Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes

Abstract

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.

Applications of calixarene nano-baskets in pharmacology

“…Rouge et al [44] used calix [4]arenes bearing alkyl ester and alkyl acid moieties at the lower rim, Pires et al [45] used calix [4]arenes bearing two hydrazide function or ornithine, glutamic/aspartic acid groups at the lower rim, and Latxague et al [46] used calix [4]arenes bearing diamino-tetraesters, diamino-tetraalcohols, diamino-tetraacid and tetraaryloxypentoxy groups at the lower rim. They compared their calixarene derivatives with 4-3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl-benzoic acid as a new oral chelator.…”

Antiproliferative effect on HepaRG cell cultures of new calix[4]arenes

“…presence of one equivalent of K 2 CO 3 as a base, in refluxing CH 3 CN [42][43][44][45] . Hydrolysis of 8a with 15% sodium hydroxide in ethanol under reflux gave, after acidification, the crystalline diacid 9 (95%) 45,49,50 .…”

“…Hydrolysis of 8a with 15% sodium hydroxide in ethanol under reflux gave, after acidification, the crystalline diacid 9 (95%) 45,49,50 .…”

“…In these complexes, the Fe is bound to all seven O atoms of the calixarene with the shortest Fe-O distance to the phenolate O atom 41 . Thus, taking into account our experience in the field of the synthesis of new compounds of the calix [4]arene type [42][43][44] , we previously prepared new calix [4]arene podands bearing two aspartic/glutamic acid or ornithine groups at the lower rim, and a mono hydrazidocalixarene 45 . In this series, two compounds 1-2 exhibited interesting antiproliferative activity in the rat hepatoma cell line Fao.…”

Antiproliferative effect on HepaRG cell cultures of new calix[4]arenes. Part II

“…Consequently, some calixarene derivatives possess affinity and selectivity for Fe(III) and have a much lower affinity for Mg(II), Ca(II) and Zn(II) [35][36]. Thus, taking into account our experience in the field of the synthesis of new compounds of the type calix [4]arenes [37][38][39], we have previously prepared new calix [4]arene podands bearing at the lower rim two aspartic/glutamic acid or ornitine groups, mono hydrazidocalixarene and alkyl (ester or acid) [40,41]. In these series, three compounds II-IV exhibited an interesting antiproliferative activity in the rat hepatoma cell line Fao (Figure 1).…”