J. Iran. Chem. Soc., Vol. 2, No. 2 June 2005, pp.124~134.

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Design, Synthesis, and Cytotoxicity of 4-Sulfonamide Substituted Benzamidobenzimidazolones and an Acyl Benzimidazolone

G.A. Khodarahmia,*, C.S. Chenb, G.H. Hakimelahia,c,d, C.T. Tsengd and J.W. Chernb

aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran
bSchool of Pharmacy, National Taiwan University, Taipei, Taiwan
cInstitutes of Chemistry, Academia Sinica, Taipei 115, Taiwan
dTaiGen Biotechnology, Shin Ming Rd., Taipei 114, Taiwan

4-Sulfonamide substituted benzamidobenzimidazolones were designed and docked into the active site model of CDK2, using an oxindole inhibitor as the template. Compounds 6a-6i were then prepared from the reaction of the sulfonyl chloride 1 with different amines to give the corresponding acids (2a-2i), which were converted to their corresponding acyl chlorides (3a-3i). Reaction of 3a-3i with o-nitrophenylhydrazine afforded the respective nitro derivatives (4a-4i). The nitro groups were then reduced to give the corresponding amines (5a-5i), which, upon reaction with ethyl chloroformate, the target compounds (6a-6i) were produced. Target benzimidazolone derivatives (9a-9e) were also prepared from the reaction of isopropenyl benzimidazolone (8) with different sulfonyl or acyl chlorides. The target compounds were then tested by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against the cancer cell lines, Hep G2, HT-29, CL1-5 and AGS. Despite similar binding properties of the flexible benzamidobenzimidazolones and rigid cytotoxic oxindole inhibitors at the active site of CDK2, biological screening results indicated that benzamidobenzimidazolones did not exhibit significant cell growth inhibition in vitro. Their analogue, 3-acyl benzimidazolone (12), however, revealed cytotoxicity similar to that of the reference oxindole inhibitor.

Keywords: Benzimidazolone, Sulfonamide, Cytotoxicity, CDK2

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