94542-24-2Relevant academic research and scientific papers
Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer
Virgilio, Antonella,Spano, Daniela,Esposito, Veronica,Di Dato, Valeria,Citarella, Giuseppe,Marino, Natascia,Maffia, Veronica,De Martino, Daniela,De Antonellis, Pasqualino,Galeone, Aldo,Zollo, Massimo
, p. 41 - 50 (2013/01/15)
The human (h)-prune protein is a member of the DHH protein superfamily and it has a cAMP phosphodiesterase activity. Its overexpression in breast, colorectal and gastric cancers correlates with depth of invasion and a high degree of lymph-node metastasis. One mechanism by which h-prune stimulates cell motility and metastasis processes is through its phosphodiesterase activity, which can be suppressed by dipyridamole, a pyrimido[5,4-d]pyrimidine analogue. To obtain new and more potent agents that have high specificity towards inhibition of this h-prune activity, we followed structure-activity-relationship methodologies starting from dipyridamole and synthesised eight new pyrimido-pyrimidine derivatives. We analysed these newly generated compounds for specificity towards h-prune activities in vitro in cellular models using scintillation proximity assay for cAMP-PDE activity, cell index in cell proliferation assays and transwell methodology for two-dimensional cell migration in a top-down strategy of selection. Our findings show that two pyrimido[5,4-d]pyrimidine compounds are more effective than dipyridamole in two highly metastatic cellular models of breast cancer in vitro. Future studies will assess their therapeutic effectiveness against breast and other cancers where there is over-expression of h-prune, and in ad-hoc, proof of concept, animal models.
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
Curtin, Nicola J.,Barlow, Hannah C.,Bowman, Karen J.,Calvert, A. Hilary,Davison, Richard,Golding, Bernard T.,Huang, Bing,Loughlin, Peter J.,Newell, David R.,Smith, Peter G.,Griffin, Roger J.
, p. 4905 - 4922 (2007/10/03)
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 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.
Controlled stepwise conversion of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine into 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines
Northen, Julian S.,Boyle, F. Thomas,Clegg, William,Curtin, Nicola J.,Edwards, Andrew J.,Griffin, Roger J.,Golding, Bernard T.
, p. 108 - 115 (2007/10/03)
For the rational synthesis of 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines, required as purine mimetics, sequential nucleophilic substitutions of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine have been investigated. Reaction conditions have been devised leading to 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines with patterns of substitution denoted as abab (reaction with nucleophile 1 at C-4 and C-8, followed by nucleophile 2 at C-2 and C-6) or abac (reaction with nucleophile 1 at C-4 and C-8, nucleophile 2 at C-2 and nucleophile 3 at C-6) or abcd (reaction with nucleophile 1 at C-4, nucleophile 2 at C-8, nucleophile 3 at C-2 and nucleophile 4 at C-6). The use of low temperature, relatively dilute solution and careful addition of the amine nucleophile can control the critical first step. The third step in the production of the abcd pattern leads to two regioisomers, which have been structurally characterised by 1H NMR and a crystal structure analysis. Selected 2,4,6,8-tetrasubstituted pyrimido[5,4-d]pyrimidines were tested as inhibitors of the cyclin-dependent kinase 1 complex (cyclin B/CDK1), but none of the compounds showed significant activity.
