Novel pyrimidopyrimidine derivatives for inhibition of cellular proliferation and motility induced by h-prune in breast cancer

Antonella Virgilio, Daniela Spano, Veronica Esposito, Valeria Di Dato, Giuseppe Citarella, Natascia Marino, Veronica Maffia, Daniela De Martino, Pasqualino De Antonellis, Aldo Galeone, Massimo Zollo

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)41-50
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume57
DOIs
StatePublished - Nov 2012
Externally publishedYes

Keywords

  • Breast cancer
  • Cellular motility
  • Phosphodiesterase
  • cAMP
  • h-Prune

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