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Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6- aminopyrimidine inhibitors of cyclin-dependent kinase 2

Lookup NU author(s): Dr Francesco Marchetti, Kerry Louise Sayle, Dr Johanne Bentley, Professor William Clegg, Professor Nicola CurtinORCiD, Professor Jane Endicott, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Karen Haggerty, Dr Ross Harrington, Dr Veronique Mesguiche, Professor Herbie Newell, Rachel Parsons, Lan Wang, Dr Ian HardcastleORCiD, Professor Martin NobleORCiD

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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 O 6-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. This journal is © The Royal Society of Chemistry.

Publication metadata

Author(s): Marchetti F, Sayle KL, Bentley J, Clegg W, Curtin NJ, Endicott JA, Golding BT, Griffin RJ, Haggerty K, Harrington RW, Mesguiche V, Newell DR, Noble MEM, Parsons RJ, Pratt DJ, Wang L, Hardcastle IR, Mesguiche V, Newell DR, Noble MEM, Parsons RJ, Pratt DJ, Wang L, Hardcastle IR

Publication type: Article

Publication status: Published

Journal: Organic and Biomolecular Chemistry

Year: 2007

Volume: 5

Issue: 10

Pages: 1577-1585

Date deposited: 05/07/2010

ISSN (print): 1477-0520

ISSN (electronic): 1477-0539

Publisher: Royal Society of Chemistry

URL: http://dx.doi.org/10.1039/b703241b

DOI: 10.1039/b703241b

PubMed id: 17571187

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