- A self-complementary nucleoside: Synthesis, solid-state structure, and fluorescence behavior
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A novel self-complementary nucleoside (AT), featuring two complementary nucleobases linked through an ethynyl group has been synthesized. The rigid aromatic nucleobases provided AT with a pale-blue fluorescence. Unlike most fluorescent organic molecules, nucleoside AT gives enhanced fluorescence in solid state. It exhibits considerably enhanced fluorescence intensity and a remarkable redshift (ca. 70 nm) in its emission maximum upon an increase in concentration or decrease in temperature as a result of the formation of aggregates stabilized through hydrogen bonding and π-π stacking of well-organized AT assemblies; these interactions are also evident in the solid-state structure, determined by X-ray crystallography. DFT calculations supported the preference of such aggregation processes.
- Bang, Eun-Kyoung,Won, Jiyeon,Moon, Dohyun,Lee, Jin Yong,Kim, Byeang Hyean
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- 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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p. 5645 - 5653
(2021/05/31)
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- INHIBITORS OF LOW MOLECULAR WEIGHT PROTEIN TYROSINE PHOSPHATASE (LMPTP) AND USES THEREOF
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Protein tyrosine phosphatases (PTPs) are key regulators of metabolism and insulin signaling. As a negative regulator of insulin signaling, the low molecular weight protein tyrosine phosphatase (LMPTP) is a target for insulin resistance and related conditions. Described herein are compounds capable of modulating the level of activity of LMPTP, compositions, and methods of using these compounds and compositions.
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Paragraph 00236; 00245
(2021/01/23)
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- INHIBITORS OF LOW MOLECULAR WEIGHT PROTEIN TYROSINE PHOSPHATASE (LMPTP) AND USES THEREOF
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Protein tyrosine phosphatases (PTPs) are key regulators of metabolism and insulin signaling. As a negative regulator of insulin signaling, the low molecular weight protein tyrosine phosphatase (LMPTP) is a target for insulin resistance and related conditions. Described herein are compounds capable of modulating the level of activity of LMPTP, compositions, and methods of using these compounds and compositions.
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Paragraph 00249; 00258; 00266; 00270; 00271
(2019/07/20)
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- Protease inhibitors (by machine translation)
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The invention relates to a Grp94 specific Hsp - 90 inhibitor, a protease inhibitor of the preparation method, to solve the existing problems on the preparation method of the blank defect, comprising the following processing steps: in the three flasks, is put into the water-free of dimethyl formamide, under the protection of nitrogen, adding 3, 5 - dichloro dithiol, completely dissolved after stirring, then slowly adding sodium hydride, stirring at room temperature the reaction 1 hours; then and then adding 8 - bromo - 9 - (3 - isopropylamino) propyl adenine, after adding gradually raising the temperature to 150 degrees, reflux reaction for 6 hours; after the reaction is complete cooling to room temperature, the reaction liquid is slowly added to the water, quenching the unreacted sodium hydride, methylene chloride/methanol mixed solution extraction, the organic phase is used for the saturated salt water and saturated ammonium chloride solution washing several times, and then after the saturated sodium bicarbonate multi-time extraction, for water-free magnesium sulfate drying, steaming and, for column chromatography column purification. (by machine translation)
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Paragraph 0023; 0036; 0037; 0038
(2018/09/28)
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- SELECTIVE GRP94 INHIBITORS AND USES THEREOF
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The disclosure relates to novel selective Grp94 inhibitors, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as cancer, comprising administering to an animal in need thereof an effective amount of such compounds.
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Paragraph 0270
(2015/02/25)
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- Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94
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Grp94 is involved in the regulation of a restricted number of proteins and represents a potential target in a host of diseases, including cancer, septic shock, autoimmune diseases, chronic inflammatory conditions, diabetes, coronary thrombosis, and stroke. We have recently identified a novel allosteric pocket located in the Grp94 N-terminal binding site that can be used to design ligands with a 2-log selectivity over the other Hsp90 paralogs. Here we perform extensive SAR investigations in this ligand series and rationalize the affinity and paralog selectivity of choice derivatives by molecular modeling. We then use this to design 18c, a derivative with good potency for Grp94 (IC50 = 0.22 μM) and selectivity over other paralogs (>100- and 33-fold for Hsp90α/β and Trap-1, respectively). The paralog selectivity and target-mediated activity of 18c was confirmed in cells through several functional readouts. Compound 18c was also inert when tested against a large panel of kinases. We show that 18c has biological activity in several cellular models of inflammation and cancer and also present here for the first time the in vivo profile of a Grp94 inhibitor.
- Patel, Hardik J.,Patel, Pallav D.,Ochiana, Stefan O.,Yan, Pengrong,Sun, Weilin,Patel, Maulik R.,Shah, Smit K.,Tramentozzi, Elisa,Brooks, James,Bolaender, Alexander,Shrestha, Liza,Stephani, Ralph,Finotti, Paola,Leifer, Cynthia,Li, Zihai,Gewirth, Daniel T.,Taldone, Tony,Chiosis, Gabriela
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p. 3922 - 3943
(2015/05/27)
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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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p. 1469 - 1476
(2013/05/09)
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- Structure-activity relationships of adenine and deazaadenine derivatives as ligands for adenine receptors, a new purinergic receptor family
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Adenine derivatives bearing substituents in the 2-, N6-, 7-, 8-, and/or 9-position and a series of deazapurines were synthesized and investigated in [3H]adenine binding studies at the adenine receptor in rat brain cortical membrane preparations (rAde1R). Steep structure-activity relationships were observed. Substitution in the 8-position (amino, dimethylamino, piperidinyl, piperazinyl) or in the 9-position (2-morpholinoethyl) with basic residues or introduction of polar substituents at the 6-amino function (hydroxy, amino, acetyl) represented the best modifications. Functional evaluation of selected adenine derivatives in adenylate cyclase assays at 1321N1 astrocytoma cells stably expressing the rAde1R showed that all compounds investigated were agonists or partial agonists. A subset of compounds was additionally investigated in binding studies at human embryonic kidney (HEK293) cells, which also express a high-affinity adenine binding site. Structure-affinity relationships at the human cell line were similar to those at the rAde1R, but not identical. In particular, N 6-acetyladenine (25, Ki rat: 2.85 μM; Ki human: 0.515 μM) and 8-aminoadenine (33, Ki rat: 6.51 μM; Ki human: 0.0341 μM) were much more potent at the human as compared to the rat binding site. The new AdeR ligands may serve as lead structures and contribute to the elucidation of the functions of the adenine receptor family. 2009 American Chemical Society.
- Borrmann, Thomas,Abdelrahman, Aliaa,Volpini, Rosaria,Lambertucci, Catia,Alksnis, Edgars,Gorzalka, Simone,Knospe, Melanie,Schiedel, Anke C.,Cristalli, Gloria,Müller, Christa E.
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supporting information; scheme or table
p. 5974 - 5989
(2010/03/24)
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- HSP90 Inhibitors Containing a Zinc Binding Moiety
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The present invention relates to HSP90 inhibitors and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 33; 38
(2008/12/08)
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- A facile one-pot synthesis of 8-oxo-7,8-dihydro-(2′-deoxy)adenosine in water
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Reaction of 2-mercaptoethanol with 8-bromo-2′-deoxyadenosine and 8-bromo-adenosine in aqueous solution and in the presence of triethylamine gave the 8-oxo-adenine derivatives in very good yields. Some mechanistic details are reported.
- Chatgilialoglu, Chryssostomos,Navacchia, Maria Luisa,Postigo, Al
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p. 711 - 714
(2007/10/03)
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- Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90
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Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC50 = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.
- Llauger, Laura,He, Huazhong,Kim, Joungnam,Aguirre, Julia,Rosen, Neal,Peters, Ulf,Davies, Peter,Chiosis, Gabriela
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p. 2892 - 2905
(2007/10/03)
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- Synthesis of acyclic nucleoside and nucleotide analogs derived from 6-amino-7H-purin-8(9H)-one
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Reaction of 8-bromoadenine derivatives 2 with sodium acetate in acetic acid and cleavage of (S)-7-[(trityloxy)methyl]-7,8-dihydro[1,3]oxazolo[3,2-e]purin-4-amine (12) and diisopropyl (S)-[[(4-amino-8,9-dihydro-7H-[1,3]oxazino[3,2-e]purin-8-yl)oxy]methyl]phosphona te (13a) were used for the synthesis of the corresponding N9-substituted derivatives of 6-amino-7H-purin-8(9H)-one 3a-3c and 7. Alkylation of 6-amino-7H-purin-8(9H)-one (3a) with diverse alkylation agents afforded the title N9-monosubstituted 3b, 3d and 7a and N7,N9-disubstituted acyclic nucleoside and nucleotide analogs 6b, 6d and 8a.
- Janeba, Zlatko,Holy, Antonin,Masojidkova, Milena
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p. 1126 - 1144
(2007/10/03)
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- Synthesis of acyclic adenine 8,N-anhydronucleosides
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9-(4-Hydroxybutyl)adenine (10) was obtained by reaction of adenine with 4-[(2-tetrahydropyran-2-yl)oxy]butyl chloride (7) in the presence of DBU. 8-Bromo-9-(4-hydroxybutyl)adenine (13) was prepared by bromination of 10 or by alkylation of 8-bromoadenine (11) with 4-bromoethyl acetate followed by methanolysis. Tosylation of compound 13 afforded the 4-tosyloxy derivative 15 which gave on heating with methylamine or cyclopropylamine 6-methyl-(17a) or 6-cyclopropyl-7,8,9,10-tetrahydro-6H-[1,3]diazepino[1,2-e]purin-4-amine (17b), while the reaction with hydrazine afforded 7,8,9,10-tetrahydro-6H-[1,3]diazepino-[1,2-e]purine-4,6-diamine (17d). Treatment of compound 13 with thionyl chloride gave 9-(4-chlorobutyl)-8-chloroadenine (18) as the main product which was transformed to 17b, 6-propyl-7,8,9,10-tetrahydro-6H-[1,3]diazepino[1,2-e]purin-4-amine (17c) or 7,8,9,10-tetrahydro-6H-[1,3]diazepino[1,2-e]purin-4-amine (17e) by reaction with cyclopropylamine, propylamine or ammonia, respectively. Compound 17e was quite stable both in acid and alkaline solutions, at room temperature or at 90 °C. Compound 13 was converted to 9-(4-hydroxybutyl)-8-methylaminoadenine (19) by reaction with methylamine. Compound 19 failed to undergo intramolecular cyclization to diazepine 17a on treatment with diphenyl carbonate, bis(4-nitrophenyl) carbonate or 1,1′-carbonyldiimidazole.
- Meszarosova, Katerina,Holy, Antonin,Masojidkova, Milena
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p. 1109 - 1125
(2007/10/03)
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- Hydrolysis of 2'-Deoxypurine Nucleosides. The Effect of Substitution at the C-8 Position.
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The hydrolytic stability of 2'-deoxypurine nucleosides is decreased by introduction of electronwithdrawing substituents at the C-8 position in the series of compounds 2-8, 10-14.The sulfone group causes a 2.9 x 104 rate acceleration for glycosidic, bond cleavage in compound 14.
- Laayoun, Ali,Decout, Jean-Luc,Lhomme, Jean
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p. 4989 - 4990
(2007/10/02)
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- A NEW METHOD FOR THE PREPARATION OF N-(NUCLEOSIDYL)-α-AMINO ACIDS USING TRIOCTYLMETHYLAMMONIUM SALTS OF α-AMINO ACIDS
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8-Bromoadenosine reacts with trioctylmethylammonium salts of α-amino acids (e.g. glycine) to yield N-(adenosin-8-yl)-α-amino acids which can be readily separated from the starting material by two subsequent extraction steps at different pH values.
- Schroeder, Frank Roland,Cramer, Friedrich
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p. 3571 - 3572
(2007/10/02)
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