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

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.

NHC-Ag(I) and NHC-Au(I) Complexes with N-Boc-Protected α-Amino Acidate Counterions Powerfully Affect the Growth of MDA-MB-231 Cells

“…The resonances of methyl protons of the Boc group were around 1.3–1.4 ppm, those of methyl carbons were around 27–28 ppm, and those of quaternary carbons were about 77 ppm. The 13 C NMR spectra of all the tested complexes showed a shift of their carbene carbons to a higher field with respect to the signals of halogenide complexes. ,,, Finally, the complexes were thermally and hydrolytically stable. In fact, thermogravimetric analyses showed that they were stable up to temperatures around 150 °C and decomposed before melting.…”

“…The 13 C NMR spectra of all the tested complexes showed a shift of their carbene carbons to a higher field with respect to the signals of halogenide complexes. 3,4,10,12 Finally, the complexes were thermally and hydrolytically stable. In fact, thermogravimetric analyses showed that they were stable up to temperatures around 150 °C and decomposed before melting.…”

“…Besides NHCs, other classes of ligands were used, such as phosphines, thiolates, pyridines, amino acids, and peptides . Recently, some Ag and Au complexes stabilized by NHC ligands and bearing carboxylate salts of tert -butyloxy­carbonyl (Boc)- N -protected amino acids as anionic ligands (Figure ) were synthesized, characterized, and demonstrated to induce a significant cell disaggregation, after 24 h, using a 3D MeWo cell culture . In this work, different cancer cell models, viz ., two breast and two uterine cancer cell lines and two different normal cell lines, MCF-10A and Hek-293 cells, were adopted in order to gain data about the selectivity of the complexes.…”

“…The silver and gold complexes (Figure ) were prepared following the reported procedure, , shown in Scheme , via the reaction of the appropriate NHC-metal halogenide with 1.2 equiv of N -Boc-protected amino acid. The products were obtained after filtration on Celite to remove the insoluble silver halogenide, followed by evaporation of the solvent under reduced pressure.…”

“…9 Recently, some Ag and Au complexes stabilized by NHC ligands and bearing carboxylate salts of tert-butyloxycarbonyl (Boc)-N-protected amino acids as anionic ligands (Figure 2) were synthesized, characterized, and demonstrated to induce a significant cell disaggregation, after 24 h, using a 3D MeWo cell culture. 10 In this work, different cancer cell models, viz., two breast and two uterine cancer cell lines and two different normal cell lines, MCF-10A and Hek-293 cells, were adopted in order to gain data about the selectivity of the complexes. We obtained thrilling IC 50 values in the low nanomolar range with high selectivity against the more aggressive and metastatic MDA-MB-231 cells.…”