Synthesis of boranoate, selenoate, and thioate analogs of AZTp4A and Ap4A

Han, Qianwei; Sarafianos, Stefan G.; Arnold, Eddy; Parniak, Michael A.; Gaffney, Barbara L.; Jones, R. A. C.

doi:10.1016/j.tet.2009.07.079

Cited by 8 publications

(5 citation statements)

References 29 publications

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“…This is probably due to the unexpectedly high steric hindrance by the dichloromethylene group on the phosphorous atoms. Compound 16 was prepared, albeit in low yield, by zinc chloride catalyzed coupling of the cyclic trimetaphosphate 17 with MeSAMP(S) (Scheme 2) [50]. …”

Section: Resultsmentioning

confidence: 99%

New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

Yanachkov

Chang

Yanachkova

et al. 2016

European Journal of Medicinal Chemistry

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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.

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Section: Resultsmentioning

confidence: 99%

New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

Yanachkov

Chang

Yanachkova

et al. 2016

European Journal of Medicinal Chemistry

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“…The synthesis of boranophosphate analogs of nucleoside oligophosphates is usually accomplished by taking advantage of the reactivity of trivalent phosphorus derivatives. Several approaches for the synthesis of boranophosphate-containing mono- and dinucleoside oligophosphates have been developed on the basis of trivalent phosphorus chemistry, most of which encompass a reaction sequence consisting of 5′-phosphitylation of a suitably protected nucleoside, new pyrophosphate bond formation via a reaction with a phosphate-nucleophile, boronation with a BH 3 –Lewis base complex and finally an alkali-mediated removal of the protecting groups ( 23 , 41 , 56–60 ). However, such approach would not be applicable for our purpose, i.e.…”

Section: Discussionmentioning

confidence: 99%

Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes

Kowalska

Nogal

Darżynkiewicz

et al. 2014

Nucleic Acids Research

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Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of novel therapeutic interventions. We report the synthesis and properties of 11 dinucleotide cap analogs bearing a single boranophosphate modification at either the α-, β- or γ-position of the 5′,5′-triphosphate chain. The compounds can potentially serve either as inhibitors of translation in cancer cells or reagents for increasing expression of therapeutic proteins in vivo from exogenous mRNAs. The BH3-analogs were tested as substrates and binding partners for two major cytoplasmic cap-binding proteins, DcpS, a decapping pyrophosphatase, and eIF4E, a translation initiation factor. The susceptibility to DcpS was different between BH3-analogs and the corresponding analogs containing S instead of BH3 (S-analogs). Depending on its placement, the boranophosphate group weakened the interaction with DcpS but stabilized the interaction with eIF4E. The first of the properties makes the BH3-analogs more stable and the second, more potent as inhibitors of protein biosynthesis. Protein expression in dendritic cells was 2.2- and 1.7-fold higher for mRNAs capped with m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2, respectively, than for in vitro transcribed mRNA capped with m27,3′-OGpppG. Higher expression of cancer antigens would make mRNAs containing m27,2′-OGppBH3pG D1 and m27,2′-OGppBH3pG D2 favorable for anticancer immunization.

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“…Numerous methods for their synthesis have been developed, several of them providing synthetic routes to dinucleoside tri-or tetraphosphates modified at non-bridging positions in the phosphate group(s). 29,[35][36][37][38][39][40] However, most of these methods have drawbacks with regard to synthesis of mRNA cap analogs. These include limited structural variety of possible products available by a particular method (e.g., limitation to symmetrical compounds or those modified at the a-position with respect to nucleoside) or requirement for protected nucleosides as starting materials.…”

Section: Discussionmentioning

confidence: 99%

Towards mRNA with superior translational activity: synthesis and properties of ARCA tetraphosphates with single phosphorothioate modifications

et al. 2010

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We describe the chemical synthesis and preliminary biophysical and biochemical characterization of a series of mRNA 5' end (cap) analogs designed as reagents for obtaining mRNA molecules with augmented translation efficiency and stability in vivo and as useful tools to study mRNA metabolism. The analogs share three structural features: (i) 5',5'-bridge elongated to tetraphosphate to increase their affinity to translation initiation factor eIF4E (ii) a single phosphorothioate modification at either the α, β, γ or δ-position of the tetraphosphate to decrease their susceptibility to enzymatic degradation and/or to modulate their interaction with specific proteins and (iii) a 2'-O-methyl group in the ribose of 7-methylguanosine, characteristic to AntiReverse Cap Analogs (ARCAs), which are incorporated into mRNA during in vitro transcription exclusively in the correct orientation. The dinucleotides bearing modified tetraphosphate bridge were synthesized by ZnCl 2 mediated coupling between two mononucleotide subunits with isolated yields of 30-65%. The preliminary biochemical results show that mRNAs capped with new analogs are 2.5-4.5 more efficiently translated in a cell free system than m 7 GpppG-capped mRNAs, which makes them promising candidates for RNA-based therapeutic applications such as gene therapy and anti-cancer vaccines.

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Synthesis of boranoate, selenoate, and thioate analogs of AZTp4A and Ap4A

Cited by 8 publications

References 29 publications

New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors

Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes

Towards mRNA with superior translational activity: synthesis and properties of ARCA tetraphosphates with single phosphorothioate modifications

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