5971-68-6Relevant articles and documents
Synthesis and biological evaluation of 5-substituted O4- alkylpyrimidines as CDK2 inhibitors
Marchetti, Francesco,Cano, Celine,Curtin, Nicola J.,Golding, Bernard T.,Griffin, Roger J.,Haggerty, Karen,Newell, David R.,Parsons, Rachel J.,Payne, Sara L.,Wang, Lan Z.,Hardcastle, Ian R.
experimental part, p. 2397 - 2407 (2010/07/09)
CDK2 inhibitory structure-activity relationships have been explored for a range of 5-substituted O4-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 O4-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 N2-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 N2-arylsulfonamido-5-(hydroxyiminomethyl) series the O4-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, GI50 = 0.57 μM).
