Anticancer activity of new water-soluble sulfonated thiosemicarbazone copper(II) complexes targeting disulfide isomerase

• Published in: European journal of medicinal chemistry 2024-10, Vol.276, p.116697, Article 116697
• Main Authors: Miglioli, Francesca, De Franco, Michele, Bartoli, Jennifer, Scaccaglia, Mirco, Pelosi, Giorgio, Marzano, Cristina, Rogolino, Dominga, Gandin, Valentina, Carcelli, Mauro
• Format: Article
• Language: English
• Subjects: Animals; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination compounds; Copper - chemistry; Copper - pharmacology; Copper complexes; Cuproptosis; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mice; Molecular Structure; Protein disulfide isomerase; Protein Disulfide-Isomerases - antagonists & inhibitors; Protein Disulfide-Isomerases - metabolism; Solubility; Structure-Activity Relationship; Thiosemicarbazones; Thiosemicarbazones - chemical synthesis; Thiosemicarbazones - chemistry; Thiosemicarbazones - pharmacology; Water - chemistry; Water soluble metal complexes; X-ray structure
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116697

Copper complexes have shown promising anticancer properties, but they are often poorly soluble in aqueous solutions, thus limiting their possible medical developments and applications. We have recently isolated some copper(II) complexes with salicylaldehyde thiosemicarbazone ligands exhibiting remarkable nanomolar cytotoxic activity, but in vivo tests evidenced several difficulties related to their poor solubility. To overcome these limitations and increase solubility in aqueous solution, herein we report the synthetic strategy that led to the introduction of the sulfonic group on the ligands, then separated as salts (NaH2L1 - NaH2L5), as well as the synthesis and characterization of the related copper(II) complexes. The characterization of the complexes is completed by the analysis of the structures obtained by X-rays diffraction on single crystals on the species [Cu(HL5)(H2O)]2.2H2O, [Cu(HL2)(H2O)2].2H2O, and [Cu(HL1)(H2O]2.2H2O. While the uncoordinated ligands do not affect cancer cell viability, copper(II) complexes exhibit low to sub-micromolar cytotoxic activity, which is maintained in 3D (HCT-15 and 2008) spheroidal models of cancer cell. Notably, copper(II) complexes were selective towards cancer cells, showing high selectivity indexes. Investigations focused on elucidating the mechanism of action evidenced the protein disulfide-isomerase as an innovative molecular target for this class of water-soluble copper(II) complexes. Finally, preliminary in vivo experiments performed with the most representative derivative in the murine Lewis Lung Carcinoma, highlight its significant antitumor efficacy and better tolerability profile with respect to the reference metallodrug, suggesting for this sulfonated Cu(II) complex a potential clinical relevance. [Display omitted] •Water-soluble thiosemicarbazonic copper(II) complexes were synthetized.•Copper(II) complexes exhibit low to sub-micromolar cytotoxic activity.•Mechanistic insights revealed protein disulfide isomerase as a target.•Preliminary in vivo studies highlighted significant antitumor efficacy.