Objectives The aim of the study was to evaluate the antitumour effect in vitro of newly synthesized 7-substituted-2,3-dihydro-1,8-naphthyridines. Methods Characterization tools included cell viability assay, caspase 3/7 induction, DNA fragmentation, fibroblastic growth factor type 1 receptor kinase inhibition, and in-vitro antiangiogenic analysis. Key findings Treatment of MIA PaCa-2 human pancreatic cancer cells with test compounds showed time- and concentration-dependent cytotoxicity with IC50 values in the micromolar range. Compounds with an aminoalkyl or a diaminoalkyl side chain at the 7-position exhibited remarkable cytotoxicity, whereas the presence of a methyl group or a cyclic amine in the same position led to a significant decrease in their biological activity. Cytotoxicity screening demonstrated that the most active was compound 11 (mean 50% inhibition of cell proliferation [IC50] 11 mM). This compound had an in-vitro antitumor efficacy superior to 5-fluorouracil (the lowest cell viability value after treatment [Emax] 0.2% and 19%, respectively) and proved to be less toxic than 5-fluorouracil against noncancerous human oral epithelial cells. In addition, compound 11 induced apoptosis in MIA PaCa-2 cells and it was able to promote antiangiogenic effects in vitro. Finally, its cytotoxicity was enhanced in pancreatic cancer cells stimulated with fibroblastic growth factor, while no substantial effect was observed on human bronchial smooth muscle cells stimulated with the same growth factor. Conclusions These findings suggest that 1,8-naphthyridine derivatives are a promising class of compounds in cancer research. In particular, the antitumor activity of compound 11 is worth further investigation.

Synthesis and in-vitro antitumour activity of new naphthyridine derivatives on human pancreatic cancer cells

NENCETTI, SUSANNA;ORLANDINI, ELISABETTA;LAPUCCI, ANNALINA;BRESCHI, MARIA CRISTINA;FOGLI, STEFANO
2009

Abstract

Objectives The aim of the study was to evaluate the antitumour effect in vitro of newly synthesized 7-substituted-2,3-dihydro-1,8-naphthyridines. Methods Characterization tools included cell viability assay, caspase 3/7 induction, DNA fragmentation, fibroblastic growth factor type 1 receptor kinase inhibition, and in-vitro antiangiogenic analysis. Key findings Treatment of MIA PaCa-2 human pancreatic cancer cells with test compounds showed time- and concentration-dependent cytotoxicity with IC50 values in the micromolar range. Compounds with an aminoalkyl or a diaminoalkyl side chain at the 7-position exhibited remarkable cytotoxicity, whereas the presence of a methyl group or a cyclic amine in the same position led to a significant decrease in their biological activity. Cytotoxicity screening demonstrated that the most active was compound 11 (mean 50% inhibition of cell proliferation [IC50] 11 mM). This compound had an in-vitro antitumor efficacy superior to 5-fluorouracil (the lowest cell viability value after treatment [Emax] 0.2% and 19%, respectively) and proved to be less toxic than 5-fluorouracil against noncancerous human oral epithelial cells. In addition, compound 11 induced apoptosis in MIA PaCa-2 cells and it was able to promote antiangiogenic effects in vitro. Finally, its cytotoxicity was enhanced in pancreatic cancer cells stimulated with fibroblastic growth factor, while no substantial effect was observed on human bronchial smooth muscle cells stimulated with the same growth factor. Conclusions These findings suggest that 1,8-naphthyridine derivatives are a promising class of compounds in cancer research. In particular, the antitumor activity of compound 11 is worth further investigation.
Banti, I; Nencetti, Susanna; Orlandini, Elisabetta; Lapucci, Annalina; Breschi, MARIA CRISTINA; Fogli, Stefano
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/203637
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