4105-39-9Relevant academic research and scientific papers
An RNA complex of the HIV-1 A-loop and tRNALys,3 is stabilized by nucleoside modifications
Bajji, Ashok C.,Sundaram, Mallikarjun,Myszka, David G.,Davis, Darrell R.
, p. 14302 - 14303 (2002)
The HIV transcription initiation complex involves a putative interaction between the primer tRNA anticodon and a conserved A-rich loop in the HIV genome. Surface plasmon resonance was used to demonstrate that the hypermodified nucleosides in the tRNA anti
Molecular recognition in purinergic receptors. 2. Diastereoselectivity of the h-P2Y1-receptor
Major, Dan T.,Nahum, Victoria,Wang, Yingfei,Reiser, Georg,Fischer, Bilha
, p. 4405 - 4416 (2004)
In the companion paper, part 1, we described the construction of an improved molecular model for the h-P2Y1 receptor (h-P2Y 1-R) and proposed a rational for the stereoelectronic selectivity of the receptor. Here, we extend our studies on the molecular recognition of the h-P2Y1-R to the exploration of the diastereoselectivity of this receptor. For this purpose, we implemented an integrative approach combining synthesis, spectral analysis, biochemical assays, and computational analysis. Specifically, we selected and synthesized novel ATP analogues bearing a chiral center on the phosphate chain. We analyzed the conformation of the chiral ATP analogues in solution by 1H/13C NMR and assigned the absolute configuration of the diastereoisomers. The coordination mode of these analogues with a Mg2+ ion was evaluated by 31P NMR. These chiral analogues were biochemically evaluated and found to be potent h-P2Y 1-R ligands. An EC50 difference of ca. 20-fold was observed between the diastereoisomers. Their spectral absolute configuration assignment was confirmed by comparison of the biochemical results to those of ATP-α-S diastereoisomers whose chirality is known. Finally, a computational analysis was performed for the elucidation of molecular recognition employing molecular mechanics (docking) studies on the receptor:ligands complexes. On the basis of the current results, we hypothesize that h-P2Y1-R's chiral discrimination originates from the requirement that the nucleotide analogue interacts with a Mg2+ ion within the receptor binding site. This Mg2+ ion is possibly coordinated with both Asp204 and the ATP's α, β, γ-phosphates in a Λ configuration.
Chemical Synthesis of Oligoribonucleotide (ASL of tRNALys T. brucei) Containing a Recently Discovered Cyclic Form of 2-Methylthio-N6-threonylcarbamoyladenosine (ms2ct6A)
Debiec, Katarzyna,Matuszewski, Michal,Podskoczyj, Karolina,Leszczynska, Grazyna,Sochacka, Elzbieta
supporting information, (2019/08/26)
The synthesis of the protected form of 2-methylthio-N6-threonylcarbamoyl adenosine (ms2t6A) was developed starting from adenosine or guanosine by using the optimized carbamate method and, for the first time, an isocyanate route. The hypermodified nucleoside was subsequently transformed into the protected ms2t6A-phosphoramidite monomer and used in a large-scale synthesis of the precursor 17nt ms2t6A-oligonucleotide (the anticodon stem and loop fragment of tRNALys from T. brucei). Finally, stereochemically secure ms2t6A→ms2ct6A cyclization at the oligonucleotide level efficiently afforded a tRNA fragment bearing the ms2ct6A unit. The applied post-synthetic approach provides two sequentially homologous ms2t6A- and ms2ct6A-oligonucleotides that are suitable for further comparative structure–activity relationship studies.
Methyl aryl thioether compound, and synthetic method and applications thereof
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Paragraph 0146; 0147; 0148, (2017/07/21)
The invention discloses a methyl aryl thioether compound represented by formula 2, and a synthetic method and applications thereof. According to the synthetic method, in a reaction solvent, an aryl halide or an aromatic halide, dimethyl carbonate, and potassium thioacetate are taken as reaction raw materials, reaction is carried out in the presence of metal palladium catalyst under the action of a ligand and an alkali so as to obtain the methyl aryl thioether compound. The reaction conditions of the synthetic method are mild; the raw materials are cheap and easily available; reaction operation is simple; yield is relatively high. The methyl aryl thioether compound can be used for providing skeleton structures for the synthesis of a plurality of natural products and medicines, and can be widely applied in industrialized large-scale production.
New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors
Yanachkov, Ivan B.,Chang, Hung,Yanachkova, Milka I.,Dix, Edward J.,Berny-Lang, Michelle A.,Gremmel, Thomas,Michelson, Alan D.,Wright, George E.,Frelinger, Andrew L.
supporting information, p. 204 - 218 (2015/11/24)
Currently approved platelet adenosine diphosphate (ADP) receptor antagonists target only the platelet P2Y12 receptor. Moreover, especially in patients with acute coronary syndromes, there is a strong need for rapidly acting and reversible antiplatelet agents in order to minimize the risk of thrombotic events and bleeding complications. In this study, a series of new P1,P4-di(adenosine-5′) tetraphosphate (Ap4A) derivatives with modifications in the base and in the tetraphosphate chain were synthesized and evaluated with respect to their effects on platelet aggregation and function of the platelet P2Y1, P2Y12, and P2X1 receptors. The resulting structure-activity relationships were used to design Ap4A analogs which inhibit human platelet aggregation by simultaneously antagonizing both P2Y1 and P2Y12 platelet receptors. Unlike Ap4A, the analogs do not activate platelet P2X1 receptors. Furthermore, the new compounds exhibit fast onset and offset of action and are significantly more stable than Ap4A to degradation in plasma, thus presenting a new promising class of antiplatelet agents.
NOVEL ANTITHROMBOTIC DIADENOSINE TETRAPHOSPHATES AND RELATED ANALOGS
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Page/Page column 17-19, (2010/07/10)
The invention features compounds of formula I and methods of their use as antiplatelet and antithrombotic compounds: H /N=Qχ2 O O O O Λ Q2 — N, H R6/ N I f ) ( ^ XM O-Mγτ OM°τ X1MQ' ) r ( ^rf HO OH HO OQHi Nχi R2 Formula (I).
2-MeS-β,γ-CCl2-ATP is a potent agent for reducing intraocular pressure
Eliahu, Shay,Martín-Gil, Alba,Perez De Lara, María Jesús,Pintor, Jesús,Camden, Jean,Weisman, Gary A.,Lecka, Joanna,Sévigny, Jean,Fischer, Bilha
experimental part, p. 3305 - 3319 (2010/09/06)
Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8-14. Analogues 8-14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 °C. In human blood serum, analogues 8-14 exhibited high stability, e.g., analogues 9 and 10-14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8-14 were highly stable at pH 1.4 (t1/2 1 h-30 days). Analogues 8-14 were agonists of the P2Y1 receptor (EC50 0.57-9.54 μM). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.
Synthesis of the tRNALys,3 anticodon stem-loop domain containing the hypermodified ms2t6A nucleoside
Bajji, Ashok C.,Davis, Darrell R.
, p. 5352 - 5358 (2007/10/03)
The synthesis of a protected form of the hypermodified nucleoside, N-[(9-β-D-ribofuranosyl-2- methylthiopurin-6-yl)carbamoyl]threonine, (ms2t6A) is reported. The hypermodified nucleoside was subsequently elaborated to the protected nucleoside phosphophoramidite using a protecting group strategy compatible with standard RNA oligonucleotide chemistry. The phosphoramidite reagent was then used to synthesize the 17-nucleotide RNA hairpin having the sequence of the anticodon stem-loop (ASL) domain of human tRNALys,3, the primer for HIV-1 reverse transcriptase. Introduction of the modification at position 37 of the tRNA ASL modestly decreases the thermodynamic stability of the RNA hairpin as has been seen previously for the prokaryotic t6A nucleoside lacking the 2-methylthio substituent. 2D NOESY NMR spectra of the ms2t6A containing tRNA ASL indicate that the threonyl side chain adopts a conformation similar to that seen in the solution structure of the analogous t6A containing E. coli tRNALys, despite the presence of the bulky methylthio group. This synthetic approach allows for site-specific incorporation of the hypermodified nucleoside and should facilitate future studies directed at understanding the roles of nucleoside modification in modulating the stability and specificity of biologically important RNA-RNA interactions. Our synthesis of the ms2t6A containing RNAs demonstrates that this methodology is suitable for obtaining quantities of RNA required for structural studies of the HIV primer tRNA.
Photoinduced Alkylthiolation of Halogenated Purine Nucleosides
Nair, Vasu,Young, David A.
, p. 450 - 453 (2007/10/02)
A new highly efficient methodology for the synthesis of biologically important methylmercaptopurine nucleosides is described.The approach represents a substantial improvement over earlier reported methods for this class of compounds.
