Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer.
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.
Dipartimento di Chimica delle Sostanze Naturali, Università degli Studi di Napoli Federico II, Via Domenico Montesano 49, 80131 Naples, Italy.
Antonella
A
Virgilio
Daniela
D
Spano
Veronica
V
Esposito
Valeria
V
Di Dato
Giuseppe
G
Citarella
Natascia
N
Marino
Veronica
V
Maffia
Daniela
D
De Martino
Pasqualino
P
De Antonellis
Aldo
A
Galeone
Massimo
M
Zollo
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015194:Diffusion Chambers, Culture; D004176:Dipyridamole / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D009363:Neoplasm Proteins; D004176:Dipyridamole; C438732:PRUNE1 protein, human; D010744:Phosphoric Monoester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases