35662-04-5Relevant articles and documents
Novel Irreversible Agonists Acting at the A1 Adenosine Receptor
J?rg, Manuela,Glukhova, Alisa,Abdul-Ridha, Alaa,Vecchio, Elizabeth A.,Nguyen, Anh T. N.,Sexton, Patrick M.,White, Paul J.,May, Lauren T.,Christopoulos, Arthur,Scammells, Peter J.
, p. 11182 - 11194 (2016)
The A1 adenosine receptor (A1AR) is an important G protein-coupled receptor that regulates a range of physiological functions. Herein we report the discovery of novel irreversible agonists acting at the A1AR, which have the potential to serve as useful research tools for studying receptor structure and function. A series of novel adenosine derivatives bearing electrophilic substituents was synthesized, and four compounds, 8b, 15a, 15b, and 15d, were shown to possess similar potency and efficacy to the reference high efficacy agonist, NECA, in an assay of ERK1/2 phosphorylation assay. Insensitivity to antagonist addition in a real-time, label-free, xCELLigence assay was subsequently used to identify compounds that likely mediated their agonism through an irreversible interaction with the A1AR. Of these compounds, 15b and 15d were more directly validated as irreversible agonists of the A1AR using membrane-based [3H]DPCPX and [35S]GTPγS binding experiments.
New conjugates of mycophenolic acid and their antiproliferative activity
Prejs, Micha?,Cholewinski, Grzegorz,Siebert, Agnieszka,Trzonkowski, Piotr,Dzierzbicka, Krystyna
, p. 1057 - 1062 (2016)
The new conjugates of mycophenolic acid (MPA) were obtained in the reaction of N6-(ω-aminoalkyl)adenosines with MPA in the presence of EDCI as a coupling reagent. New compounds 4a–h were evaluated on leukemia cell line (Jurkat) and PBMC from healthy donors. Length of the linker influenced observed activity. The compound 4b possessing 1,3-diamine spacer exhibited the most promising results and can be considered to further investigations.
Synthesis and application for adenosine derivative
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Paragraph 0026-0030, (2020/07/02)
The invention belongs to the field of chemical synthesis, and specifically relates to a synthesis and an application for an adenosine derivative. The adenosine compound disclosed by the invention hasa structure as shown in a formula I which is described in the specification. According to the invention, an inhibitor of a potential SAHN protein is designed; a structure of biotin is introduced intoadenosine; an obtained compound can replace MTA to construct a system for screening the inhibitor on the basis of an AlphaLISA Technology; and invasive microorganisms are selectively killed. The invention provides a novel synthesis method for synthesizing a purine derivative with a biotin structure in the future, and also provides a novel compound for developing an inhibitor with higher specificity and stability and for immunological research.
Synthesis and antiproliferative activity of conjugates of adenosine with muramyl dipeptide and nor-muramyl dipeptide derivatives
Samsel, Monika,Dzierzbicka, Krystyna,Trzonkowski, Piotr
supporting information, p. 3587 - 3591 (2014/07/22)
We synthesized a series of MDP(D,D) and nor-MDP(D,D) derivatives conjugated with adenosine through a spacer as potential immunosuppressants. New conjugates 8a-k were evaluated on two leukemia cell lines (Jurkat and L1210) and PBMC from healthy donors. The conjugates 8a-k and MDP(D,D)/nor-MDP(D,D) derivatives 7e, f, i, j were active against L1210 cell line. Unconjugated nor-MDP(D,D) had better antiproliferative properties, but the conjugates 8b, f, g had the highest values of selectivity index. Both cell lines as well as PBMC were resistant to analogs 11a, b with the 6-aminohexanoic linker.
Anti-malarial activity of N6-substituted adenosine derivatives. Part I
Golisade, Abolfasl,Wiesner, Jochen,Herforth, Claudia,Jomaa, Hassan,Link, Andreas
, p. 769 - 777 (2007/10/03)
The synthesis and biological evaluation of novel N6-substituted adenosine derivatives is reported. The first series of compounds was obtained using an established procedure for the nucleophilic substitution of a 1-(6-chloro-purin-9-yl)-β-D-1-deoxy-ribofuranose with various amines. In addition, attachment of two different amino-functionalised spacer arms at the N6-position of adenosine enabled derivatisation by an innovative polymer-assisted protocol. Thus, we were able to prepare three series of substituted derivatives that displayed activity versus the multiresistant Plasmodium falciparum strain Dd2 in cell culture experiments.
Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: Elucidation of a novel binding mode for a 2-Amino-N6-substituted adenosine
Bressi,Choe,HoughHough,Buckner,Van Voorhis,Verlinde,Hol,Gelb
, p. 4135 - 4150 (2007/10/03)
As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N6-, 2-amino-N6-, and N2-substituted adenosine analogues were synthesized and tested to establish structure - activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N6-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N6-[2-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 μM. 2-[[2-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 μM. To explore the potential of an additive effect that having the N6 and N2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N6,N2-disubstituted adenosine analogues to yield N6-(2-phenylethyl)-2-[(2-phenylethyl)amino]adenosine (69) as a 30 μM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A? X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this 'flipped and rotated' binding mode.
A chemical method for site-specific modification of RNA: The convertible nucleoside approach
Allerson, Charles R.,Chen, Swaine L.,Verdine, Gregory L.
, p. 7423 - 7433 (2007/10/03)
Knowledge of RNA structure can greatly facilitate the understanding of its biological function. However, the physical properties of RNA, especially its conformational heterogeneity, present an impediment to high-resolution structural analysis. Thus,lower resolution methods such as biochemical probing, phylogenetic analysis, and molecular modeling have come to serve an important role in RNA science. This situation has created the need for a means by which to constrain RNA structure, either to reduce its conformational flexibility or to help distinguish between alternative structural models. To address this need, we have developed chemistry that permits the site-specific introduction of functionalizable tethers into RNA. Here we report the design and synthesis of reagents for use in solid-phase RNA synthesis that allow the functionalization of the base moiety of C, C, and A residues. Upon incorporation into oligonucleotides and subsequent treatment with alkylamines, the convertible nucleoside derivatives reported here give rise to functionally tethered N4-alkyl-C, N6-alkyl-A, and N2-alkyl-G residues in RNA. The derivatized RNAs can then be used to target the attachment of chemical probes or the placement of disulfide cross-links as structural constraints. The attachment of nonnatural functional groups to RNA in this fashion provides a powerful means of both probing its structural environment and constraining its conformation. The size and functionality of the N-alkyl modification is determined solely by the choice of alkylamine, thereby permitting the preparation of a wide range of functionally tethered RNAs.
SIMULTANEOUS CONVERSION OF N-(1)-(2-AMINOETHYL)-ADENOSINE TO N6-(2-AMINOETHYL)ADENOSINE AND TRICYCLIC 1,N6-ETHANOADENOSINE UNDER MILD AQUEOUS CONDITIONS
Bueckmann, Andreas F.,Wray, Victor,Plas, Henk C. van der
, p. 1399 - 1420 (2007/10/02)
Under mild aqueous conditions (50 deg C, pH range 6-7) N(1)-(2AE)-adenosine (2) can be converted to N6-(2AE)-adenosine (7) by Dimroth rearrangement at unexpectedly high rate.In a parallel reaction tricyclic 1,N6-ethanoadenosine (6) is formed.The latter reaction is new in heterocyclic organic chemistry and is strongly catalysed by the monoanions of phosphoric and arsenic acid and, less strongly, by the acetate anion.
