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