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Resistance-modifying agents. 11. Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity. Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to α1-acid glycoprotein

Lookup NU author(s): Professor Nicola Curtin, Hannah Barlow, Professor Alan Calvert, Richard Davison, Professor Bernard Golding, Professor Herbie Newell, Peter Smith, Professor Roger Griffin

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Abstract

The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, α1-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of 3H-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4́-methoxybenzylamino, 3́,4́-dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.


Publication metadata

Author(s): Curtin, N., Barlow, H., Bowman, K., Calvert, A. H., Davison, R., Golding, B., Huang, B., Loughlin, P., Newell, D., Smith, P., Griffin, R.

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2004

Volume: 47

Issue: 20

Pages: 4905-4922

Print publication date: 23/09/2004

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm040772w

DOI: 10.1021/jm040772w

PubMed id: 15369395


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