Ternary copper(ii) complexes of 1,10-phenanthroline and coumarin-based oxylacetates as pro-apoptotic UPR CHOP inducers

We prepared six complexes with the formula [Cu(phen)(2)(Lx)](ClO4)(x: 1-6), where auxiliary ligands Lx are coumarin carboxylate derivatives bearing an oxylacetate moiety in the 6th or 7th position and different substituents in the 3rd or 4th position. Complexes show a pentacoordinated geometry around a metal ion. The possibility to complete the coordination sphere in an octahedral geometry makes the molecule able to further react. Complexes show affinity toward DNA mainly through electrostatic interactions and groove binding, while the interactions with DNA base pairs are guaranteed by the auxiliary ligands. The heteroleptic Cu(ii) complexes show cytotoxic activity in the micromolar concentration range, and mechanistic studies have shown how they can interfere at the endothelial reticulum level inducing the pro-apoptotic branch of the unfolded protein response (UPR). The actin-normalized CHOP to BiP density ratios suggest that the novel compounds induce preferentially the pro-apoptotic UPR signalling driven by the CHOP, in a dose-dependent way and according to the substituents in the coumarin moiety.

Automated summary

We synthesized six complexes [Cu(phen)(2)(Lx)](ClO4)(x: 1-6), in which the auxiliary ligand Lx is a coumarin carboxylate derivative with an oxylacetate moiety at the 6th or 7th position and different substituents at the 3rd or 4th position. The complexes exhibit a pentacoordinated geometry around the metal ion. They show affinity towards DNA mainly through electrostatic interactions and groove binding, and the interactions with DNA base pairs are mediated by the auxiliary ligands. The Cu(II) complexes display cytotoxic activity in the micromolar concentration range and can induce the pro-apoptotic branch of the unfolded protein response (UPR) by interfering at the endoplasmic reticulum level. The actin-normalized CHOP to BiP density ratios suggest that the novel compounds preferentially induce the pro-apoptotic UPR signaling driven by CHOP, in a dose-dependent manner and depending on the substituents in the coumarin moiety.