title: Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors.
abstract: CDK2 inhibitory structure-activity relationships have been explored for a range of 5-substituted O(4)-alkylpyrimidines. Variation of the 5-substituent in the 2,6-diaminopyrimidine series confirmed the 5-nitroso substituent as optimal, and showed that 5-formyl and 5-acetyl substituents were also tolerated at this position. A series of O(4)-alkyl-N(2)-aryl-5-substituted-6-aminopyrimidines revealed interesting structure-activity relationships. In the 5-nitroso series, the optimum O(4)-alkyl substituents were cyclohexylmethyl or sec-butyl, combined with a 2-sulfanilyl group. By contrast, in the N(2)-arylsulfonamido-5-formyl series, the cyclohexylmethyl compound showed relatively poor activity compared with the sec-butyl derivative (22j, (R)-4-(4-amino-6-sec-butoxy-5-formylpyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC(50) = 0.8 nM). Similarly, in the N(2)-arylsulfonamido-5-(hydroxyiminomethyl) series the O(4)-sec-butyl substituent conferred greater potency than the cyclohexylmethyl (23c, (rac)-4-(4-amino-6-sec-butoxy-5-(hydroxyiminomethyl)pyrimidin-2-ylamino)benzenesulfonamide; CDK2 IC(50) = 7.4 nM). The 5-formyl derivatives show selectivity for CDK2 over other CDK family members, and are growth inhibitory in tumour cells (e.g. 22j, GI(50) = 0.57 microM).
authors.affiliation: Northern Institute for Cancer Research, Bedson Building, Newcastle University, Newcastle Upon Tyne, UK NE1 7RU.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.forename: Céline
authors.initials: C
authors.lastname: Cano
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Karen
authors.initials: K
authors.lastname: Haggerty
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Parsons
authors.forename: Sara L
authors.initials: SL
authors.lastname: Payne
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
mesh_terms: D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D010100:Oxygen / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2; D010100:Oxygen