Toggle Main Menu Toggle Search

Open Access padlockePrints

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

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

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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 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

URL: http://dx.doi.org/10.1039/b925481a

DOI: 10.1039/b925481a


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share