title: 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.
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.
authors.affiliation: Northern Institute for Cancer Research, School of Natural Sciences-Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Barlow
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Bowman
authors.forename: A Hilary
authors.initials: AH
authors.lastname: Calvert
authors.forename: Richard
authors.initials: R
authors.lastname: Davison
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.forename: Bing
authors.initials: B
authors.lastname: Huang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Loughlin
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D001671:Biochemistry / Q000379:methods; D001692:Biological Transport / Q000187:drug effects; D004176:Dipyridamole / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D007939:Leukemia L1210; D051379:Mice; D009705:Nucleosides / Q000378:metabolism*; D009961:Orosomucoid / Q000187:drug effects / Q000378:metabolism* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D009705:Nucleosides; D009961:Orosomucoid; D011743:Pyrimidines; D004176:Dipyridamole; D013936:Thymidine