- Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase
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Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.
- Stanford, Stephanie M.,Diaz, Michael A.,Ardecky, Robert J.,Zou, Jiwen,Roosild, Tarmo,Holmes, Zachary J.,Nguyen, Tiffany P.,Hedrick, Michael P.,Rodiles, Socorro,Guan, April,Grotegut, Stefan,Santelli, Eugenio,Chung, Thomas D. Y.,Jackson, Michael R.,Bottini, Nunzio,Pinkerton, Anthony B.
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supporting information
p. 5645 - 5653
(2021/05/31)
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- Solvent-directed Regioselective Benzylation of Adenine: Characterization of N9-benzyladenine and N3-benzyladenine
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The preferred sites for the benzylation of adenine under basic conditions were proven to be the N9 and N3 positions. Formation of the N9-benzyladenine product is favored in polar aprotic solvents, such as DMSO, whereas the proportion of N3-benzyladenine f
- Buyens, Dominique M. S.,Mangondo, Paidamwoyo,Cukrowski, Ignacy,Pilcher, Lynne A.
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p. 2946 - 2950
(2017/09/26)
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- Synthetic strategies to 9-substituted 8-oxoadenines
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Three synthetic routes to 9-substituted 8-oxoadenines have been studied: bromination of adenine followed by N-9-alkylation/arylation and finally hydrolysis; bromination of adenine, hydrolysis, and N-functionalization as the last step; and N-9-alkylation of adenine, halogenation, and finally hydrolysis. As long as the N-9-functional group is compatible with conditions required for introduction of the halogen, the latter strategy was the most efficient. Also, a strategy starting from 5-amino-4,6-dichloropyrimidine was found to be a very good alternative for synthesis of 9-substituted 8-oxoadenines. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications1 to view the free supplemental file. Copyright Taylor & Francis Group, LLC.
- Siah, Huey-San Melanie,Gundersen, Lise-Lotte
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supporting information
p. 1469 - 1476
(2013/05/09)
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- SYNTHESIS OF ADENINE 7-OXIDE FROM ADENINE: UTILIZATION OF A BENZYL GROUP AS A CONTROL SYNTHON AT THE 3-POSITION
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The first unequivocal synthetic route to adenine 7-oxide (7) has been established.The route started with peroxycarboxylic acid oxidation of 3-benzyladenine (5), readily obtainable from adenine (2) by benzylation, 8nd proceeded through nonreductive debenzylation of the resulting 3-benzyladenine 7-oxide (6).
- Fujii, Tozo,Ogawa, Kazuo,Saito, Tohru,Kobayashi, Keiko,Itaya, Taisuke
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p. 477 - 480
(2007/10/02)
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- EASY ALKYLATION OF PURINE BASES BY SOLID-LIQUID PHASE TRANSFER CATALYSIS WITHOUT SOLVENT. STRUCTURAL ANALYSIS BY 2D HETERONUCLEAR 1H 13C CORRELATED NMR SPECTROSCOPY
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Solid-liquid PTC without added organic solvent promotes alkylation of purine derivatives leading in particular to an efficient synthesis of the antiviral DHPA.The location of the substituent on the ring was determined by analysis of coupling interactions
- Platzer, Nicole,Galons, Herve,Bensaid, Younes,Miocque, Marcel,Bram, Georges
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p. 2101 - 2108
(2007/10/02)
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- Heterocyclic Ambident Nucleophiles. III* The Alkylation of Sodium Adenide
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The alkylation of sodium adenide in HCONMe2 (30 deg) with various alkylating agents was analysed by 1H n.m.r. spectroscopy.Widely varying N3:N7:N9 alkylation patterns were observed, depending on the alkylating agent.These patterns are interpreted in terms of the electrostatic, thermodynamic and steric factors involved in the different SN2 transition states appropriate to each alkylating agent.Hydrogen bonding association between the 6-amino group and certain carbonyl containing alkylating agents is proposed to explain the enhancedN7-alkylation in some cases.Support for this latter proposal was obtain from a comparison of the adenine alkylation results with the corresponding alkylation patterns of 6-pivaloylamino- and 6-chloro-purine.
- Rasmussen, Malcolm,Hope, Janet M.
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p. 525 - 534
(2007/10/02)
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- Heterocyclic Ambident Nucleophiles. IV* The alkylation of Metal Salts of Adenine
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The N3:N7:N9 alkylation patterns for reactions of the lithium, sodium, and potassium salts of adenine with various alkylating agents in dimethyl sulfoxide were determined by 1H n.m.r. spectroscopy.Only for the Li+ salt was any significant effect of ionic association noticed.Of the alkylating agents used, only chloromethyl pivalate gave a concentration dependent alkylation pattern.The latter effect was most pronounced with the heterogenous alkylation conditions of anhydrous Na2CO3/HCONMe2, adenine, and chloromethyl pivalate; here, increasingconcentrations changed the main reaction from N7- to N9-alkylation.Solvent effects on the alkylation patterns were also studied.Within the common dipolar aprotic solvent group, (Me2N)3PO, HCONMe2 and Me2SO, effects were small; in protic solvents, particularly formamide, enhanced N3-alkylation was observed.
- Rasmussen, Malcolm,Hope, Janet M.
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p. 535 - 542
(2007/10/02)
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- Les systemes biphasiques. 3. Alkylation des purines en catalyse par transfert de phase (1a)
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The phase transfer catalysed methylation of adenine gave selectively 9-methyladenine (98percent), while benzylation yields 9-benzyladenine as the major product accompanied by very small amounts of the 3-isomer.Alkylation of xanthine, theobromine and theophylline by the same technique gave also the corresponding N.alkyl derivatives in high yields, with no other O-alkylated regioisomer.These alkylation procedures, owing to their simplicity and selectivity, constitute a considerable improvement upon classical techniques.
- Hedayatullah, Mir
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p. 249 - 251
(2007/10/02)
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- Phase-Transfer Catalysis in the N-Benzylation of Adenine
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A convenient phase-transfer catalysis in the N-benzylation of adenine is described.The benzylation of adenine with benzyl halides in a two-phase system containing phase-transfer catalyst gave 9-benzylated adenines as a major product accompanied with 3-benzylated adenines.
- Shinkai, I.,Zwan, M. C. Vander,Hartner, F. W.,Reamer, R. A.,Tull, R. J.,Weinstock, L. M.
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p. 197 - 198
(2007/10/02)
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