Activity and Selectivity of Novel Chemical Metallic Complexes with Potential Anticancer Effects on Melanoma Cells

Maria Camilla Ciardulli; Annaluisa Mariconda; Marco Sirignano; Erwin Pavel Lamparelli; Raffaele Longo; Pasqualina Scala; Raffaella D'Auria; Antonietta Santoro; Liberata Guadagno; Giovanna Della Porta; Pasquale Longo

doi:10.3390/molecules28124851

Activity and Selectivity of Novel Chemical Metallic Complexes with Potential Anticancer Effects on Melanoma Cells

Molecules. 2023 Jun 19;28(12):4851. doi: 10.3390/molecules28124851.

Affiliations

¹ Department of Medicine, Surgery and Dentistry, University of Salerno, Via S. Allende, 84081 Baronissi, Italy.
² Department of Science, University of Basilicata, Viale dell'Ateneo Lucano 10, 85100 Potenza, Italy.
³ Department of Chemistry and Biology "Adolfo Zambelli", University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
⁴ Department of Industrial Engineering, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy.
⁵ Interdepartment Centre BIONAM, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy.

Abstract

Human malignant melanoma cells from lymph node metastatic site (MeWo) were selected for testing several synthesized and purified silver(I) and gold(I) complexes stabilized by unsymmetrically substituted N-heterocyclic carbene (NHC) ligands, called L20 (N-methyl, N'-[2-hydroxy ethylphenyl]imidazol-2-ylide) and M1 (4,5-dichloro, N-methyl, N'-[2-hydroxy ethylphenyl]imidazol-2-ylide), having halogenide (Cl^- or I^-) or aminoacyl (Gly=N-(tert-Butoxycarbonyl)glycinate or Phe=(S)-N-(tert-Butoxycarbonyl)phenylalaninate) counterion. For AgL20, AuL20, AgM1 and AuM1, the Half-Maximal Inhibitory Concentration (IC₅₀) values were measured, and all complexes seemed to reduce cell viability more effectively than Cisplatin, selected as control. The complex named AuM1 was the most active just after 8 h of treatment at 5 μM, identified as effective growth inhibition concentration. AuM1 also showed a linear dose and time-dependent effect. Moreover, AuM1 and AgM1 modified the phosphorylation levels of proteins associated with DNA lesions (H2AX) and cell cycle progression (ERK). Further screening of complex aminoacyl derivatives indicated that the most powerful were those indicated with the acronyms: GlyAg, PheAg, AgL20Gly, AgM1Gly, AuM1Gly, AgL20Phe, AgM1Phe, AuM1Phe. Indeed, the presence of Boc-Glycine (Gly) and Boc-L-Phenylalanine (Phe) showed an improved efficacy of Ag main complexes, as well as that of AuM1 derivatives. Selectivity was further checked on a non-cancerous cell line, a spontaneously transformed aneuploid immortal keratinocyte from adult human skin (HaCaT). In such a case, AuM1 and PheAg complexes resulted as the most selective allowing HaCaT viability at 70 and 40%, respectively, after 48 h of treatment at 5 μM. The same complexes tested on 3D MeWo static culture induced partial spheroid disaggregation after 24 h of culture, with almost half of the cells dead.

Keywords: 3D culture; N-heterocyclic carbene complexes; human malignant melanoma cells; immortal keratinocyte from adult human skin; live cell imaging; metallorganic anticancer agents; selectivity; toxicity.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cisplatin / pharmacology
Coordination Complexes* / chemistry
Heterocyclic Compounds* / chemistry
Humans
Melanoma* / drug therapy
Methane / chemistry
Molecular Structure

Substances

Coordination Complexes
Antineoplastic Agents
Cisplatin
Methane
Heterocyclic Compounds

Grants and funding

This research was funded by University of Salerno funds for basic research (397FARB19DELLAPORTA, 397FARB20DELLAPORTA).