Gold(III) complexes with thiosemicarbazonate ligands as potential anticancer agents: Cytotoxicity and interactions with biomolecular targets.

Gold(III) complexes have been studied for the past years due to their anticancer properties and great affinity to biotargets, such as enzymes and proteins, which support their pharmacological applications. Within this scope, in this work the antiproliferative activities of two Au(III)-thiosemicarbazonate complexes, [AuClL1] (1, L1: (E,Z)-N-ethyl-N'-(3-nitroso-kN)butan-2-ylidene)carbamohydrazonothioato-k2N2,S) and [Au(Hdamp)L2]Cl (2, L2: N-(N'',N''-diethylaminothiocarbonyl)-N'(N''', N'''-dimethylcarbothioamide)benzamidineto-kN,k2S and Hdamp: 2-(N,N-dimethylaminomethyl)-phenyl-C1), and their affinities to possible biological targets were investigated. Three different tumor cell lines were used to perform the cytotoxicity assays, including one cisplatin-resistant model, and the results showed lower EC50 for 1 over 2 in every case: B16F10 (4.1 µM and 15.6 µM), A431 (4.0 µM and >50 µM) and OVCAR3 (4.2 µM and 24.5 µM). However, a lower toxicity to fibroblast 3T3 cell line was observed for 2 (30.58 µM) when compared to 1 (7.17 µM), resulting in comparable therapeutic indexes. Both complexes presented strong affinity to HSA: they distorted the secondary structure of the protein, as verified by circular dichroism, but 1 additionally presented the apparent fluorescence quenching constant (Kapp) ten times greater than 2, which was probably due to the fact of 1 being able to denature HSA. The ethidium bromide displacement assay showed that neither 1 nor 2 are strong DNA intercalators, which is in agreement with what was observed through the UV-vis titration. In both cases, the 260 nm band presented hyperchromism, which can indicate ionic interactions or DNA damage. In fact, 1 was able to damage the pGEM plasmid, similarly to cisplatin, as verified by agarose gel electrophoresis and Atomic Force Microscopy. Biophysical studies in cancer cells model membranes were also performed in order to investigate the interaction of the gold complexes to lipid bilayers and revealed that the compounds interact with the membranes by exhibiting partition coefficients of 103 order of magnitude. Overall, both complexes were found to be promising candidates for the development of a future anticancer drug against low sensitive or cisplatin resistant tumors.

Vascular tone and angiogenesis modulation by catecholamine coordinated to ruthenium.

Catecholamines participate in angiogenesis, an important tumor development process. However, the way catecholamines interact with their receptors has not been completely elucidated, and doubts still remain as to whether these interactions occur between catechol and/or amine sites and particular amino acid residues on the catecholamine receptors. To evaluate how catechol and amine groups contribute to angiogenesis, we immobilized the catechol site through ruthenium ion (Ru) coordination, to obtain species with the general formula [Ru(NH3)4(catecholamine-R)]Cl. We then assessed the angiogenic activity of the complexes in a chorioallantoic membrane model (CAM) and examined vascular reactivity and calcium mobilization in rat aortas and vascular cells. [Ru(NH3)4(catecholamine-R)]Cl acted as partial agonists and/or antagonists of their respective receptors and induced calcium mobilization. [Ru(NH3)4(isoproterenol)]+ [Ru(NH3)4(noradrenaline)]+, and [Ru(NH3)4(adrenaline)]+ behaved as antiangiogenic complexes, whereas [Ru(NH3)4(dopamine)]+ proved to be a proangiogenic complex. In conclusion, catecholamines and [Ru(NH3)4(catecholamine-R)]Cl can modulate angiogenesis, and catechol group availability can modify the way these complexes impact the vascular tone, suggesting that catecholamines and their receptors interact differently after catecholamine coordination to ruthenium.