Antitumoral and Antimicrobial Activities of Block Copolymer Micelles Containing Gold Bisdithiolate Complexes.

Gold(III) bisdithiolate complexes have been reported as potential antimicrobial and antitumoral agents. The complex [Au(cdc)2]- (cdc=cyanodithioimido carbonate) displayed antimicrobial and outstanding antitumor activity against the ovarian cancer cells A2780 and A2780cisR, which are sensitive and resistant to cisplatin, respectively. However, poor water solubility may hamper its clinical use. Block copolymer micelles (BCMs) may solubilize hydrophobic drugs, improving their bioavailability and circulation time in blood. Aiming to provide water solubility, prolonged availability, and enhanced therapeutic indexes, BCMs loaded with [Au(cdc)2]- were synthesized and characterized. The BCM-[Au(cdc)2] micelles were prepared with a loading efficiency of 64.6% and a loading content of 35.3 mg [Au(cdc)2]-/gBCM. A hydrodynamic diameter of 77.31 ± 27.00 nm and a low polydispersity index of 0.18 indicated that the micelles were homogenous and good candidates for drug delivery. Cytotoxic activity studies against A2780/A2780cisR cells showed that BCM-[Au(cdc)2] maintained relevant cytotoxic activity comparable to the cytotoxicity observed for the same concentration of gold complexes. The Au uptake in A2780 cells, determined by PIXE, was ca. 17% higher for BCMs-[Au(cdc)2] compared to [Au(cdc)2]-. The BCMs-[Au(cdc)2] presented antimicrobial activity against S. aureus Newman and C. glabrata CBS138. These results evidenced the potential of BCM-[Au(cdc)2] for drug delivery and its promising anticancer and antimicrobial activities.

Tuning the Biological Activity of Camphorimine Complexes through Metal Selection.

The cytotoxic activity of four sets of camphorimine complexes based on the Cu(I), Cu(II), Ag(I), and Au(I) metal sites were assessed against the cisplatin-sensitive A2780 and OVCAR3 ovarian cancer cells. The results showed that the gold complexes were ca. one order of magnitude more active than the silver complexes, which in turn were ca. one order of magnitude more active than the copper complexes. An important finding was that the cytotoxic activity of the Ag(I) and Au(I) camphorimine complexes was higher than that of cisplatin. Another relevant aspect was that the camphorimine complexes did not interact significantly with DNA, in contrast with cisplatin. The cytotoxic activity of the camphorimine complexes displayed a direct relationship with the cellular uptake by OVCAR3 cells, as ascertained by PIXE (particle-induced X-ray emission). The levels of ROS (reactive oxygen species) formation exhibited an inverse relationship with the reduction potentials for the complexes with the same metal, as assessed by cyclic voltammetry. In order to gain insight into the toxicity of the complexes, their cytotoxicity toward nontumoral cells (HDF and V79 fibroblasts) was evaluated. The in vivo cytotoxicity of complex 5 using the nematode Caenorhabditis elegans was also assessed. The silver camphorimine complexes displayed the highest selectivity coefficients (activity vs. toxicity).

[Co/Fe(α-Alkyl-tpdt)2]x-: Alkyl-Substituted Cobalt and Iron Bis-dithiolenethiophenic Complexes.

Tetraphenylphosphonium salts of Co and Fe complexes with alkyl-substituted, tert-butyl (tb), and isopropyl (dp) 2,3-thiophenedithiolate (α-tpdt) ligands, namely, TPP[Co(α-tb-tpdt)2] (3), TPP2[Fe(α-tb-tpdt)2]2 (4a-b), TPP[Co(α-dp-tpdt)2] (5), and TPP[Fe(α-dp-tpdt)2] (6) were prepared and characterized by cyclic voltammetry, single crystal X-ray diffraction, magnetic susceptibility measurements, and 57Fe Mössbauer spectroscopy. Compound 3 and 5 are isostructural with their Au and Ni analogues with a square-planar coordination geometry. Compound 4 presents two polymorphs (4a-b) both showing a Fe(III) bisdithiolene dimerization. The magnetic susceptibility of 3 and 5 exhibits behavior dominated by antiferromagnetic interactions, with room-temperature magnetic moments of 3.40 and 3.36 µB, respectively, indicating that these square-planar Co(III) complexes assume an intermediate spin electronic configuration (S = 1) as supported by multiconfigurational and DFT calculations.

Gold(iii) bis(dithiolene) complexes: from molecular conductors to prospective anticancer, antimicrobial and antiplasmodial agents.

The anticancer, antimicrobial and antiplasmodial activities of six gold(iii) bis(dithiolene) complexes were studied. Complexes 1-6 showed relevant anticancer properties against A2780/A2780cisR ovarian cancer cells (IC50 values of 0.08-2 µM), also being able to overcome cisplatin resistance in A2780cisR cells. Complex 1 also exhibited significant antimicrobial activity against Staphylococcus aureus (minimum inhibitory concentration (MIC) values of 12.1 ± 3.9 µg mL-1) and both Candida glabrata and Candida albicans (MICs of 9.7 ± 2.7 and 19.9 ± 2.4 µg mL-1, respectively). In addition, all complexes displayed antiplasmodial activity against the Plasmodium berghei parasite liver stages, even exhibiting better results than the ones obtained using primaquine, an anti-malarial drug. Mechanistic studies support the idea that thioredoxin reductase, but not DNA, is a possible target of these complexes. Complex 1 is stable under biological conditions, which would be important if this compound is ever to be considered as a drug. Overall, the results obtained evidenced the promising biological activity of complex 1, which might have potential as a novel anticancer, antimicrobial and antiplasmodial agent to be used as an alternative to current therapeutics.

On the path to gold: Monoanionic Au bisdithiolate complexes with antimicrobial and antitumor activities.

The emergence of resistance to antimicrobial and anticancer drugs poses severe threats to public health worldwide, highlighting the need for more efficient treatments. Here, four monoanionic Au bisdithiolate complexes [Au(mnt)2]- (where mnt = 1,1-dicyanoethylene-2,2-dithiolate)(1), [Au(i-mnt)2]- (where i-mnt = 2,2-dicyanoethylene-1,1-dithiolate)(2), [Au(cdc)2]- (where cdc = cyanodithioimido carbonate)(3), and [Au(qdt)2]- (where qdt = quinoxaline-2,3-dithiolate)(4) were screened for their antimicrobial and antitumor activities. Complexes 3 and 4 showed antibacterial activity against Staphylococcus aureus [minimal inhibitory concentration (MIC) = 15.3 and 14.7 µg/mL, respectively]. Complex 3 also caused significant growth inhibition of Candida glabrata (MIC = 7.0 µg/mL). Concentrations of complexes 1-4 up to 125 µg/mL had no growth inhibition activity against Escherichia coli. The cytotoxic activity of complexes 1-4 was evaluated against the ovarian cancer cells A2780 and A2780cisR, sensitive and resistant to cisplatin, respectively. All compounds showed high cytotoxic activities against both tumoral cell lines, exhibiting IC50 values in the low micromolar range (0.9-5.5 µM) upon 48 h incubation. In contrast to complex 1, the complexes 2-4 induced a dose-dependent formation of reactive oxygen species (ROS), similar to the observed for the reference drugs auranofin and cisplatin. Opposite to 4, complexes 1-3 were able to activate caspase 3/7, suggesting the involvement of apoptosis in the mechanism of cell death. Contrasting with cisplatin, complexes 3, 4 and auranofin did not cause DNA damage. Combined, these data provide evidence that these monoanionic gold bisdithiolates, particularly complex 3, are potential lead compounds to further explore as therapeutic drugs.

Gold and Nickel Extended Thiophenic-TTF Bisdithiolene Complexes.

Gold and nickel bisdithiolene complexes with methyl and tert-butyl substituted thiophenetetrathiafulavalenedithiolate ligands (α-mtdt and α-tbtdt) were prepared and characterized. These complexes were obtained, under anaerobic conditions, as tetrabutylammonium salts. The diamagnetic gold monoanion (n-Bu4N)[Au(α-mtdt)2] (3) and nickel dianionic species (n-Bu4N)x[Ni(α-mtdt)2] (x = 1,2) (4) were similar to the related non-substituted extended thiophenic-TTF (TTF = tetrathiafulvalene) bisdithiolenes. However the introduction of the large, bulky substituent tert-butyl, led to the formation of a Au (I) dinuclear complex, (n-Bu4N)2[Au2(α-tbtdt)2] (5). The neutral methyl substituted gold and nickel complexes were easily obtained through air or iodine exposure as polycrystalline or amorphous fine powder. [Au(α-mtdt)2] (6) and [Ni(α-mtdt)2] (7) polycrystalline samples display properties of a metallic system with a room temperature electrical conductivity of 0.32 S/cm and ≈4 S/cm and a thermoelectric power of ≈5 µV/K and ≈32 µV/K, respectively. While [Au(α-mtdt)2] (6) presented a Pauli-like magnetic susceptibility typical of conducting systems, in [Ni(α-mtdt)2] (7) large magnetic susceptibilities indicative of high spin states were observed. Both electric transport properties and magnetic properties for gold and nickel [M(α-mtdt)2] are indicative that these compounds are single component molecular conductors.