ar)alkylamino substitution led to the largest improvement in potency. N6-Monosubstitution was superior to symmetrical N6,N6-disubstitution. The most potent inhibitors were N6-(4-chlorobenzyl)- (10l, PSB-12441, Ki 7.23 nM), N6-phenylethyl- (10h, PSB-12425, Ki 8.04 nM), and N6-benzyl-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (10g, PSB-12379, Ki 9.03 nM). Replacement of the 6-NH group in 10g by O (10q, PSB-12431) or S (10r, PSB-12553) yielded equally potent inhibitors (10q, 9.20 nM; 10r, 9.50 nM). Selected compounds investigated at the human enzyme did not show species differences; they displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. Moreover, high metabolic stability was observed. These compounds represent the most potent eN inhibitors described to date.
Site-selective direct arylation of unprotected adenine nucleosides mediated by palladium and copper: insights into the reaction mechanism
Storr, Thomas E.,Firth, Andrew G.,Wilson, Karen,Darley, Kate,Baumann, Christoph G.,Fairlamb, Ian J.S.
, p. 6125 - 6137 (2008/09/21)
Reaction conditions facilitating the site-selective direct aryl functionalisation at the C-8 position of adenine nucleosides have been identified. Many different aromatic components may be effectively cross-coupled to provide a diverse array of arylated adenine nucleoside products without the need for ribose or adenine protecting groups. The optimal palladium catalyst loading lies between 0.5 and 5 mol %. Addition of excess mercury to the reaction had a negligible affect on catalysis, suggesting the involvement of a homogeneous catalytic species. A study by transmission electron microscopy (TEM) shows that metal containing nanoparticles, ca. 3 nm with good uniformity, are formed during the latter stages of the reaction. Stabilised PVP palladium colloids (PVP=N-polyvinylpyrrolidone) are catalytically active in the direct arylation process, releasing homogenous palladium into solution. The effect of various substituted 2-pyridine ligand additives has been investigated. A mechanism for the site-selective arylation of adenosine is proposed.
Design of allele-specific protein methyltransferase inhibitors
Lin,Jiang,Schultz,Gray
, p. 11608 - 11613 (2007/10/03)
Protein arginine methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine side chains in target proteins, regulate transcription, RNA processing, and receptor-mediated signaling. To specifically address the functional role of the individual members of this family, we took a "bump-and-hole" approach and designed a series of N6-substituted S-adenosylhomocysteine (SAH) analogues that are targeted toward a yeast protein methyltransferase RMT1. A point mutation was identified (E117G) in Rmt1 that renders the enzyme susceptible to selective inhibition by the SAH analogues. A mass spectrometry based enzymatic assay revealed that two compounds, N6-benzyl- and N6-naphthylmethyl-SAH, can inhibit the mutant enzyme over the wild-type with the selectivity greater than 20. When the E117G mutation was introduced into the Saccharomyces cerevisiae chromosome, the methylation of Np13p, a known in vivo Rmt1 substrate, could be moderately reduced by N6-naphthylmethyl-SAH in the resulting allele. In addition, an N6-benzyl-SAM analogue was found to serve as an orthogonal SAM cofactor. This analogue is preferentially utilized by the mutant methyltransferase relative to the wild-type enzyme with a selectivity greater than 67. This specific enzyme/inhibitor and enzyme/substrate design should be applicable to other members of this protein family and facilitate the characterization of protein methyltransferase function in vivo when combined with RNA expression analysis.
Mild and efficient functionalization at C6 of purine 2′-deoxynucleosides and ribonucleosides
Lin, Xiaoyu,Robins, Morris J.
, p. 3497 - 3499 (2007/10/03)
(Equation Presented) Treatment of sugar-protected inosine and 2′-deoxyinosine derivatives with a cyclic secondary amine or imidazole and I2/Ph3P/EtN(i-Pr)2/(CH2-Cl 2 or toluene) gave quantitative conversions into 6-N-(substituted)purine nucleosides. SNAr reactions with (imidazol-1-yl) derivatives gave 6-(N, O, or S)-substituted products. The 6-(benzylsulfonyl) group underwent SNAr displacement with an arylamine at ambient temperature.
