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- W2262610395 abstract "B245 Cyclin-dependent kinases (CDKs) are a class of serine/threonine protein kinases that regulate progression of the eukaryotic cell-cycle, and act especially at cell-cycle checkpoints.[1] Aberrant cell-cycle progression is associated with loss of checkpoint function, which correlates with increased CDK activity in human tumours.[2] On this premise CDK inhibitors may have therapeutic benefits for the treatment of cancer and other proliferative diseases.[3] A structure-based approach to inhibitor design resulted in the identification of 2-arylamino-O6-alkylguanines as potent inhibitors of CDK2. These were exemplified by NU6102 (4-(6-(cyclohexylmethoxy)-9H-purin-2-ylamino)benzenesulfonamide; IC50 = 5 nM). Structure-activity studies with this inhibitor class revealed that the purine core is not a prerequisite for potent inhibition of CDKs. Thus, compounds containing the 2,6-diamino-4-alkoxypyrimidine pharmacophore have been recognized as an alternative class of CDK inhibitors. Comparable activity to the purines has been found in the corresponding pyrimidines, where an intramolecular hydrogen bond between a 5-substituent, e.g. nitroso, and a 6-amino group imposes a 9purine-mimetic9 structure (4-(4-amino-6-(cyclohexylmethoxy)-5-nitrosopyrimidin-2-ylamino)benzenesulfonamide; IC50 = 1 nM versus CDK2).[4] Results for the corresponding O6-alkylguanines guided systematic structural modifications at the pyrimidine 2-, 4- and 5-positions.[5] Replacement of the 5-nitroso substituent of the parent inhibitor by a group that is more acceptable from a toxicological standpoint has been one of the most prominent goals of this work. The synthesis and structure-activity relationships for the new series of CDK inhibitors, exemplified by 4-(4-amino-6-(cyclohexylmethoxy)-5-formylpyrimidin-2-ylamino)benzenesulfonamide (IC50 = 49 nM versus CDK2), will be discussed in this presentation. 1. Morgan, D. O. Annu. Rev. Cell Dev. Biol. 1997, 13, 261. 2. Harper, J. W., Adams, P. D. Chem. Rev. 2001, 101, 2511; Adams, J. A. Chem. Rev. 2001, 101, 2271. 3. Meijer, L.; Leclerc S; Leost, M. Pharmacol.Ther. 1999, 82, 279. 4. Sayle, K. L. ; Bentley, J.; Boyle, F. T.; Calvert, A. H.; Cheng, Y.; Curtin, N. J.; Endicott, J. A.; Golding, B. T.; Hardcastle, I. R.; Jewsbury, P.; Mesguiche, V.; Newell, D. R.; Noble, M. E. M.; Parsons, R. J.; Pratt, D. J.; Wang, L. Z.; Griffin, R. J. Bioorg. Med. Chem. Lett. 2003, 13, 3079; 5. 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.; Hardcastle, I. R. Org. Biomol. Chem. 2007, 5, 1577." @default.
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- W2262610395 date "2007-11-01" @default.
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- W2262610395 title "Design and synthesis of inhibitors of cyclin-dependent kinases as potential antitumor agents" @default.
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