Synthesis and Biological Evaluation of N2‐Substituted 2, 4‐Diamino‐6‐cyclohexylmethoxy‐5‐nitrosopyrimidines and Related 5‐Cyano‐NNO‐azoxy Derivatives as Cyclin‐Dependent Kinase 2 (CDK2) Inhibitors. (29th June 2016)

• Record Type: Journal Article
• Authors: Cortese, Daniela; Chegaev, Konstantin; Guglielmo, Stefano; Wang, Lan Z.; Golding, Bernard T.; Cano, Céline; Fruttero, Roberta
• Is Part Of: ChemMedChem. Volume 11:Number 16(2016)
• Page Start: 1705
• Page End: 1708
• Publication Date: 2016-06-29
• Subjects: antitumor agents -- cyclin-dependent kinases -- inhibitors -- nitrosation -- substituted pyrimidines; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600108
• Languages: English
• ISSNs: 1860-7179

Abstract

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 was8 b ((2 S )‐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 was9 b (4‐amino‐5‐[( Z )‐cyano‐NNO‐azoxy]‐2‐{[(2 S )‐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. Abstract : Say yes to NNO ! Starting from compound NU6027, a series of 2, 4‐diamino‐5‐nitrosopyrimidines were synthesized. Structure–activity relationship studies of this compound class led to an improved understanding of the criteria for inhibitory activity toward cyclin‐dependent kinase 2. The cyano‐NNO‐azoxy substituent was confirmed to be a valuable alternative to a 5‐nitroso group.