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Synthesis and biological evaluation of 5-substituted O4-alkylpyrimidines as CDK2 inhibitors

Lookup NU author(s): Dr Francesco Marchetti, Dr Celine CanoORCiD, Professor Nicola CurtinORCiD, Emeritus Professor Bernard Golding, Professor Roger Griffin, Dr Karen Haggerty, Professor Herbie Newell, Rachel Parsons, Sara Payne, Lan Wang, Dr Ian HardcastleORCiD


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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 IC50 = 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 IC50 = 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 mu M).

Publication metadata

Author(s): Marchetti F, Cano C, Curtin NJ, Golding BT, Griffin RJ, Haggerty K, Newell DR, Parsons RJ, Payne SL, Wang LZ, Hardcastle IR

Publication type: Article

Publication status: Published

Journal: Organic & Biomolecular Chemistry

Year: 2010

Volume: 8

Issue: 10

Pages: 2397-2407

Print publication date: 18/03/2010

ISSN (print): 1477-0520

ISSN (electronic): 1477-0539

Publisher: Royal Society of Chemistry


DOI: 10.1039/b925481a


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