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Synthesis of sulfonamide-based kinase inhibitors from sulfonates by exploiting the abrogated SN2 reactivity of 2,2,2-trifluoroethoxysulfonates

Lookup NU author(s): Dr Christopher Wong, Professor Roger Griffin, Dr Ian HardcastleORCiD, Dr Julian Scott Northen, Lan Wang, Emeritus Professor Bernard Golding


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The attenuated S(N)2 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 O-6-cyclohexyl-methoxy2-(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 O-6-cyclohexylmethoxy-2-(3'-sulfamoylanilino)purine (IC50 = 0.21 mu M). 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 IC50 values in the 0.5-1.5 mu M range. N-(4-tert-Butylphenyl)-1-[3-(6-cyclohexylmethoxy-9H-purin-2-ylamino)phenyl]methanesulfonamide was markedly less active (IC50 = 34 mu M), suggesting a steric effect within the ATP-binding domain.

Publication metadata

Author(s): Wong C, Griffin RJ, Hardcastle IR, Northen JS, Wang LZ, Golding BT

Publication type: Article

Publication status: Published

Journal: Organic & Biomolecular Chemistry

Year: 2010

Volume: 8

Issue: 10

Pages: 2457-2464

Print publication date: 24/03/2010

ISSN (print): 1477-0520

ISSN (electronic): 1477-0539

Publisher: Royal Society of Chemistry


DOI: 10.1039/b922717b


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