- Enhanced selectivity for inhibition of analog-sensitive protein kinases through scaffold optimization
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The ability to inhibit any protein kinase of interest with a small molecule is enabled by a combination of genetics and chemistry. Genetics is used to modify the active site of a single kinase to render it distinct from all naturally occurring kinases. Next, organic synthesis is used to develop a small molecule, which does not bind to wild-type kinases but is a potent inhibitor of the engineered kinase. This approach, termed chemical genetics, has been used to generate highly potent mutant kinase-specific inhibitors based on a pyrazolopyrimidine scaffold. Here, we asked if the selectivity of the resulting pyrazolopyrimidines could be improved, as they inhibit several wild-type kinases with low-micromolar IC50 values. Our approach to improve the selectivity of allele-specific inhibitors was to explore a second kinase inhibitor scaffold. A series of 6,9-disubstituted purines was designed, synthesized, and evaluated for inhibitory activity against several kinases in vitro and in vivo. Several purines proved to be potent inhibitors against the analog-sensitive kinases and exhibited greater selectivity than the existing pyrazolopyrimidines.
- Zhang, Chao,Shokat, Kevan M.
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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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- Copper-Catalyzed C NH2Arylation of 2-Aminobenzimidazoles and Related C-Amino-NH-azoles
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A copper(II)-catalyzed selective C NH2arylation of 2-aminobenzimidazoles and related C-amino-NH-azoles was achieved in presence of 2,2′-bipyridine and cesium carbonate at 60 °C under open air conditions and this is first method for the copper-catalyzed selective C NH2arylation in the presence of other reactive nucleophilic sites. Previously unexplored heteroaromatics possessing multiple nucleophilic sites that are selectively arylated at the C NH2position are obtained, providing an exceptional tool for rapid delivery of a diverse array of medicinally important C NH(aryl) derivatives of aminoazoles without any protection/deprotection of ring N H bonds. It is first example for the selective C NH2arylation of 5-aminoindazole, 4-aminopyrazole, 5-aminopyrazole, 9H-purine-6-amine, and 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives. (Figure presented.) .
- Rao, Desaboini Nageswar,Rasheed, Sk.,Kumar, Karampoori Anil,Reddy, Annem Siva,Das, Parthasarathi
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- Chemoenzymatic synthesis of cytokinins from nucleosides: Ribose as a blocking group
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Nucleoside phosphorylases are involved in the salvage pathways of nucleoside biosynthesis and catalyze the reversible reaction of a nucleobase with α-d-ribose-1-phosphate to yield a corresponding nucleoside and an inorganic phosphate. The equilibrium of these reactions is shifted towards nucleosides, especially in the case of purines. Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) is widely used in labs and industry for the synthesis of nucleosides of practical importance. Bacterial PNPs have relatively broad substrate specificity utilizing a wide range of purines with different substituents to form the corresponding nucleosides. To shift the reaction in the opposite direction we have used arsenolysis instead of phosphorolysis. This reaction is irreversible due to the hydrolysis of the resulting α-d-ribose-1-arsenate. As a result, heterocyclic bases are formed in quantitative yields and can be easily isolated. We have developed a novel method for the preparation of cytokinins based on the enzymatic cleavage of the N-glycosidic bond of N6-substituted adenosines in the presence of PNP and Na2HAsO4. According to the HPLC analysis the conversion proceeds in quantitative yields. In the proposed strategy the ribose residue acts as a protective group. No contamination of the final products with AsO43- has been detected via HPLC-HRMS; simple analytical arsenate detection via ESI-MS has been proposed.
- Oslovsky, Vladimir E.,Solyev, Pavel N.,Polyakov, Konstantin M.,Alexeev, Cyril S.,Mikhailov, Sergey N.
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- Differential Pharmacophore Definition of the cAMP Binding Sites of Neuritogenic cAMP Sensor-Rapgef2, Protein Kinase A, and Exchange Protein Activated by cAMP in Neuroendocrine Cells Using an Adenine-Based Scaffold
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We recently reported that the adenylate cyclase (AC) inhibitor SQ22,536 (9-tetrahydrofuranyl-adenine) also has inhibitory activity against the neuroendocrine-specific neuritogenic cAMP sensor-Rapgef2 (NCS-Rapgef2), a guanine nucleotide exchanger and activator for the small effector GTPase Rap1. Cell-based assays that distinguish signaling through the three intracellular cAMP sensors NCS-Rapgef2, exchange protein activated by cAMP (Epac), and protein kinase A (PKA), as well as AC, were used. These, collectively, assess the activities of adenine (6-amino-purine) derivatives modified at several positions to enhance selectivity for NCS-Rapgef2 by decreasing affinity for adenylate cyclase (AC), without increasing affinity for PKA or Epac. Testing of each adenine derivative in whole-cell assays incorporates features of cell permeability, target selectivity, and intrinsic potency into a single EC50 or IC50, making robust extrapolation to compound activity in vivo more likely. N6-MBC-cAMP is a selective PKA activator (EC50 = 265 μM) with low efficacy at NCS-Rapgef2. 8-CPT-2′-O-Me-cAMP and ESI-09 are confirmed as Epac-selective, for stimulation and inhibition, respectively, versus both PKA and NCS-Rapgef2. The compound N6-Phe-cAMP is a full agonist of NCS-Rapgef2 (EC50 = 256 μM). It has little or no activity against Epac or PKA. The compound N6-phenyl-9-tetrahydrofuranyladenine is a novel and potent NCS-Rapgef2 inhibitor without activity at PKA, Epac, or ACs, as assayed in the neuroendocrine NS-1 cell line. This line has been engineered to allow high-content screening for activation and inhibition of AC, PKA, Epac, and NCS-Rapgef2 and the cellular activities initiated by these signaling pathway protein components.
- Emery, Andrew C.,Alvarez, Ryan A.,Eiden, Maribeth V.,Xu, Wenqin,Siméon, Fabrice G.,Eiden, Lee E.
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- Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors
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The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive.
- Monastyrskyi, Andrii,Bayle, Simon,Quereda, Victor,Grant, Wayne,Cameron, Michael,Duckett, Derek,Roush, William
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supporting information
p. 400 - 404
(2017/12/28)
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- Method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK)
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The present invention relates to a method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) and the use of the compounds in the prevention or treatment of disease, including pre-diabetes, type 2 diabetes, syndrome X, metabolic syndrome and obesity.
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Paragraph 0051-0052
(2014/10/16)
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- SERMS FOR THE TREATMENT OF ESTROGEN RECEPTOR-MEDIATED DISORDERS
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Novel compounds for the treatment of estrogen receptor-mediated disorders, including breast cancer, and methods of treatment using the novel compounds. The novel compounds, when administered in a safe and effective amount, present extended binding to estrogen receptors in breast tissue without activating the estrogen receptors. Estrogen is blocked from binding to the estrogen receptors for an extended period of time, effectively hindering growth of breast cancer cells.
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Page/Page column 8
(2012/11/06)
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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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body text
p. 9268 - 9275
(2009/04/05)
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- An efficient synthesis of substituted cytosines and purines under focused microwave irradiation
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A rapid nucleophilic displacement reaction of 6-chloropurine, 2-amino-6-chloropurine and 5-bromocytosine with various nucleophiles under focused microwave irradiation is described. Using this method, the desired products were obtained with the yields up to 99% in?a?short reaction time.
- Huang, Ling-Kuen,Cherng, Yen-Chih,Cheng, Yann-Ru,Jang, Jing-Pei,Chao, Yi-Ling,Cherng, Yie-Jia
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p. 5323 - 5327
(2008/02/01)
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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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- Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors
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On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
- Laufer, Stefan A.,Domeyer, David M.,Scior, Thomas R. F.,Albrecht, Wolfgang,Hauser, Dominik R. J.
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p. 710 - 722
(2007/10/03)
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- Synthesis of 6-alkyl- and arylamino-9-(tetrahydro-2-pyranyl)purines via 6-methylsulfonylpurine
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A series of six potential plant hormones, 6-alky- and arylamino-9- (tetrahydro-2-pyranyl)purines were prepared in three steps in 35 to 45% overall yield from 6-methylthiopurine via 6-methylsulfonylpurine.
- Villar, Jose Daniel Figueroa,Motta, Marita Almeida
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p. 1005 - 1015
(2007/10/03)
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- Synthesis of New 1-Chalcogenapurines by the Reaction of 5-Aminoimidazole-4-carbonitrile with Isochalcogenocyanates
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1-Chalcogenapurines and 1-substituted 1,6-dihydro-6-imino-9H-purine 2(3H)-chalcogenone (4a,b,13) were synthesized by the reaction of 5(4)-aminoimidazole -4(5)-carbonitrile (3) with various isochalcogenocyanates in pyridine.The reaction of 3 with methyl isothiocyanate in pyridine afforded only the 1,6-dihydro-1-methyl-6-imino-9H-purine-2(3H)-thione (4a).On the other hand, the reactions of 3 with ethoxycarbonyl isothiocyanate, benzoyl isothiocyanate or benzhydryl isoselenocyanate preferentially gave the 1-chalcogenapurine derivatives (12c,d, 15).In turn, both 1,6-dihydro-1-phenyl-6-imino-9H-purine-2(3H)-thione (4b) and 6,9-dihydro-2-phenylamino-6-(3-phenylthioureido)imino-1-thiapurine (6) were produced by the reaction of 3 with phenylisothiocyanate.Modes of cyclization reactions involving 3 and isochalcogenocyanate (R-N=C=X, X: S,Se) depend in remarkable extent on the chalcogene atom as well as R portion of R-N=C=X.
- Matsumoto, Hiroatsu,Hara, Sumiko,Nagata, Nobuyuki,Ikeda, Kazuyoshi,Mizuno, Yoshihisa
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- Decomplexation of (η-Arene)(η-cyclopentadienyl)iron(II) Hexafluorophosphates: a Convenient One-pot Arylation Procedure
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A study has been made of the relative merits of range of decomplexation reagents in the demetallation of salts. 1,8-Phenanthroline have good yields of the free ligand when simple arene complexes were used but did not demetallate more sterically hindered species.The reaction was found to be light sensitive.Bipyridine gave much lower yields.Potassium tert-butoxide in pyridine or DMSO was found to be an excellent demetallating agent even with sterically crowded complexes.A one-pot arylation procedure was developed and extended to include a number of important heterocyclic derivatives.The mechanism of these decomplexation reactions is briefly adressesd.
- Brown, Richard A.,Fernando, Sharon I. S.,Roberts, Roger M. G.
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p. 197 - 202
(2007/10/02)
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