title: 4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2.
abstract: The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs cdk2/cyclinA3=2.2+/-0.6 microM), 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 O(4)-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2 microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity. Substitutions at the N(6) 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 (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3A 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.
authors.affiliation: Northern Institute of Cancer Research and Department of Chemistry, Bedson Building, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Mesguiche
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Parsons
authors.forename: Christine E
authors.initials: CE
authors.lastname: Arris
authors.forename: Johanne
authors.initials: J
authors.lastname: Bentley
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Boyle
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Davies
authors.forename: Jane A
authors.initials: JA
authors.lastname: Endicott
authors.forename: Ashleigh E
authors.initials: AE
authors.lastname: Gibson
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Philip
authors.initials: P
authors.lastname: Jewsbury
authors.forename: Louise N
authors.initials: LN
authors.lastname: Johnson
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Martin E M
authors.initials: ME
authors.lastname: Noble
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D042846:CDC2-CDC28 Kinases; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C475622:4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009603:Nitroso Compounds; D011743:Pyrimidines; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases