Pyrazolone-Based Zn(II) Complexes Display Antitumor Effects in Mutant p53-Carrying Cancer Cells

• Published in: Journal of medicinal chemistry 2024-09, Vol.67 (17), p.15676-15690
• Main Authors: Xhafa, Sonila, Di Nicola, Corrado, Tombesi, Alessia, Pettinari, Riccardo, Pettinari, Claudio, Scarpelli, Francesca, Crispini, Alessandra, La Deda, Massimo, Candreva, Angela, Garufi, Alessia, D'Orazi, Gabriella, Galindo, Agustín, Marchetti, Fabio
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Mutation; Pyrazolones - chemical synthesis; Pyrazolones - chemistry; Pyrazolones - pharmacology; Schiff Bases - chemical synthesis; Schiff Bases - chemistry; Schiff Bases - pharmacology; Structure-Activity Relationship; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Zinc - chemistry; Zinc - metabolism; Zinc - pharmacology
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01298

The synthesis and characterization of nine Schiff bases of pyrazolone ligands ( = 1-9) and the corresponding zinc(II) complexes - of composition [Zn(L ) ] ( = 1-9) are reported. The molecular structures of complexes , , , , and were determined by single-crystal X-ray diffraction analysis, highlighting in all cases a distorted tetrahedral geometry around the Zn(II) ion. Density functional theory studies are performed on both the ligands and the derived complexes. A mechanism of dissociation and hydrolyzation of the coordinated Schiff base ligands is suggested, confirmed experimentally by powder X-ray diffraction study and photophysical studies. Complexes were investigated in vitro as anticancer agents, along with mutant p53 (mutp53) protein levels in human cancer cell lines carrying R175H and R273H mutp53 proteins. Only those complexes with the highest Zn(II) ion release via dissociation have shown a significant cytotoxic activity with reduction of mutp53 protein levels.