Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes.
Cell cycle progression is dependent on intracellular iron level and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing two aspartic/glutamic acid, ornithine groups or hydrazide function at the lower rim, designed as potential iron chelators. The synthesis only afforded calix[4]arenes in the cone conformation. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the rat hepatoma cell line Fao by measuring mitochondrial succinate dehydrogenase activity. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicated that among all tested compounds, monohydrazidocalix[4]arene 2 which is not cytotoxic in Fao cells exhibits interesting antiproliferative activity. This effect, independent on iron depletion, remains to be further explored. Moreover, it also shows that new substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.
Pires
Viviane Silva
VS
EA 3901, DMAG, UFR de Pharmacie et de Médecine, Université de Picardie Jules Verne, 1 rue des Louvels, 80037 Amiens, France.
Gaboriau
Francois
F
Guillon
Jean
J
Nascimento
Sophie
S
Dassonville
Alexandra
A
Lescoat
Gerard
G
Desplat
Vanessa
V
Rochette
Jacques
J
Jarry
Christian
C
Sonnet
Pascal
P
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D047250:Calixarenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000077588:Deferasirox; D004354:Drug Screening Assays, Antitumor; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001565:Benzoates; D007502:Iron Chelating Agents; D010636:Phenols; D014230:Triazoles; C121325:calix(4)arene; D047250:Calixarenes; D017665:Hydroxyl Radical; D000077588:Deferasirox