Two new heteroleptic pentacoordinated Zn(II) complexes (1 and 2) containing 4,4 0 -disubstituted 2,2 0bipyridines as the main ligand and curcumin (curc) as an ancillary ligand have been synthesized, spectroscopically and structurally characterized, and tested in vitro towards different human cancer cell lines. While the nitrogen ligands are almost inactive, Zn(II) curc derivatives 1 and 2 show promising and selective anticancer properties. In particular the curc Zn(II) complex 1 shows the strongest growth inhibition in all cell lines, being even more effective than the pure curc in the LAN-5 neuroblastoma cell line. Furthermore, the curc moiety makes the complexes 1 and 2 fluorescent, a feature enabling investigation of their interaction with DNA through a new optical method previously tested with the reference fluorescent intercalator ethidium bromide. This analysis demonstrates that the interaction mode of curc, 1 and 2 with DNA in the double helix favors their alignment perpendicular to the DNA axis, suggesting a partial inter-base intercalation of these Zn(II) complexes.

Tris-beta-diketonate lanthanide(III) complexes (Ln = Eu, Er, Yb, Tb), of general formula [Ln(acac)3 L(m)], with chelating ligands such as 4,7-disubstituted-1,10-phenanthrolines and 4,4'-disubstituted-2,2'-bipyridines, have been synthesized and fully characterized. The inductive effects of the para-substituents on the aromatic N-donor ligands have been investigated both in the solid and in the solution states. Single-crystal X-ray structures have been determined for the diethyl 1,10-phenanthroline-4,7-dicarboxylate europium and 4,4'-dimethoxy-2,2'-bipyridine erbium derivatives, revealing a distorted square antiprismatic geometry around the lanthanide atom in both cases. The influence exerted by the p,p'-substituents with respect to the nitrogen coordinating atoms on the Ln-N bond distances is discussed comparing the geometrical parameters with those found for the crystal structures containing the fragments [Ln(III)(phen)] and [Ln(III)(bipy)] obtained from the Cambridge Structural Database. The influence exerted by the electron-attracting groups on the coordination ability of the ligands, that in some cases becomes lack of coordination of the lanthanide ions, has been also detected in solution where the loss of the ligand has been followed by UV-vis spectroscopy. Moreover, the use of relatively long alkoxy chains as substituents on the 1,10-phenanthroline ligand led to the formation of a promesogenic lanthanide complex, whose thermal behavior is encouraging for the synthesis of new lanthanide liquid-crystalline species.

TP53, one of the most important oncosuppressors, is frequently mutated in cancer. Several p53 mutant proteins escape proteolytic degradation and are highly expressed in an aberrant conformation often acquiring pro-oncogenic activities that promote tumor progression and resistance to therapy. Therefore, it has been vastly proposed that reactivation of wild-type (wt) function(s) from mutant p53 (mutp53) may have therapeutic significance. We have previously reported that Zn(II) restores a folded conformation from mutp53 misfolding, rescuing wild-type (wt) p53/DNA-binding and transcription activities. However, whether Zn(II) affects mutp53 stability has never been investigated. Here we show that a novel Zn(II) compound induced mutp53 (R175H) protein degradation through autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins. Accordingly, pharmacological or genetic inhibition of autophagy prevented Zn(II)-mediated mutp53H175 degradation as well as the ability of the Zn(II) compound to restore wtp53 DNA-binding and transcription activity from this mutant. By contrast, inhibition of the proteasome failed to do so, suggesting that autophagy is the main route for p53H175 degradation. Mechanistically, Zn(II) restored the wtp53 ability to induce the expression of the p53 target gene DRAM (damage-regulated autophagy modulator), a key regulator of autophagy, leading to autophagic induction. Accordingly, inhibition of wtp53 transactivation by pifithrin-α (PFT-α) impaired both autophagy and mutp53H175 degradation induced by curcumin-based zinc compound (Zn(II)-curc). Viewed together, our results uncover a novel mechanism employed by Zn(II)-curc to reactivate mutp53H175, which involves, at least in part, induction of mutp53 degradation via wtp53-mediated autophagy.

New Zn(II)-curcumin based heteroleptic complexes (1-5) have been synthesized and fully characterized, with the aim to improve the bioactivity of the precursor derivative [(bpy-9)Zn(curc)Cl] (A), a potentially intercalating antitumor agent recently reported. Some structural changes have been made starting from the reference complex A, in order to introduce new functionalities, such as electrostatic and/or covalent interactions. In particular, keeping the same N,N chelating ligand, namely bpy-9, two completely different Zn(II) species have been obtained: a tetracoordinated Zn(II) cation with tetrafluoroborate as counterion (1) and a dimeric neutral complex in which the sulfate anion acts as a bridging group through two Zn(II) centres (2). Moreover, by changing the N,N chelating unit, [(L(n))Zn(curc)Cl] complexes (3-5), in which the Zn(II) ion shows the same pentacoordination seen in the precursor complex A, have been obtained. The antitumour activity of all new Zn(II) complexes was tested in vitro against the human neuroblastoma cell line SH-SY5Y in a biohybrid membrane system and the results indicate that all species exhibit strong cytotoxic activity. In particular the ionic tetrafluoroborate Zn(II) complex, 1, and the neutral phenanthroline based Zn(II) derivative, 4, show the strongest growth inhibition, being even more effective than the model complex A. Both complexes have a dose-dependent anti-proliferative effect on cells as demonstrated by the decrease of viability and the increase of Annexin V and PI-positive cells with the increase of their concentration. Cells treated with complexes 1 and 4 undergo apoptosis that involves the activation of JNK, caspase 3 and MMP changes. Finally, complex 1 is more effective in the induction of caspase-3 activation demonstrating its ability to trigger the execution-phase of cell apoptosis.