Resistance-modifying agents. 11.(1) Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity. Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to alpha1-acid glycoprotein

Journal of Medicinal Chemistry
N J CurtinRoger J Griffin

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, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of (3)H-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 4'-methoxybenzylamino, 3',4'-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, ...Continue Reading

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Citations

Jul 3, 2013·European Journal of Medicinal Chemistry·Ahmed M FargualyMarwa T M Sarg
Sep 3, 2014·European Journal of Medicinal Chemistry·Li-Ying MaHong-Min Liu
Oct 13, 2012·European Journal of Medicinal Chemistry·Antonella VirgilioMassimo Zollo
Aug 16, 2012·Organic & Biomolecular Chemistry·Tristan ReuillonBernard T Golding
Oct 24, 2020·Cell Chemical Biology·Ryan M EsquejoTimothy F Osborne
Jan 21, 2011·ACS Combinatorial Science·Ghazaleh Imani ShakibaeiAyoob Bazgir

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