Nucleoside Transport Inhibitors: Structure−Activity Relationships for Pyrimido[5,4-d]pyrimidine Derivatives That Potentiate Pemetrexed Cytotoxicity in the Presence of α₁-Acid Glycoprotein

Abstract

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 α(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 [(3)H]thymidine incorporation assay, employing COR-L23 cells, the diastereoisomers of 6 (IC(50) = 26 nM) exhibited activity comparable with 3 (IC(50) = 15 nM). The monophenyl carbamate and mono-4-methoxyphenyl carbamate exhibited the best ENT-inhibitory activity in the COR-L23 assay (IC(50) = 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.

Re-Discovery of Pyrimidine Salvage as Target in Cancer Therapy

“…Already in the 1980s and 1990s, the vasodilators dipyridamole and dilazep were identified to inhibit nucleoside transport via targeting hENT1 and, however less potent, hENT2 ( Figure 2 A,D) [ 56 , 57 , 58 ]. Even though targeting nucleoside uptake in combination with other cytotoxic agents was thought to be a promising anti-cancer strategy, clinical phase I studies did not show the desired efficacy, and targeting nucleoside uptake moved out of the focus [ 59 , 60 , 61 , 62 , 63 , 64 ]. Only recently, the potential of dipyridamole to reduce triple-negative breast cancer progression and metastasis in xenograft models was uncovered, which has to be further evaluated in clinical trials [ 65 ].…”

“…The failure of dipyridamole in the clinics can be explained by its observed binding to serum protein α 1 -acid glycoprotein (AGP) causing insufficient target engagement and, therefore, the low response rate in vivo as well as in cancer patients [ 63 , 64 ]. To overcome the observed limitations, new chemically optimized hENT1 and hENT2 inhibitors were developed and identified.…”

A Convenient Method to Prepare Pyrano[2,3-d]pyrimidine Derivatives

“…随着人们对该类化合物的深入研究, 发现一些杂环 稠合的嘧啶酮衍生物同样具备出色的生物活性, 如吡喃 并 [2,3-d]嘧啶酮衍生物可用作降血压药物 [7] 、抗血小板 药物 [8] 、抗癌药物 [9] 、抗疟疾药物 [10] 、抗微生物药物 [11] 、 神经肽感受器良好的拮抗剂 [12] 等. 因此, 探索合成新颖…”

Chemoprevention Activity of Dipyridamole in the MMTV-PyMT Transgenic Mouse Model of Breast Cancer

“…Studies suggest that DPM possesses beneficial properties within the endothelium of the vasculature in addition to its anti-platelet effects, including direct and indirect effects such as inhibition of proliferation, antioxidant and anti-inflammatory properties, and downstream effects on cell signaling (13). DPM was previously reported to increase the cytotoxicity of antimetabolites like pemetrexed on human cancer cells (14, 15). Our in vitro study of nucleoside transport inhibitors as chemopreventive agents has found that DPM shows chemopreventive activity in the JB6 cell tumor promotion model (our unpublished results).…”