Cancer is the second leading cause of death worldwide. Cisplatin has challenged cancer treatment; however, resistance and side effects hamper its use. New agents displaying improved activity and more reduced side effects relative to cisplatin are needed. In this work we present the synthesis, characterization and biological activities of three complexes with quinoline-substituted 2,2′:6′,2″-terpyridine ligand: [Pt(4′-(2-quin)-terpy)Cl](SO3CF3) (1), [Au(4′-(2-quin)-terpy)Cl](PF6)2·CH3CN (2) and [Cu(4′-(2-quin)-terpy)Cl](PF6) (3). The three complexes displayed a high antiproliferative activity in ovarian carcinoma cell line (A2780) and even more noticeable in a colorectal carcinoma cell line (HCT116) following the order 3 > 2 > 1. The complexes IC50 are at least 20 × lower than the IC50 displayed by cisplatin (15.4 μM) in HCT116 cell line while displaying at the same time, much reduced cytotoxicity in a normal dermal fibroblast culture. These cytotoxic activities seem to be correlated with the inclination angles of 2-quin unit to the central pyridine. Interestingly, all complexes can interact with calf-thymus DNA (CT-DNA) in vitro via different mechanisms, although intercalation seems to be the preferred mechanism at least for 2 and 3 at higher concentrations of DNA. Moreover, circular dichroism (CD) data seems to indicate that complex 3, more planar, induces a high destabilization of the DNA double helix (shift from B-form to Z-form). Higher the deviation from planar, the lower the cytotoxicity displayed by the complexes. Cellular uptake may be also responsible for the different cytotoxicity exhibited by complexes with 3 > 2 >1. Complex 2 seems to enter cells more passively while complex 1 and 3 might enter cells via energy-dependent and -independent mechanisms. Complexes 1–3 were shown to induce ROS are associated with the increased apoptosis and autophagy. Moreover, all complexes dissipate the mitochondrial membrane potential leading to an increased BAX/BCL-2 ratio that triggered apoptosis. Complexes 2 and 3 were also shown to exhibit an anti-angiogenic effect by significantly reduce the number of newly formed blood vessel in a CAM model with no toxicity in this in vivo model. Our results seem to suggest that the increased cytotoxicity of complex 3 in HCT116 cells and its potential interest for further translation to pre-clinical mice xenografts might be associated with: 1) higher % of internalization of HCT116 cells via energy-dependent and -independent mechanisms; 2) ability to intercalate DNA and due to its planarity induced higher destabilization of DNA; 3) induce intracellular ROS that trigger apoptosis and autophagy; 4) low toxicity in an in vivo model of CAM; 5) potential anti-angiogenic effect.

This study describes for the first time the iron- and copper-mediated gelation of FucoPol, fucose-rich bacterial polysaccharide. The ability of FucoPol to gel in the presence of metal cations, including iron(III) and copper(II), was used for the preparation of hydrogel beads. Iron mediated the formation of stable and not cytotoxic gel beads, while copper resulted in fragile and cytotoxic ones. Copper-mediated beads coated with an iron-mediated gel layer were more stable and had reduced cytotoxicity. The resulting polymeric structures had differing morphology, physical properties and cytotoxicity, which support their use in several applications, including biomedicine, agriculture and bioremediation.

Nucleic acid amplification technologies (NAATs) have become fundamental tools in molecular diagnostics, due to their ability to detect small amounts of target molecules. Since its development, Polymerase Chain Reaction (PCR) has been the most exploited method, being stablished as the “gold standard” technique for DNA amplification. However, the requirement for different working temperatures leads to the need of a thermocycler machine or complex thermal apparatus, which have been preventing its application in novel integrated devices for single workflow and high throughput analysis. Conversely, isothermal amplification methods have been gaining attention, especially for point-of-care diagnosis and applications. These non-PCR based methods have been developed by mimicking the in vivo amplification mechanisms, while performing the amplification with high sensitivity, selectivity and allowing for high-throughput analysis. These favorable capabilities have pushed forward the implementation and commercialization of several platforms that exploit isothermal amplification methods, mostly against virus, bacteria and other pathogens in water, food, environmental and clinical samples. Nevertheless, the future of isothermal amplification methods is still dependent on achieving technical maturity and broader commercialization of enzymes and reagents.

Edible flowers are being used as a new ingredient in modern gastronomy. Recently, these products have also gained interest as an important source of phenolic compounds with potential for biomedical applications. The present work studied a methanolic extract of Rosa x hybrida in which 35 individual phenolic compounds were identified. The extract has been evaluated for its antiproliferative properties in ovarian carcinoma cells. Results showed that the antiproliferative effect was associated with the induction of autophagy and apoptosis with the concomitant ROS increase probably related to mitochondria dysfunction. These antiproliferative effects might be associated with some components of the extract such as quercetin. The extract did not induce damage in healthy cells and that it was able to improve the wound healing activity. The present study also evaluated the properties of the mentioned extract in vivo in C. elegans. Tests demonstrated a lack of toxicity in the worm model. Promising results have been obtained in transgenic strains of C. elegans that produce human beta amyloid peptide, suggesting the possible utility of the extract from the point of view of Alzheimer disease. Altogether, results suggest that Rosa x hybrida extracts could be a new tool for the development of functional foods.

Cancer is still one of the deadliest diseases worldwide despite the efforts in its early detection and treatment strategies. However, most chemotherapeutic agents still present side effects in normal tissues and acquired resistance that limit their efficacy. Spiropyrazoline oxindoles might be good alternatives as they have shown antiproliferative activity in human breast and colon cancer cell lines, without eliciting cytotoxicity in healthy cells. However, their potential for ovarian cancer was never tested. In this work, the antiproliferative activity of five spiropyrazoline oxindoles was assessed in ovarian cancer cells A2780 and the biological targets and mechanism of action of the most promising compound evaluated. Compound 1a showed the highest antiproliferative effect, as well as the highest selectivity for A2780 cells compared to healthy fibroblasts. This antiproliferative effect results from the induction of cell death by mitochondria-mediated apoptosis and autophagy. In vitro DNA interaction studies demonstrated that 1a interacts with DNA by groove-binding, without triggering genotoxicity. In addition, 1a showed a strong affinity to bovine serum albumin that might be important for further inclusion in drug delivery platforms. Proteomic studies reinforced 1a role in promoting A2780 endoplasmatic reticulum (ER) stress by destabilizing the correct protein folding which triggers cell death via apoptosis and autophagy.

Palladacycles are versatile organometallic compounds that show potential for therapeutic use. Here are described the synthesis and characterization of mono- and dinuclear palladacycles bearing diphosphines. Their biological effect was investigated in A2780, an ovarian-derived cancer line, and in normal dermal fibroblasts. The compounds displayed selective cytotoxicity toward the A2780 cell line. Compound 3 decreased the cell viability through cell cycle retention in G0/G1, triggered apoptosis through the intrinsic pathway, and induced autophagy in A2780 cells. Compound 9 also induced cell cycle retention, apoptosis, and cellular detachment. Notably, compound 9 induced the production of intracellular reactive oxygen species (ROS). Our work demonstrated that compound 3 enters A2780 cells via active transport, which requires energy, while compound 9 enters A2780 cells mostly passively. The potential effect of palladacycles in angiogenesis was investigated for the first time in an in vivo chorioallantoic membrane model, showing that while compound 3 displayed an antiangiogenic effect crucial to fighting cancer progression, compound 9 promoted angiogenesis. These results show that palladacycles may be used in different clinical applications where pro- or antiangiogenic effects may be desirable.

In this work, we prepared new biocompatible N-alkyl cholinium-based ionic liquids to be used as cosolvents to improve the solubility of poorly water-soluble drugs, namely, sodium diclo-fenac and paracetamol. In this set of ionic liquids, we intend to understand the effect of increasing the asymmetry of the ionic liquid cation/anion by growing the length of one of the alkyl chains attached to the nitrogen center/sulfonate center on the dissolution capacity of the ionic liquid. The addition of these new ionic liquids to water increased the dissolution capacity of the drugs up to four-times that in water, and improved the pharmacodynamic properties of these drugs, especially the case of sodium diclofenac. The intermolecular interactions between the drugs and ionic liquids were investigated by NMR. Two-dimensional1H/1H nuclear overhauser effect spectroscopy (NO-ESY) revealed an interaction between sodium diclofenac and the alaninate anion from the [C2Ch]2[SucAla]. In the case of paracetamol and [C4Ch][C2SO3], it was possible to observe two inter-molecular interactions between the hydroxyl group of paracetamol and two protons from the cation [C4Ch]+. Interestingly, the ionic liquid bearing a succinyl-DL-alaninate anion, [SucAla]2−, and a N-ethyl cholinium cation, [C2Ch]+, which presented the highest ability to dissolve sodium diclofenac, showed no cytotoxicity up to 500 mM. Therefore, this ionic liquid is a potential candidate for drug delivery applications.

Cancer is one of the worst health issues worldwide, representing the second leading cause of death. Current chemotherapeutic drugs face some challenges like the acquired resistance of the tumoral cells and low specificity leading to unwanted side effects. There is an urgent need to develop new compounds that may target resistant cells. The synthesis and characterization of two Cu(i) complexes of general formula [Cu(PP)(LL)][BF4], where PP is a phosphane ligand (triphenylphosphine or 1,2-bis(diphenylphosphano) ethane) and LL = is a heteroaromatic bidentate ligand (4,4′-dimethyl-2,2′-bipyridine and 6,3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine). The new compounds were fully characterized by spectroscopic techniques (NMR, FTIR and UV-vis.), elemental analysis (C, H, N and S) and two structures were determined by single X-ray diffraction studies. The antiproliferative potential of the new Cu(i) complexes were studied in tumor (breast adenocarcinoma, ovarian carcinoma and in colorectal carcinoma sensitive and resistant to doxorubicin) and normal (fibroblasts) cell lines. Complexes1-4did not show any antiproliferative potential. Amongst the complexes5-8, complex8shows high cytotoxic potential against colorectal cancer sensitive and resistant to doxorubicin and low cytotoxicity towards healthy cells. We show that complexes5-8can cleave pDNA and, in particular, thein vitropDNA cleavage is due to an oxidative mechanism. This oxidative mechanism corroborates the induction of reactive oxygen species (ROS), that triggers HCT116 cell deathviaapoptosis, as proved by the increased expression of BAX protein relative to BCL-2 protein and the depolarization of mitochondrial membrane potential, andviaautophagy. Additionally, complex8can block the cell cycle in the G1 phase, also exhibiting a cytostatic potential. Proteomic analysis confirmed the apoptotic, autophagic and cytostatic potential of complex8, as well as its ability to produce ROS and cause DNA damage. The interference of the complex in folding and protein synthesis and its ability to cause post-translational modifications was also verified. Finally, it was observed that the complex causes a reduction in cellular metabolism. The results herein demonstrated the potential of Cu(i) complexes in targeting doxorubicin sensitive and resistant cells which is positive and must be further explored usingin vivoanimal models.

The use of nanomaterials to improve medical diagnostics and therapeutics has been rapidly increasing. Among these materials are gold nanoparticles, which can be functionalized to target specific cells, acting as nanovectors for drug delivery, enhanced contrast agents as well as other targeted therapies. Au nanoparticles are very useful as they selectively accumulate in tumour sites due to the enhanced permeability-retention effect. There is however little information about the spatial distribution of the nanoparticles within tumours, which might hinder efficient therapies. In this study, X-ray fluorescence was used to investigate the diffusion of gold nanoparticles in cancer cell spheroids mimicking true tumour growth. Functionalization of the nanoparticles has the effect of allowing better diffusion into and out of the spheroid, while those nanoparticles that are only partially covered rapidly formed aggregates. This clustering led to size exclusion during transport within the tumour, changing its distribution profile while greatly increasing the nanoparticle concentration.