Nucleoside Transport Inhibitors: Structure鈭扐ctivity Relationships for Pyrimido[5,4-d]pyrimidine Derivatives That Potentiate Pemetrexed Cytotoxicity in the Presence of 伪1-Acid Glycopr

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• 作者：Kappusamy Saravanan ; Hannah C. Barlow ; Marion Barton ; A. Hilary Calvert ; Bernard T. Golding ; David R. Newell ; Julian S. Northen ; Nicola J. Curtin ; Huw D. Thomas ; Roger J. Griffin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 24, 2011
• 年：2011
• 卷：54
• 期：6
• 页码：1847-1859
• 全文大小：1091K
• 年卷期：v.54,no.6(March 24, 2011)
• ISSN：1520-4804

文摘

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 伪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 [³H]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.