Ternary Copper (II) complexes of 1,10-phenanthroline and coumarin-based oxylacetates as pro-apoptotic UPR CHOP inducer

We prepared six complexes with formula [Cu(phen)2(Lx)](ClO4)(x: 1 – 6) where the 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 the 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 pointed out how they can interfere at Endotelial Reticulum level inducing the pro-apoptotic branch of the Unfoled 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 chop, in a dose-dependent way and according to the substituents in the coumarinic moiety.