Home
Resources
Publications
N2-substituted O6-cyclohexylmethylguanine Derivatives: Potent Inhibitors of Cyclin-Dependent Kinases 1 and 2

N2-substituted O6-cyclohexylmethylguanine Derivatives: Potent Inhibitors of Cyclin-Dependent Kinases 1 and 2

Ian R Hardcastle, Christine E Arris, Johanne Bentley, F Thomas Boyle, Yuzhu Chen, Nicola J Curtin, Jane A Endicott, Ashleigh E Gibson, Bernard T Golding, Roger J Griffin, Philip Jewsbury, Jerome Menyerol, etc.

J Med Chem. 2004 Jul 15;47(15):3710-22.

PMID: 15239650

Abstract:

The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N(2)-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N(2)-NH group and the requirement for an aromatic N(2)-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC(50) = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC(50) = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC(50) = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP161058839	NU2058		161058-83-9	Price

As a specialist in analytical chemical Products, Alfa Chemistry offers consumers a wealth of raw materials and a full range of technologies and services.

QUICK LINKS

HEADQUARTERS

Tel:

Fax:

Email: