- Pyrimido five-membered heterocyclic compound and application as mutant IDH2 inhibitor
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The invention relates to a pyrimido five-membered heterocyclic compound and an application of the pyrimido five-membered heterocyclic compound as a mutant IDH2 inhibitor, and specifically discloses apyrimido five-membered heterocyclic compound capable of being used as a mutant IDH2 inhibitor, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof. The invention also relates to a pharmaceutical composition containing the compound, and application of the pharmaceutical composition in preparation of drugs for preventing and/or treating mutantIDH2 mediated diseases.
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Paragraph 0159-0162; 0258-0261
(2020/11/11)
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- Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer
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In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC50 values of 70.7 nM, 23.1 nM and 0.80 μM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might be related to increasing intracellular ROS levels. Importantly, compound 14d exhibited desirable pharmacokinetic (PK) properties with the intraperitoneal bioavailability of 50.8percent in ICR mice, and potent in vivo antitumor activity in the HCT116 xenograft model. Therefore, compound 14d could be considered as a promising lead compound for the development of multitargeting anticancer agents.
- Cheng, Chunhui,Ullah, Sadeeq,Yuan, Qipeng,Yun, Fan
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- Syntheses and biological evaluation of novel hydroxamic acid derivatives containing purine moiety as histone deacetylase inhibitors
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The novel hydroxamates containing purine scaffold were designed, synthesized and screened for their biological activities as histone deacetylase (HDAC) inhibitors. Some of them exhibited excellent acti-HDACs activities and antiproliferative activities, th
- Xu, Zhaoxing,Yang, Yongchao,Mai, Xi,Liu, Bin,Xiong, Yuanzhen,Feng, Lihuang,Liao, Yijing,Zhang, Yu,Wang, Huanlu,Ouyang, Leiting,Liu, Shuhao
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p. 439 - 451
(2018/04/09)
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- Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases
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Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from their regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure-activity relationship assessment of adenine-based inhibitors using biochemical and docking methods. These studies have resulted in several observations. First, interaction of an inhibitor's amine group with the conserved active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic electron-withdrawing groups at several positions in the adenine core enhance potency. The selectivity of these inhibitors was tested against heat shock protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.
- Goswami, Manibarsha,Wilke, Kaelyn E.,Carlson, Erin E.
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supporting information
p. 8170 - 8182
(2017/10/18)
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- Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases
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This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors
- Vincetti, Paolo,Caporuscio, Fabiana,Kaptein, Suzanne,Gioiello, Antimo,Mancino, Valentina,Suzuki, Youichi,Yamamoto, Naoki,Crespan, Emmanuele,Lossani, Andrea,Maga, Giovanni,Rastelli, Giulio,Castagnolo, Daniele,Neyts, Johan,Leyssen, Pieter,Costantino, Gabriele,Radi, Marco
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p. 4964 - 4975
(2015/07/02)
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- Microwave assisted synthesis of 2,6-substituted aromatic-aminopurine derivatives
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A series of novel 2, 6-diaromatic-aminopurines (6a-6t) have been synthesized from guanine and characterized fully. The effects of different catalysts on the N-alkylation of 2-position of purine ring were discussed.
- Lu, Hong-Fei,Zhang, Liang-Ze,Wu, Ding-Ming,Zhou, Jun-Tao
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experimental part
p. 1140 - 1144
(2011/11/04)
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- N-Alkylation of 2,6-dichloropurine hydrochloride with a variety of alcohols over alumina catalyst
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2,6-Dichloropurine hydrochloride reacts with various types of alcohols using different alumina catalysts and converts into its N-9-alkyl-2-chloro-6- hydroxy-9H-purine products to an extent of 49-74%. The product selectivity depends on the stability of carbocation generated from the alcohol. More stable carbocation formulates both N-7 and N-9-alkyl-2,6-dichloropurine products, whereas the less stable carbocation results in exclusively N-9-alkyl-2-chloro-6- hydroxy-9H-purine. The catalytic activity of alumina prepared using the sol-gel method has larger Brunauer, Emmett, and Teller (BET) surface area and hence shows significantly greater catalytic activity than the commercially available alumina samples. Copyright
- Tumma, Harikrishna,Nagaraju,Reddy, K. Vijayakumar
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experimental part
p. 1856 - 1866
(2010/07/02)
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- SUBSTITUTED 6-ANILINOPURINE DERIVATIVES AS INHIBITORS OF CYTOKININ OXIDASE/DEHYDROGENASE AND PREPARATIONS CONTAINING THESE DERIVATIVES
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The invention relates to substituted 6-anilinopurine derivatives of the general formula I, wherein R denotes one to five substituents independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, alkyloxy and alkyl group, and R2 denotes amino, halogen, nitro, thio, alkylthio or alkyl group for use as inhibitors of cytokinin oxidase/dehydrogenase. The invention also relates to the compositions containing these derivatives.
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Page/Page column 5-6
(2010/08/07)
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- Discovery of novel purine derivatives with potent and selective inhibitory activity against c-Src tyrosine kinase
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We report here the discovery of novel purine derivatives with potent and selective inhibitory activity against c-Src tyrosine kinase by adopting a strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and bioass
- Huang, He,Ma, Jingui,Shi, Jianmei,Meng, Linghua,Jiang, Hualiang,Ding, Jian,Liu, Hong
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experimental part
p. 4615 - 4624
(2010/08/06)
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- Novel potent inhibitors of A. thaliana cytokinin oxidase/dehydrogenase
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The synthesis of a new group of 2-X-6-anilinopurines, including compounds with potential cytokinin-like activities, with various substitutions (X = H, halogen, amino, methylthio or nitro) on the phenyl ring is described. The prepared compounds have been characterized using standard physico-chemical methods, and the influence of individual substituents on biological activity has been compared in three different bioassays, based on the stimulation of tobacco callus growth, retention of chlorophyll in excised wheat leaves and the dark induction of betacyanin synthesis in Amaranthus cotyledons. The biological activity of the prepared compounds was also assessed in receptor assays, in which the ability of the compounds to activate the cytokinin receptors AHK3 and AHK4/CRE1 was studied. Finally, the interactions of the compounds with the Arabidopsis cytokinin oxidase/dehydrogenase AtCKX2 (heterologously expressed) were investigated. Systematic testing led to the identification of two very potent inhibitors of AtCKX2: 2-chloro-6-(3-methoxyphenyl)aminopurine and 2-fluoro-6-(3-methoxyphenyl)aminopurine.
- Zatloukal, Marek,Gemrotova, Marketa,Dolezal, Karel,Havlicek, Libor,Spichal, Lukas,Strnad, Miroslav
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experimental part
p. 9268 - 9275
(2009/04/05)
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- Synthesis of C-nucleosidic ATP mimics as potential FGFR3 inhibitors
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Receptor tyrosine kinases (RTKs) play an important role in signal transduction pathways, and in particular, FGFR3 is one of the four RTKs related to the fibroblast growth factor family. This paper describes the synthesis of C-nucleosidic ATP mimics, as po
- Busca, Patricia,McCort, Isabelle,Prange, Thierry,Le Merrer, Yves
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p. 2403 - 2409
(2007/10/03)
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- Microwave-assisted regioselective synthesis of acyclic nucleosides through an alkylating reaction with 2-oxa-1,4-butanediol diacetate
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An efficient and green procedure for the synthesis of purine acyclic nucleosides through microwave-assisted, alkylation of various purine nucleobases with 2-oxa-1,4-butanediol diacetate in the absence of solvent and catalyst is described. The advantages of using this method include its environmental friendliness, simple manipulation, short reaction time, high regioselectivity, and good yields.
- Qu, Guirong,Han, Suhui,Zhang, Zhiguang,Geng, Mingwei,Xue, Feng
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p. 819 - 824
(2007/10/03)
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- USE OF 9H-PURINE-2,6-DIAMINE DERIVATIVES IN THE TREATMENT OF PROLIFERATIVE DISEASES AND NOVEL 9H-PURINE-2,6-DIAMINE DERIVATIVES
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The invention relates to the use of 9H-purine-2,6-diamine compounds and salts thereof in the treatment of proliferative diseases and for the manufacture of pharmaceutical preparations for the treatment of said diseases, pharmaceutical preparations compris
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Page/Page column 35
(2010/02/14)
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- 2-Amino-6-anilino-purines and their use as medicaments
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2-Amino-6-anilino-purine derivatives of the formula I in which the symbols are as defined in claim 1, are described. These compounds inhibit p34cdc2/cyclin Bcdc13 kinase and protein tyrosine kinase pp60c-src and can be used for treatment of hyperproliferative diseases, for example tumor diseases, and diseases which respond to inhibition of the activity of protein tyrosine kinase pp60c-src, in particular osteoporosis.
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- Synthesis and activity of 2,6,9-trisubstituted purines
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The preparation of a series of 2,6,9-trisubstituted purines and the structure-activity data for the inhibition of cyclin dependent kinase, CDK2 are presented.
- Schow, Steven R.,Mackman, Richard L.,Blum, Cheri L.,Brooks, Eric,Horsma, Amy G.,Joly, Alison,Kerwar, Suresh S.,Lee, Gavin,Shiffman, Dov,Nelson, Marek G.,Wang, Xingbo,Wick, Michael M.,Zhang, Xiaoming,Lum, Robert T.
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p. 2697 - 2702
(2007/10/03)
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- N6,9-Disubstituted Adenines: Potent, Selective Antagonists at the A1 Adenosine Receptor
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N6-Substituted 9-methyladenines are potent antagonists of the activation of A1 adenosine receptors.The present study assessed the effect of N6 and N-9-substituents on the binding of adenines to the A1 and A2 receptors, respectively, of rat brain cortex and striatum and also on the antagonism of the A2 receptor mediated stimulation of the adenylate cyclase of PC12 cells by N-ethyladenosine-5'-uronamide.The potency ranking of 9-substituted adenines varied directly with the hydrophobicity of the substituent: cyclopentyl > phenyl > tetrahydrofuryl > ethyl > methyl > 2-hydroxyethyl.The 9-substituted adenines showed little selectivity for either receptor and the R enantiomer of N6-(1-phenyl-2-propyl)-9-methyladenine was only 4-fold more potent than the S enantiomer at the A1 receptor.An N6-cyclopentyl substituent increased potency at the A1 receptor and decreased potency at the A2 receptor, resulting in selectivity for the A1 receptor of up to 39-fold.The N6-cyclopentyl group completely overshadowed the effect of the hydrophobicity of the 9-substituent.A 2-chloro substituent did not alter the potency of an N6-substituted 9-methyladenine.
- Thompson, Robert D.,Secunda, Sherrie,Daly, John W.,Olsson, Ray A.
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p. 2877 - 2882
(2007/10/02)
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