Synthesis and in-vitro antitumour activity of new naphthyridine derivatives on human pancreatic cancer cells.
OBJECTIVE
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, fibroblast growth factor type 1 receptor kinase inhibition, and in-vitro antiangiogenic analysis.


RESULTS
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 mum). This compound had an in-vitro antitumour efficacy superior to 5-fluorouracil (the lowest cell viability value after treatment (E(max)) 0.2% and 19%, respectively) and proved to be less toxic than 5-fluorouracil against non-cancerous 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 fibroblast 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 antitumour activity of compound 11 is worth further investigation.
Banti
Irene
I
Department of Pharmaceutical Sciences, University of Pisa, Italy.
Nencetti
Susanna
S
Orlandini
Elisabetta
E
Lapucci
Annalina
A
Breschi
Maria Cristina
MC
Fogli
Stefano
S
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005346:Fibroblast Growth Factors / Q000008:administration & dosage; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D009287:Naphthyridines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013997:Time Factors; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D009287:Naphthyridines; D005346:Fibroblast Growth Factors; D005472:Fluorouracil