- N-Substituted pyrrolopyrimidines and purines as p90 ribosomal S6 protein kinase-2 (RSK2) inhibitors
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The RSK2 kinase is the downstream effector of the Ras/Raf/MEK/ERK pathway, that is often aberrantly activated in acute myeloid leukemia (AML). Recently, we reported a structure-activity study for BI-D1870, the pan-RSK inhibitor, and identified pteridinones that inhibited cellular RSK2 activity that did not result in concomitant cytotoxicity. In the current study, we developed a series of pyrrolopyrimidines and purines to replace the pteridinone ring of BI-D1870, with a range of N-substituents that extend to the substrate binding site to probe complementary interactions, while retaining the 2,6-difluorophenol-4-amino group to maintain interactions with the hinge domain and the DFG motif. Several compounds inhibited cellular RSK2 activity, and we identified compounds that uncoupled cellular RSK2 inhibition from potent cytotoxicity in the MOLM-13 AML cell line. These N-substituted probes have revealed an opportunity to further examine substituents that extend from the ATP- to the substrate-binding site may confer improved RSK potency and selectivity.
- Casalvieri, Kimberly A.,Matheson, Christopher J.,Warfield, Becka M.,Backos, Donald S.,Reigan, Philip
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supporting information
(2021/06/02)
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- Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation
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The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations.
- Calzaferri, Francesco,Narros-Fernández, Paloma,De Pascual, Ricardo,De Diego, Antonio M.G.,Nicke, Annette,Egea, Javier,García, Antonio G.,De Los Ríos, Cristóbal
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p. 2272 - 2290
(2021/03/01)
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- 2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
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Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5-10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2. This journal is
- Bayliss, Richard,Boxall, Kathy,Carbain, Benoit,Coxon, Christopher R.,Fry, Andrew M.,Golding, Bernard T.,Griffin, Roger J.,Hardcastle, Ian R.,Harnor, Suzannah J.,Mas-Droux, Corine,Matheson, Christopher J.,Newell, David R.,Richards, Mark W.,Sivaprakasam, Mangaleswaran,Turner, David,Cano, Céline
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p. 707 - 731
(2020/08/24)
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- Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines
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Purines and related heterocycles substituted at C-2 with 4′-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at
- Coxon, Christopher R.,Anscombe, Elizabeth,Harnor, Suzannah J.,Martin, Mathew P.,Carbain, Benoit,Golding, Bernard T.,Hardcastle, Ian R.,Harlow, Lisa K.,Korolchuk, Svitlana,Matheson, Christopher J.,Newell, David R.,Noble, Martin E. M.,Sivaprakasam, Mangaleswaran,Tudhope, Susan J.,Turner, David M.,Wang, Lan Z.,Wedge, Stephen R.,Wong, Christopher,Griffin, Roger J.,Endicott, Jane A.,Cano, Céline
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p. 1746 - 1767
(2017/03/17)
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- A 2 - fluoro adenine synthesis method (by machine translation)
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The invention discloses a 2 - fluoro adenine synthesis method. Cheap 6 - chloropurine as raw materials, to the 9 bit NH to tetrahydropyranyl protection, then and trifluoromethanesulfonic anhydride reaction, in 2 introduces nitro, then and NH4 F reaction, nitro into atomic fluorine will at the same time, getting rid of the tetrahydro-pyranyl, finally being ammonia saturated methanol solution, the 6 position chlorine atom is converted into amino, to obtain 2 - fluoro adenine, total yield of 58%. The method easily obtained and cheap materials, to avoid the use of expensive and harmful toxic reagent, avoid the use of dangerous and corrosivity of the operation steps, and the reaction scale expanded to 200 g of the scale, the yield is not obviously dropped. The invention application for 2 - fluoro adenine synthesis provides a new synthetic pathway, has potential application prospect. (by machine translation)
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Paragraph 0019; 0025; 0026
(2017/10/13)
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- Synthesis of some biologically active halogenopurines
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A series of some biologically active halogenopurines were synthesized from commercially available guanine (1). The reaction of guanine with acetic anhydride yielded 2,9-diacetylguanine (2-1) by acetylation reaction. Further treatment of 2-1 with POCl3 by PEG-2000 phase transfer catalysis furnished the important compound 3a, then 2-amino-6-halogenopurines (3b-d) were obtained through chlorine-exchange halogenations between KX and 3a by TPPB phase transfer catalyst. Further, 2-halogenopurines (2-2a-d, 4-2a-d, 5a-d) were efficiently prepared from 2-amino-6-substituted purines (1, 3a, 4-1) via a diazotization catalyzed by their corresponding CuX, and some new compounds 2-2a, 2-2c, 2-2d, 4-2c, 4-2d, 5b, 5c and 5d have been discovered. The structures of synthesized compounds were mainly established on the basis of their elemental analysis, 1H NMR, as well as their mass spectral data. All the title compounds were screened for their antifungal activities, and some of the compounds showed promising activity.
- Hu, Yu Lin,Liu, Xiang,Lu, Ming,Ge, Qiang,Liu, Xiao Bin
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experimental part
p. 429 - 436
(2010/12/29)
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- 2,6,9-Trisubstituted purine derivatives as protein A mimetics for the treatment of autoimmune diseases
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A series of 9-substituted and 2,9-disubstituted 6-(3-aminophenylamino) purines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 6-(3-aminoani
- Zacharie, Boulos,Fortin, Daniel,Wilb, Nicole,Bienvenu, Jean-Francois,Asselin, Michel,Grouix, Brigitte,Penney, Christopher
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scheme or table
p. 242 - 246
(2009/05/26)
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- Purine Derivatives, Compositions Containing Them and Use Thereof
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Purine derivatives of formula (IA1) or (IB1), compositions containing them and use thereof as medicinal products, in particular in oncology, are described
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Page/Page column 9
(2008/12/05)
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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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body text
p. 9268 - 9275
(2009/04/05)
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- PURINE DERIVATIVES AND THEIR USE FOR TREATMENT OF AUTOIMMUNE DISEASES
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Compounds useful in the treatment of autoimmune disease are described by the following general formula (I): n = 0-2 m = 0-2 m is not necessarily equal to n; where R1, R3 = NH2, F, Cl, C1-C4 alkoxy or
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Page/Page column 23-24
(2008/06/13)
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- NEW PURINE DERIVATIVES
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The present invention relates to compounds of formula (1) or pharmaceutically acceptable salts thereof, wherein one of R1 and R2 is methyl, ethyl or isopropyl, and the other is H; R3 and R4 are each independentl
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- NEW PURINE DERIVATIVES
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The present invention relates to compounds of formula (1) or pharmaceutically acceptable salts thereof, wherein one of R1 and R2 is methyl, ethyl or isopropyl, and the other is H; R3 and R4 are each independentl
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- Process for producing 2,6-dihalogenopurine
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A process for conveniently and efficiently preparing a 2,6-halogenopurine using an inexpensive starting material. A process for preparing a 2,6-dihalogenopurine, comprising treating a 2-amino-6-halogenopurine having a protective group at 7th position or 9th position with a diazotizating agent and a halogen source; and a process for preparing a 9-acyl-2-amino-6-halogenopurine, comprising treating a 2-amino-6-halogenopurine with an acylating agent in the presence of a base.
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- Purine derivatives
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This invention relates to compounds of the general formula: in which RA, RB, RC and RD are as defined herein, and to their preparation and use.
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- Combinatorial synthesis of 2,9-substituted purines
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A method for the combinatorial synthesis of 2,9-substituted purines using a Mitsunobu reaction to alkylate the N-9 position and an amination reaction to install amines at the C-2 position has been developed.
- Gray, Nathanael S.,Kwon, Soojin,Schultz, Peter G.
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p. 1161 - 1164
(2007/10/03)
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- A Highly Stereoselective Synthesis of Anti-HIV 2',3'-Dideoxy- and 2',3'-Didehydro-2',3'-dideoxynucleosides
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A general total synthesic method for the stereocontrolled synthesis of 2',3'-dideoxy- as well as 2',3'-didehydro-2',3'-dideoxynucleosides is presented.Introduction of an α-phenylselenenyl group at the 2-position of 2,3-dideoxyribosyl acetate directs the glycosyl bond formation to give >/=95percent β-isomer.This 2'-phenylselenenyl nucleoside may be converted to either the 2',3'-dideoxynucleoside by treatment with n-Bu3SnH and Et3B at room temperature or to the unsaturated derivative by treatment with H2O2/cat. pyridine.The application of this method to the syntheses of pyrimidines (ddU, ddT, ddC), 6-substituted purines (ddA, ddI, 6-chloro-ddP, N6-Me-ddA), and 2,6-disubstituted purines (2-F-ddA, 6-chloro-2-amino-ddP) as well as selected 2',3'-didehydro-2',3'-dideoxy derivatives is reported.
- Beach, J. Warren,Kim, Hea O.,Jeong, Lak S.,Nampalli, Satyanarayana,Islam, Qamrul,et al.
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p. 3887 - 3894
(2007/10/02)
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