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Nucleoside Transport Inhibitors: Structure-Activity Relationships for Pyrimido[5,4-d]pyrimidine Derivatives That Potentiate Pemetrexed Cytotoxicity in the Presence of α1-Acid Glycoprotein

Lookup NU author(s): Dr Kappusamy Saravanan, Hannah Barlow, Marion Barton, Professor Hilary Calvert, Professor Bernard Golding, Professor Herbie Newell, Dr Julian Scott Northen, Professor Nicola Curtin, Huw Thomas, Professor Roger Griffin

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Abstract

Membrane transport of nucleosides or nucleobases is mediated by transporters including the equilibrative nucleoside transporters (ENTs), and resistance to antitumor antimetabolite drugs may arise via salvage of exogenous purine or pyrimidine nucleosides or nucleobases by ENT transporters. The therapeutic utility of dipyridamole (3), a potent ENT inhibitor, is compromised by binding to the serum protein alpha(1)-acid glycoprotein (AGP). Derivatives and prodrugs of the ENT inhibitor 4,8-bis[(3,4-dimethoxybenzyl)amino]-2,6-bis[(2-hydroxypropyl)amino]pyrimido[5,4-d]pyrimidine (6, NU3108) are described, with improved in vivo pharmacokinetic properties and reduced AGP binding relative to dipyridamole. The mono- and diglycine carbamate derivatives were at least as potent as 6 and showed no reduction in potency by AGP. In a [H-3]thymidine incorporation assay, employing COR-L23 cells, the diastereoisomers of 6 (IC50 = 26 nM) exhibited activity comparable with 3 (IC50 = 15 nM). The monophenyl carbamate and mono-4-methoxyphenyl carbamate exhibited the best ENT-inhibitory activity in the COR-L23 assay (IC50 =8 and 4 nM, respectively). All of the new prodrugs were also highly effective at reversing thymidine/hypoxanthine rescue from pemetrexed cytotoxicity in the COR-L23 cell line.


Publication metadata

Author(s): Saravanan K, Barlow HC, Barton M, Calvert AH, Golding BT, Newell DR, Northen JS, Curtin NJ, Thomas HD, Griffin RJ

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2011

Volume: 54

Issue: 6

Pages: 1847-1859

Print publication date: 02/03/2011

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/jm101493z

DOI: 10.1021/jm101493z


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