title: Synthesis and Biological Evaluation of N(2) -Substituted 2,4-Diamino-6-cyclohexylmethoxy-5-nitrosopyrimidines and Related 5-Cyano-NNO-azoxy Derivatives as Cyclin-Dependent Kinase 2 (CDK2) Inhibitors.
abstract: The potent and selective cyclin-dependent kinase 2 (CDK2) inhibitor NU6027 (6-cyclohexylmethoxy-5-nitroso-2,4-diaminopyrimidine) was used as the lead for the synthesis of a series of analogues in order to provide further insight into the structure-activity relationships for 2,4-diaminopyrimidine CDK2 inhibitors. Aliphatic amino substituents were introduced at position 2. The use of linear or less sterically hindered amines gave rise to compounds endowed with slightly better activity than the lead; on the other hand, the compounds were less active if a bulkier amino substituent was used. Substitution of the 5-nitroso group with a 5-cyano-NNO-azoxy moiety afforded a new class of inhibitors, the activity of which against CDK2 was found to be similar to that of the nitroso series. The most active nitroso compound was 8 b ((2S)-2-[(4-amino-6-cyclohexylmethoxy-5-nitrosopyrimidin-2-yl)amino]propan-1-ol; IC50 =0.16 μm), while in the 5-cyano-NNO-azoxy series the most active compound was 9 b (4-amino-5-[(Z)-cyano-NNO-azoxy]-2-{[(2S)-1-hydroxypropan-2-yl]amino}-6-cyclohexylmethoxypyrimidine; IC50 =0.30 μm). Taken together, these new analogues of NU6027 enhance our understanding of the structure-activity relationships for 2,4-diaminopyrimidine CDK2 inhibitors.
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cortese
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.
authors.forename: Lan Z
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Northern Institute for Cancer Research, Bedson Building, School of Chemistry, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.affiliation: Northern Institute for Cancer Research, Bedson Building, School of Chemistry, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK.
authors.forename: Céline
authors.initials: C
authors.lastname: Cano
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, Italy. roberta.fruttero@unito.it.
authors.forename: Roberta
authors.identifier: 0000-0001-6726-1254
authors.initials: R
authors.lastname: Fruttero
mesh_terms: D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; 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: C000619891:2-((4-amino-6-cyclohexylmethoxy-5-nitrosopyrimidin-2-yl)amino)propan-1-ol; C000619892:4-amino-5-(cyano-NNO-azoxy)-2-((1-hydroxypropan-2-yl)amino)-6-cyclohexylmethoxypyrimidine; D001391:Azo Compounds; D009603:Nitroso Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: antitumor agents; cyclin-dependent kinases; inhibitors; nitrosation; substituted pyrimidines