- Synthesis of BODIPY derivatives substituted with various bioconjugatable linker groups: A construction kit for fluorescent labeling of receptor ligands
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The goal of the present study was to design small, functionalized green-emitting BODIPY dyes, which can readily be coupled to target molecules such as receptor ligands, or even be integrated into their pharmacophores. A simple two-step one-pot procedure starting from 2,4-dimethylpyrrole and ω-bromoalkylcarboxylic acid chlorides was used to obtain new ω-bromoalkyl-substituted BODIPY fluorophores (1a-1f) connected via alkyl spacers of different length to the 8-position of the fluorescent dye. The addition of radical inhibitors reduced the amount of side products. The ω-bromoalkyl-substituted BODIPYs were further converted to introduce various functional groups: iodo-substituted dyes were obtained by Finkelstein reaction in excellent yields; microwave-Assisted reaction with methanolic ammonia led to fast and clean conversion to the amino-substituted dyes; a hydroxyl-substituted derivative was prepared by reaction with sodium ethylate, and thiol-substituted BODIPYs were obtained by reaction of 1a-1f with potassium thioacetate followed by alkaline cleavage of the thioesters. Water-soluble derivatives were prepared by introducing sulfonate groups into the 2- and 6-position of the BODIPY core. The synthesized BODIPY derivatives showed high fluorescent yields and appeared to be stable under basic, reducing and oxidative conditions. As a proof of concept, 2-thioadenosine was alkylated with bromoethyl-BODIPY 1b. The resulting fluorescent 2-substituted adenosine derivative 15 displayed selectivity for the A3 adenosine receptor (ARs) over the other AR subtypes, showed agonistic activity, and may thus become a useful tool for studying A3ARs, or a lead structure for further optimization. The new functionalized dyes may be widely used for fluorescent labeling allowing the investigation of biological targets and processes.
- Heisig, Fabian,Gollos, Sabrina,Freudenthal, Sven J.,El-Tayeb, Ali,Iqbal, Jamshed,Mueller, Christa E.
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- 2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
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CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
- Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
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p. 2941 - 2957
(2020/04/10)
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- Chemical Synthesis of Oligoribonucleotide (ASL of tRNALys T. brucei) Containing a Recently Discovered Cyclic Form of 2-Methylthio-N6-threonylcarbamoyladenosine (ms2ct6A)
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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.
- Debiec, Katarzyna,Matuszewski, Michal,Podskoczyj, Karolina,Leszczynska, Grazyna,Sochacka, Elzbieta
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- New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors
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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.
- 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.
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p. 204 - 218
(2015/11/24)
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- Preparation method of Cangrelor intermediate
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The invention relates to a preparation method of a Cangrelor intermediate as indicated in formula (I).According to the preparation method, a compound of the structure as indicated in formula (II) is adopted as the raw material, solvent and reaction reagent are added, a specific reaction is conducted, a product obtained after the reaction is then subjected to purification, and the Cangrelor intermediate as indicated in formula (I) is obtained, wherein the specific structure of formula (II) can be found in the specification. The preparation method has the advantages of being easy and convenient to operate, high in product purity, high in safety of the reaction process, suitable for industrialized production and low in cost.
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Paragraph 0028; 0029
(2016/10/17)
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- Development of polar adenosine A2A receptor agonists for inflammatory bowel disease: Synergism with A2B antagonists
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Adenosine A2A receptor agonists for the local treatment of inflammatory bowel disease (IBS) were designed and synthesized. Polar groups were introduced to prevent peroral absorption and subsequent systemic, e.g., hypotensive, side effects. 4-(2-{6-Amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-2-ylthio}ethyl)benzenesulfonic acid (7, PSB-0777) was selected for further evaluation in rat ileum/jejunum preparations in ex vivo experiments. Compound 7 significantly improved impaired acetylcholine-induced contractions induced by 2,4,6-trinitrobenzenesulfonic acid and showed synergism with an A2B-selective antagonist. Thus, nonabsorbable, locally active A2A agonists, as a monotherapy or in combination with an A2B antagonist, may be an efficient novel treatment for IBS, preventing the severe systemic side effects of known A 2A agonists.
- El-Tayeb, Ali,Michael, Sebastian,Abdelrahman, Aliaa,Behrenswerth, Andrea,Gollos, Sabrina,Nieber, Karen,Mueller, Christa E.
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supporting information; scheme or table
p. 890 - 895
(2012/02/04)
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- Nucleoside-5′-monophosphates as prodrugs of adenosine A2A receptor agonists activated by ecto-5′-nucleotidase
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Prodrugs of adenosine A2A receptor agonists were developed that are activated by ecto-5′-nucleotidase (ecto-5′-NT,CD73). Because ecto-5′-NT is upregulated in inflamed tissue, the A2A agonists are expected to be released from their prodrug form at the sites of inflammation. 2-(Ar)alkyl-substituted AMP derivatives were synthesized and investigated. Certain 2-substituted AMP derivatives, including 2-hexylthio-AMP, 2-cyclopentylthio-AMP, 2-cyclohexylmethylthio-AMP, and 2-cyclohexylethylthio-AMP were accepted as substrates by ecto-5′-NT and readily converted to the corresponding 2-substituted adenosine derivatives. The 2-cyclohexylethylthio substitution was a good compromise between the requirements of the ecto-5′-NT and the adenosine A2A receptor. The corresponding AMP derivative (12g) was a similarly good substrate as AMP itself, while the resulting adenosine derivative (11g) was a relatively potent A2A agonist (radioligand binding to rat brain striatal membranes: Ki=372 nM; inhibition of anti-CD3/anti-CD28-induced IFN-γ release in mouse CD4+ cells: EC50=50 nM). Compound 11g was released from 12g by incubation with CD4+ cells isolated from wild-type mice but only to a much smaller extent by cells from ecto-5′-NT knockout mice. Compound 12g will be a new lead structure for the development of more potent and selective ecto-5′-NT- activated prodrugs of selective anti-inflammatory A2A receptor agonists.
- El-Tayeb, Ali,Iqbal, Jamshed,Behrenswerth, Andrea,Romio, Michael,Schneider, Marion,Zimmermann, Herbert,Schrader, Jürgen,Müller, Christa E.
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scheme or table
p. 7669 - 7677
(2010/09/03)
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- PHOSPHORYLATED A2A RECEPTOR AGONISTS
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A phosphorylated A2A receptor agonist providing agonist properties on the A2A receptor after dephosphorylation the phosphorylated A2A receptor agonist comprises a ribosyl moiety and a purine moiety and being phosphorylated at the 5'-position of the ribose moiety except adenosine monophosphate (AMP), adenosine diphosphate (ADP) or adenosine triphosphate (ATP), a medicament containing the compound of the invention including ADP and the use of the compound of the invention including ATP and ADP for several medical indications e. g. inflammatory events. In particular, compounds of formula (I) are also disclosed.
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Page/Page column 17
(2008/06/13)
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- Identification of potent, selective P(2Y)-purinoceptor agonists: Structure-activity relationships for 2-thioether derivatives of adenosine 5'- triphosphate
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Study of P2-purinoceptor subtypes has been difficult due to the lack of potent and selective ligands. With the goal of developing high affinity P2- purinoceptor-selective agonists, we have synthesized a series of analogues of adenine nucleotides modified on the purine ring as chain-extended 2- thioethers or as N6-methyl-substituted compounds. Chemical functionality incorporated in the thioether moiety included cyanoalkyl, nitroaromatic, amino, thiol, cycloalkyl, n-alkyl, and olefinic groups. Apparent affinity of the compounds for P(2Y)-purinoceptors was established by measurement of P(2Y)-purinoceptor-promoted phospholipase C activity in turkey erythrocyte membranes and relaxation of carbachol-contracted smooth muscle in three different preparations (guinea pig taenia coli, rabbit aorta, and rabbit mesenteric artery). Activity at P(2X)-purinoceptors was established by measurement of contraction of rabbit saphenous artery and of the guinea pig vas deferens and urinary bladder. All 11 of the 2-thioethers of ATP stimulated the production of inositol phosphates with K0.5 values of 1.5- 770 nM, with an (aminophenyl)ethyl derivative being most potent. Two adenosine diphosphate analogues were equipotent to the corresponding ATP analogues. Adenosine monophosphate analogues were full agonists, although generally 4 orders of magnitude less potent. ATP 2-thioethers displayed pD2 values in the range of 6-8 in smooth muscle assay systems for activity at P(2Y)-receptors. There was a significant correlation for the 2-thioether compounds between the pK0.5 values for inositol phosphate production and the pD2 values for relaxation mediated via the P(2Y)-purinoceptors in the guinea pig taenia coli, but not for the vascular P(2Y)-receptors or for the P(2X)-receptors. At P(2X)-receptors, no activity was observed in the rabbit saphenous artery, but variable degrees of activity were observed in the guinea pig vas deferens and bladder depending on distal substituents of the thioether moiety. N6-Methyl-ATP was inactive at P(2X)-receptors, and approximately equipotent to ATP at taenia coli P(2Y)-receptors. This suggested that hybrid N6-methyl and 2-thioether ATP derivatives might be potent and selective for certain P(2Y)-receptors, as was shown for one such derivative, N6-methyl-2-(5-hexenylthio)-ATP.
- Fischer,Boyer,Hoyle,Ziganshin,Brizzolara,Knight,Zimmet,Burnstock,Harden,Jacobson
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p. 3937 - 3946
(2007/10/02)
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- Process for preparing 2-thioadenosine
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A process for preparing 2-thioadenosine, useful as an intermediate for the preparation of S-substituted-2-thioadenosines having a platelet aggregation inhibitory activity and a coronary vasodilating activity, which comprises reacting 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime or an O-substituted oxime thereof with carbon disulfide in a closed reaction zone at a temperature of from about 50° to about 200° C in a solvent.
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- S-substituted-2-thioadenosines
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S-Substituted-2-thioadenosines represented by the formula (I): SPC1 wherein R is as defined hereinafter, useful as a platelet aggregation inhibitor and a coronary vasodilator.
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