Marchetti, F. et al. (2007) Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2. Organic and Biomolecular Chemistry, 5(10), pp. 1577-1585. (doi: 10.1039/b703241b) (PMID:17571187)
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Abstract
An efficient synthesis of 2-substituted O4-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure–activity relationships (SARs) are similar to those observed for the corresponding O6-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)- benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 ± 0.1 and 0.8 ± 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Sayle, Dr Kerry |
| Authors: | Marchetti, F., Sayle, K. L., Bentley, J., Clegg, W., Curtin, N. J., Endicott, J. A., Golding, B. T., Griffin, R. J., Haggerty, K., Harrington, R. W., Mesguiche, V., Newell, D. R., Noble, M. E.M., Parsons, R. J., Pratt, D. J., Wang, L. Z., and Hardcastle, I. R. |
| College/School: | College of Science and Engineering > Scottish Universities Environmental Research Centre |
| Journal Name: | Organic and Biomolecular Chemistry |
| Journal Abbr.: | Org. Biomol. Chem |
| Publisher: | Royal Society of Chemistry |
| ISSN: | 1477-0520 |
| ISSN (Online): | 1477-0539 |
| Published Online: | 23 April 2007 |
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