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

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, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.

Synthesis, Flow Cytometric Evaluation, and Identification of Highly Potent Dipyridamole Analogues as Equilibrative Nucleoside Transporter 1 Inhibitors

“…42 A more recent publication disclosed the synthesis and biological evaluation of a series of dipyprdamole analogs for their ENT1 inhibitory activities, and some of them showed only slightly higher activities than dipyridamole. 43 In this paper, a series of dipyridamole analogues were synthesized for a more systematic and comprehensive evaluation of ENT1 SAR. Some of the compounds showed comparative activity to NBMPR, which is a much more potent ENT1 inhibitor than dipyridamole.…”

Preclinical evaluation of a novel pyrimidopyrimidine for the prevention of nucleoside and nucleobase reversal of antifolate cytotoxicity

“…Several analogues that inhibit nucleoside transport even in the presence of physiologic concentrations of AGP were identified (15). Two of these analogues, NU3108 and NU3121, inhibited thymidine and hypoxanthine rescue from pemetrexed cytotoxicity in the presence and absence of AGP but, following the administration to mice at the maximum administrable dose, the plasma concentrations required for inhibition of thymidine incorporation, and hence rescue, into human tumor xenografts were only maintained for 2 hours (16).…”

A Mild Approach to the Synthesis of 4‐Amino‐8‐(arylamino)pyrimido[5,4‐d]pyrimidine 3‐Oxides

“…[14] Several derivatives were synthesised from the 2,4,6,8-tetrachloro derivative by nucleophilic substitution of the chlorine atoms by the desired amine. [5,10,11,15] They were also synthesised from substituted pyrimidines by reaction with convenient electrophiles or nucleophiles. [12,16,17] The 6-cyanopurines were also used as precursors of the pyrimido [5,4-d]pyrimidines by reaction with an amine.…”