N-heterocyclic-carbene vs diphosphine auxiliary ligands in thioamidato Cu(I) and Ag(I) complexes towards the development of potent and dual-activity antibacterial and apoptosis-inducing anticancer agents.

Group 11 metal complexes exhibit promising antibacterial and anticancer properties which can be further enhanced by appropriate ligands. Herein, a series of mononuclear thioamidato Cu(I) and Ag(I) complexes bearing either a diphosphine (P^P) or a N-heterocyclic carbene (NHC) auxiliary ligand (L) was synthesized, and the impact of the co-ligand L on the in vitro antibacterial and anticancer properties of their complexes was assessed. All complexes effectively inhibited the growth of various bacterial strains, with the NHC-Cu(I) complex found to be particularly effective against the Gram (+) bacteria (IC50 = 1-4 µg mL-1). Cytotoxicity studies against various human cancer cells revealed their high anticancer potency and the superior activity of the NHC-Ag(I) complex (IC50 = 0.95-4.5 µΜ). Flow cytometric analysis on lung and breast cancer cells treated with the NHC-Ag(I) complex suggested an apoptotic cell-death pathway; molecular docking calculations provided mechanistic insights, proving the capacity of the complex to bind on apoptosis-regulating proteins and affect their functionalities.

Inhibition of Cancer Cell Proliferation and Bacterial Growth by Silver(I) Complexes Bearing a CH3-Substituted Thiadiazole-Based Thioamide.

Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present a series of four Ag(I) coordination compounds bearing as ligands the CH3-substituted thiadiazole-based thioamide 5-methyl-1,3,4-thiadiazole-2-thiol (mtdztH) and phosphines, i.e., [AgCl(mtdztH)(PPh3)2] (1), [Ag(mtdzt)(PPh3)3] (2), [AgCl(mtdztH)(xantphos)] (3), and [AgmtdztH)(dppe)(NO3)]n (4), where xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dppe = 1,2-bis(diphenylphosphino)ethane, and the assessment of their in vitro antibacterial and anti-cancer efficiency. Among them, diphosphine-containing compounds 3 and 4 were found to exhibit broad-spectrum antibacterial activity characteristics against both Gram-(+) and Gram-(-) bacterial strains, showing high in vitro bioactivity with IC50 values as low as 4.6 µΜ. In vitro cytotoxicity studies against human ovarian, pancreatic, lung, and prostate cancer cell lines revealed the strong cytotoxic potential of 2 and 4, with IC50 values in the range of 3.1-24.0 µΜ, while 3 and 4 maintained the normal fibroblast cells' viability at relatively higher levels. Assessment of these results, in combination with those obtained for analogous Ag(I) complexes bearing similar heterocyclic thioamides, suggest the pivotal role of the substituent groups of the thioamide heterocyclic ring in the antibacterial and anti-cancer efficacy of the respective Ag(I) complexes. Compounds 1-4 exhibited moderate in vitro antioxidant capacity for free radicals scavenging, as well as reasonably strong ability to interact with calf-thymus DNA, suggesting the likely implication of these properties in their bioactivity mechanisms. Complementary insights into the possible mechanism of their anti-cancer activity were provided by molecular docking calculations, exploring their ability to bind to the overexpressed fibroblast growth factor receptor 1 (FGFR1), affecting cancer cells' functionalities.

Pegylated-polycaprolactone nano-sized drug delivery platforms loaded with biocompatible silver(i) complexes for anticancer therapeutics.

Cytotoxic potential of Ag(i) coordination compounds against cancer cells is widely recognized, but their frequently low water solubility and potential adverse interactions of Ag(i) ions in biological media require their incorporation into suitable platforms to ensure effective transport and delivery at target sites. Herein, we developed and evaluated the in vitro cytotoxic activity of a biodegradable copolymer-based nano-sized drug delivery system for three cytotoxically active and lipophillic Ag(i) compounds. In particular, polymer-based nanoparticles of the newly synthesized amphiphilic methoxy-poly(ethylene glycol)-poly(caprolactone) (mPEG-PCL) copolymer were prepared as carriers for [Ag(dmp2SH)(PPh3)2]NO3 (1), [Ag(dmp2SH)(xantphos)]NO3 (2) and [Ag(dmp2S)(xantphos)] (3) (dmP2SH = 4,6-dimethylpyrimidine-2-thiol, xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) which exhibit high cytotoxicity against HeLa cancer cells, while they maintain low toxicity against HDFa normal cells. Taking advantage of the favorable donor-acceptor Lewis acid-base and electrostatic interactions between functional groups of 1-3 and mPEG-PCL copolymer, the formation of [X]@mPEG-PCL (X = 1,2,3) nanoparticles with nearly spherical shape was achieved. Satisfactory loading capacities and encapsulation efficiencies were obtained (13-15% and 80-88%, respectively). Differences in their mean size diameters were observed, revealing a dependence on the individual structural characteristics of the Ag(i) compounds. In vitro release profiles of the nanoparticles showed an initial burst stage, followed by a prolonged release stage extending over 15 days, with their release rates being determined by the mean size of the nanoparticles, as well as the type and crystallinity of the encapsulated Ag(i) compounds. In vitro cytotoxicity studies revealed an increased cytotoxic activity of compounds 1-3 after their encapsulation in mPEG-PCL copolymer against HeLa cells, with the actual concentrations of the loaded compounds responsible for the inhibition of cell viability being reduced by 8 times compared to the compounds in free form. Therefore, the current drug delivery system improves the pharmacokinetic properties of the three cytotoxic and biocompatible Ag(i) compounds, and may be beneficial for future in vivo anticancer treatment.

Silver(I) complexes bearing heterocyclic thioamide ligands with NH2 and CF3 substituents: effect of ligand group substitution on antibacterial and anticancer properties.

In recent years, there has been an increasing interest in the study of Ag(I) coordination compounds as potent antibacterial and anticancer agents. Herein, a series of Ag(I) complexes bearing phosphines and heterocyclic thioamide ligands with highly electronegative NH2- and CF3-group substituents, i.e. [AgCl(atdztH)(xantphos)] (1), [Ag(µ-atdztH)(DPEphos)]2(NO3)2 (2), [Ag(atdzt)(PPh3)3] (3), [Ag(µ-atdzt)(DPEphos)]2 (4), and [Ag(µ-mtft)(DPEphos)]2 (5), where atdztH = 5-amino-1,3,4-thiadiazole-2-thiol, mtftH = 4-methyl-5-(trifluoromethyl)-1,2,4-triazol-3-thiol, xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and DPEphos = bis(2-diphenylphosphino-phenyl)ether, were synthesized, and their in vitro antibacterial and anticancer properties were evaluated. Complexes 1-4 bearing the NH2-substituted thioamide exhibited moderate-to-high activity against S. aureus, B. subtilis, B. cereus and E. coli bacterial strains. A high antiproliferative activity was also observed for 1-3 against SKOV-3, Hup-T3, DMS114 and PC3 cancer cell lines (IC50 = 4.0-11.7 µM), as well as some degree of selectivity against MRC-5 normal cells. Interestingly, 5 bearing the CF3-substituted thioamide is completely inactive in all bioactivity studies. Binding of 1-3 to drug-carrier proteins BSA and HSA is reasonably strong for their uptake and subsequent release to possible target sites. The three complexes show a significant in vitro antioxidant ability for scavenging free radicals, suggesting likely implication of this property in the mechanism of their bioactivity, but a low potential to destroy the double-strand structure of CT-DNA by intercalation. Complementary insights into possible bioactivity mechanisms were provided by molecular docking calculations, exploring the ability of complexes to bind to bacterial DNA gyrase, and to the overexpressed in the aforementioned cancer cells Fibroblast Growth Factor Receptor 1, affecting their functionalities.

Biocompatible silver(I) complexes with heterocyclic thioamide ligands for selective killing of cancer cells and high antimicrobial activity - A combined in vitro and in silico study.

A series of heteroleptic Ag(I) complexes bearing 4,6-dimethyl-2-pyrimidinethiol (dmp2SH), i.e., [AgCl(dmp2SH)(PPh3)2] (1), [Ag(dmp2SH)(PPh3)2]NO3 (2), [Ag(dmp2SΗ)(xantphos)]NO3 (3), [Ag(µ-dmp2S)(PPh3)]2 (4), [Ag(dmp2S)(xantphos)] (5), [Ag(µ-dmp2S)(DPEphos)]2 (6) (xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and DPEPhos = bis[(2-diphenylphosphino)phenyl]ether) were synthesized. The complexes display systematic variation of particular structural characteristics which were proved to have a significant impact on their in vitro cytotoxicity and antimicrobial properties. A moderate-to-high potential for bacteria growth inhibition was observed for all complexes, with 2, 3 and 5 being particularly effective against Gram-(+) bacteria (IC50 = 1.6-4.5 µM). The three complexes exhibit high in vitro cytotoxicity against HeLa and MCF-7 cancer cells (IC50 = 0.32-3.00 µΜ), suggesting the importance of coordination unsaturation and cationic charge for effective bioactivity. A very low cytotoxicity against HDFa normal cells was observed, revealing a high degree of selectivity (selectivity index ~10) and, hence, biocompatibility. Fluorescence microscopy using 2 showed effective targeting on the membrane of the HeLa cancer cells, subsequently inducing cell death. Binding of the complexes to serum albumin proteins is reasonably strong for potential uptake and subsequent release to target sites. A moderate in vitro antioxidant capacity for free radicals scavenging was observed and a low potential to destroy the double-strand structure of calf-thymus DNA by intercalation, suggesting likely implication of these properties in the bioactivity mechanisms of these complexes. Further insight into possible mechanisms of bioactivity was obtained by molecular modeling calculations, by exploring their ability to act as potential inhibitors of DNA-gyrase, human estrogen receptor alpha, human cyclin-dependent kinase 6, and human papillomavirus E6 oncoprotein.

Homoleptic and heteroleptic silver(I) complexes bearing diphosphane and thioamide ligands: Synthesis, structures, DNA interactions and antibacterial activity studies.

Three silver(I) complexes bearing different combinations of diphosphanes and N-heterocyclic thioamides or thioamidates as ligands have been synthesized and structurally characterized: the ionic, homoleptic compound [Ag(xantphos)2][BF4] (1), where xantphos = 4,5-bis(diphenylphosphano)-9,9-dimethyl-xanthene, and the neutral, heteroleptic compounds [Ag(xantphos)(κ-S-pymt)] (2), where pymt = pyrimidine-2-thiolate, and [AgCl(dppbz)(κ-S-mtdztH)] (3), where dppbz = bis(diphenylphosphano)benzene and mtdztH = 5-methyl-1,3,4-thiadiazole-2-thione. X-ray crystallography studies reveal tetrahedral coordination environments around the silver(I) ions in compounds 1 and 3, while a trigonal planar arrangement of the P2S donor set has been found around the metal center in compound 2. The interaction of the three compounds with calf-thymus DNA was monitored by UV-vis spectroscopy, DNA-viscosity measurements and indirectly by testing their ability to compete with ethidium bromide for DNA intercalation sites studied by fluorescence emission spectroscopy. Intercalation was revealed as the most possible binding mode for the neutral compounds 2 and 3 and electrostatic interactions for the cationic complex [Ag(xantphos)2]+ in 1. Complexes 1-3 have also been found to display moderate in vitro antibacterial activity against the Gram-positive B. cereus, S. aureus and the Gram-negative E. coli bacterial strains, with the homoleptic bis-phosphane silver(I) compound 1 exhibiting a lower activity than the other two neutral compounds.