- 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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supporting information
(2019/08/26)
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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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supporting information
p. 204 - 218
(2015/11/24)
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- ORAL WASHING COMPOSITION FOR PREVENTING AND/OR TREATING PERIODONTAL DISEASES
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The present invention has an object to provide a mouthwash composition for preventing and/or treating periodontal diseases safely and effectively. The present invention solves the above abject by providing a mouthwash composition for preventing and/or treating periodontal diseases, characterized in that it comprises, as an effective ingredient(s), one or more members selected from the group consisting of adenosine N1-oxide, 3'-glucosyladenosine N1-oxide, 5'-glucosyladenosine N1-oxide, 5'-adenosine diphosphate N1-oxide, and 5'-adenosine triphosphate N1-oxide but does not contain any saccharide assimilable by periodontal disease bacteria.
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Paragraph 0027
(2014/11/27)
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- THERAPEUTIC AGENT FOR INFLAMMATORY DISEASES CONTAINING ADENOSINE N1-OXIDE AS ACTIVE INGREDIENT
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The present invention has an object to provide an effective and safe therapeutic agent for inflammatory diseases such as sepsis, hepatitis, and inflammatory bowel disease, and solves the above object by providing a therapeutic agent for inflammatory diseases containing adenosine N1-oxide or a derivative thereof as an effective ingredient.
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Paragraph 0037
(2013/05/09)
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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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- Synthesis and antiviral evaluation of analogs of adenosine-N1-oxide and 1-(benzyloxy)adenosine
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The activity of a series of compounds related to adenosine-N1-oxide (1) and 1-(benzyloxy)adenosine (42) against vaccinia virus has been determined both in vitro and in a vaccinia mouse tailpox model. Significant activities have been found both in vitro and in vivo for a number of the synthetic compounds.
- Kwong, Cecil D.,Krauth, Charles A.,Shortnacy-Fowler, Anita T.,Arnett, Gussie,Hollingshead, Melinda G.,Shannon, William M.,Montgomery, John A.,Secrist III, John A.
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p. 1409 - 1443
(2007/10/03)
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- AN IMPROVED PROCEDURE FOR THE PREPARATION OF AROMATIC HETEROCYCLIC N-OXIDES
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An improved procedure for the preparation of aromatic heterocyclic N-oxide is described.Nitrogen containing heterocyclic compounds gave their N-oxides in excellent yields by the reaction of m-CPBA in DMF/MeOH in the presence of HF in a short time under mild reaction conditions.The presence of HF and MeOH is crucial for the reaction.
- Rhie, Soo Young,Ryu, Eung K.
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p. 323 - 328
(2007/10/03)
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- Reactions of 9-substituted 1-aminoadenines with nucleophiles and syntheses of 3-substituted 3H-imidazo[4,5-e][1,2,4]triazolo[1,5-c][1,2,3]triazines
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Reactions of 1-aminoadenines (2) with NH2OH gave adenine 1-oxides (6). Alkaline treatment of 2 afforded 5-amino-4-(1,2,4-triazol-3-yl)imidazoles (3), which were converted to 3H-imidazo[4,5-e][1,2,4]triazolo[1,5- c][1,2,3]triazines (5), aza analogues of 3H-[1,2,4]triazolo[3,2-i]purines (4), by treatment with NaNO2.
- Asano,Itano,Yamagata,Kohda
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p. 1453 - 1465
(2007/10/02)
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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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- 3-HYDROXYURIDINE, AN ALLELOPATHIC FACTOR OF AN AFRICAN TREE, BAILLONELLA TOXISPERMA
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A plant growth inhibitor was isolated from Baillonella toxisperma, a plant which may cause an allelopathic effect in the tropical rain forest of Cameroon.From spectral and chemical evidence, the inhibitor was identified as 3-hydroxyuridine.It inhibited both hypocotyl and root growth of cucumber and radish seedlings, and also inhibited root growth of rice seedlings, but not sheath growth.The foliar treatment of 3-hydroxdyuridine exhibited inhibitory effects on the growth of a wide variety of weeds; however, it was quite ineffective against the growth of the crop plant, Zea mays.The strong plant growth inhibitory activity, together with the occurence in most parts of the tree at high levels, indicated that 3-hydroxyuridine may involved in the allelopathy of the tree. - Keywords: Baillonella toxisperma; Sapotaceae; allelopathy; allelochemical; 3-hydroxyuridine; plant growth inhibitor; herbicidal activity.
- Ohigashi, Hajime,Kaji, Mikio,Sakaki, Masaharu,Koshimizu, Koichi
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p. 1365 - 1368
(2007/10/02)
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- A NEW SYNTHETIC ROUTE TO 2-DEUTERIOADENINES SUBSTITUTED OR UNSUBSTITUTED AT THE 9-POSITION
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9-alkyl-2-deuterioadenines (VIII b-d) , adenosine-2-d (VIIIe), and 2'-deoxyadenosine-2-d (VIIIf) were synthesized from the 9-substituted adenines Ib-f through cyclization of the monocyclic intermediates VIb-f with formic acid-d2 or 1-(formyl-d)-2-(1H)-pyridone.Hydrolysis of VIIIe, prepared through this synthetic route, with 0.5 N aqueous HCl ( reflux, 2h) gave adenine-2-d (VIIIa) in 77percent yield.Unambiguous assigments of the purine ring protons in the NMR spectra of the unlabeled adenines Ia-f have been made by comparison with those of the labeled adenines VIIIa-f.
- Fujii, Tozo,Saito, Tohru,Hayashibara, Hiromi,Kumazawa, Yukinari,Nakajima, Satoshi
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p. 2449 - 2454
(2007/10/02)
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