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4-Alkoxy-2,6-diaminopyrimidine derivatives: Inhibitors of cyclin dependent kinases 1 and 2

Lookup NU author(s): Dr Veronique Mesguiche, Rachel Parsons, Dr Christine Arris, Dr Johanne Bentley, Professor Nicola Curtin, Professor Jane Endicott, Dr Ashleigh Gibson, Professor Bernard Golding, Professor Roger Griffin, Professor Herbie Newell, Professor Martin Noble, Lan Wang, Dr Ian Hardcastle

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Abstract

The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC50 vs cdk1/cyclinB1=2.9±0.1 μM and IC50 vs cdk2/cyclinA3=2.2±0.6 μM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O4-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC50 vs cdk1/cyclinB1=12±2 μM and cdk2/cyclinA3=13±4 μM) retaining significant activity. Substitutions at the N6 position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC50 vs cdk1/cyclinB1=35±3 μM and cdk2/cyclinA3=43±3 μM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3 Å resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series. © 2002 Elsevier Science Ltd. All rights reserved.


Publication metadata

Author(s): Mesguiche, V, Parsons, R.J., Arris, C.E., Bentley, J., Boyle, F., Curtin, N.J., Davies, T.G., Endicott, J., Gibson, A., Golding, B., Griffin, R.J., Jewsbury, P., Johnson, L.N., Newell, D.R., Noble, M.E.M., Wang, L., Hardcastle, I.R.

Publication type: Article

Publication status: Published

Journal: Bioorganic and Medicinal Chemistry Letters

Year: 2003

Volume: 13

Issue: 2

Pages: 217-222

Print publication date: 01/01/2003

ISSN (print): 0960-894X

ISSN (electronic): 1464-3405

URL: http://dx.doi.org/10.1016/S0960-894X(02)00884-3

DOI: 10.1016/S0960-894X(02)00884-3

PubMed id: 12482427


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