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