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Wong C.,Northumbria University | Griffin R.J.,Northumbria University | Hardcastle I.R.,Northumbria University | Northen J.S.,Onyx Scientific Ltd | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2010

The attenuated SN2 reactivity of the 2,2,2-trifluoroethyl group has been exploited for the synthesis of a series of 6-cyclohexylmethoxy-2- arylaminopurines in which a sulfonamide moiety was attached to the aryl ring via a methylene group. These were required as potential inhibitors of serine-threonine kinases of interest for the treatment of cancer. 3-Nitrophenylmethanesulfonyl chloride was converted into the corresponding 2,2,2-trifluoroethoxysulfonyl ester by reaction with 2,2,2-trifluoroethanol in the presence of triethylamine/4-dimethylaminopyridine. Catalytic hydrogenation of the nitro group employing 2,2,2-trifluoroethanol as solvent gave 2,2,2-trifluoroethyl 3-aminophenylmethanesulfonate, which was reacted with 6-cyclohexylmethoxy-2-fluoropurine in 2,2,2-trifluoroethanol/trifluoroacetic acid to afford 2,2,2-trifluoroethyl 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino) phenylmethanesulfonate. 3-(6-Cyclohexylmethoxy-9H-purin-2-ylamino) phenylmethanesulfonamides were synthesised by microwave heating of the trifluoroethoxysulfonate with an amine and 1,8-diazabicycloundec-7-ene in tetrahydrofuran. The mechanism of this process was shown to involve an intermediate sulfene by a deuterium-labelling experiment. 3-(6- Cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide derivatives were assayed as inhibitors of human cyclin-dependent kinase 2. Previous structure-activity studies demonstrated that relocating the sulfonamide group of O6-cyclohexylmethoxy-2-(4′-sulfamoylanilino)purine from the 4- to the 3-position on the 2-arylamino ring resulted in a 40-fold reduction in potency against CDK2. In the present study, no further loss of activity was observed on introducing a methylene group between the sulfonamide and the aryl ring, 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide proving equipotent with O6-cyclohexylmethoxy-2-(3′-sulfamoylanilino) purine (IC50 = 0.21 μM). N-Alkylation of the sulfonamide reduced CDK-2 inhibitory activity, while a substituted benzyl or 3-phenylpropyl group on the sulfonamide resulted in a loss of potency compared with 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide. The dimethylaminopropyl derivative, 1-[3-(6-cyclohexylmethoxy-9H-purin-2-ylamino) phenyl]-N-(3-dimethylaminopropyl)methanesulfonamide was only 2-fold less potent than 3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenylmethanesulfonamide, suggesting an interaction between the basic dimethylamino group and the kinase. The presence of alicyclic groups on the pendant sulfonamide showed IC 50 values in the 0.5-1.5 μM range. N-(4-tert-Butylphenyl)-1-[3-(6- cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methanesulfonamide was markedly less active (IC50 = 34 μM), suggesting a steric effect within the ATP-binding domain. © 2010 The Royal Society of Chemistry. Source


Colgin N.,Durham University | Flinn T.,Onyx Scientific Ltd | Cobb S.L.,Durham University
Organic and Biomolecular Chemistry | Year: 2011

Herein, we report the synthesis of novel phenylalanine and tyrosine derivatives containing a N-methyliminodiacetic acid boronate group. These compounds can be prepared enantiomerically pure, they are stable to column chromatography and they can be stored in air for two months without degradation occurring. This new class of boronate containing aromatic amino acids has potential applications in both peptide chemistry and natural product synthesis. © 2011 The Royal Society of Chemistry. Source


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Onyx Scientific Inc. | Date: 2010-07-08

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Onyx Scientific Inc. | Date: 2010-07-29

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Onyx Scientific Inc. | Date: 2010-07-29

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