Ruthenium(II)-Arene Curcuminoid Complexes as Photosensitizer Agents for Antineoplastic and Antimicrobial Photodynamic Therapy: In Vitro and In Vivo Insights.

Photodynamic therapy (PDT) is an anticancer/antibacterial strategy in which photosensitizers (PSs), light, and molecular oxygen generate reactive oxygen species and induce cell death. PDT presents greater selectivity towards tumor cells than conventional chemotherapy; however, PSs have limitations that have prompted the search for new molecules featuring more favorable chemical-physical characteristics. Curcumin and its derivatives have been used in PDT. However, low water solubility, rapid metabolism, interference with other drugs, and low stability limit curcumin use. Chemical modifications have been proposed to improve curcumin activity, and metal-based PSs, especially ruthenium(II) complexes, have attracted considerable attention. This study aimed to characterize six Ru(II)-arene curcuminoids for anticancer and/or antibacterial PDT. The hydrophilicity, photodegradation rates, and singlet oxygen generation of the compounds were evaluated. The photodynamic effects on human colorectal cancer cell lines were also assessed, along with the ability of the compounds to induce ROS production, apoptotic, necrotic, and/or autophagic cell death. Overall, our encouraging results indicate that the Ru(II)-arene curcuminoid derivatives are worthy of further investigation and could represent an interesting option for cancer PDT. Additionally, the lack of significant in vivo toxicity on the larvae of Galleria mellonella is an important finding. Finally, the photoantimicrobial activity of HCurc I against Gram-positive bacteria is indeed promising.

Maytenus octogona Superoxide Scavenging and Anti-Inflammatory Caspase-1 Inhibition Study Using Cyclic Voltammetry and Computational Docking Techniques.

The relationship between oxidative stress and inflammation is well known, and exogenous antioxidants, primarily phytochemical natural products, may assist the body's endogenous defense systems in preventing diseases due to excessive inflammation. In this study, we evaluated the antioxidant properties of ethnomedicines from Peru that exhibit anti-inflammatory activity by measuring the superoxide scavenging activity of ethanol extracts of Maytenus octogona aerial parts using hydrodynamic voltammetry at a rotating ring-disk electrode (RRDE). The chemical compositions of these extracts are known and the interactions of three methide-quinone compounds found in Maytenus octogona with caspase-1 were analyzed using computational docking studies. Caspase-1 is a critical enzyme triggered during the activation of the inflammasome and its actions are associated with excessive release of cytokines. The most important amino acid involved in active site caspase-1 inhibition is Arg341 and, through docking calculations, we see that this amino acid is stabilized by interactions with the three potential methide-quinone Maytenus octogona inhibitors, hydroxytingenone, tingenone, and pristimerin. These findings were also confirmed after more rigorous molecular dynamics calculations. It is worth noting that, in these three compounds, the methide-quinone carbonyl oxygen is the preferred hydrogen bond acceptor site, although tingenone's other carbonyl group also shows a similar binding energy preference. The results of these calculations and cyclovoltammetry studies support the effectiveness and use of anti-inflammatory ethnopharmacological ethanol extract of Maytenus octogona (L'Héritier) DC.

Scavenging of Superoxide in Aprotic Solvents of Four Isoflavones That Mimic Superoxide Dismutase.

Isoflavones are plant-derived natural products commonly found in legumes that show a large spectrum of biomedical activities. A common antidiabetic remedy in traditional Chinese medicine, Astragalus trimestris L. contains the isoflavone formononetin (FMNT). Literature reports show that FMNT can increase insulin sensitivity and potentially target the peroxisome proliferator-activated receptor gamma, PPARγ, as a partial agonist. PPARγ is highly relevant for diabetes control and plays a major role in Type 2 diabetes mellitus development. In this study, we evaluate the biological role of FMNT, and three related isoflavones, genistein, daidzein and biochanin A, using several computational and experimental procedures. Our results reveal the FMNT X-ray crystal structure has strong intermolecular hydrogen bonding and stacking interactions which are useful for antioxidant action. Cyclovoltammetry rotating ring disk electrode (RRDE) measurements show that all four isoflavones behave in a similar manner when scavenging the superoxide radical. DFT calculations conclude that antioxidant activity is based on the familiar superoxide σ-scavenging mode involving hydrogen capture of ring-A H7(hydroxyl) as well as the π-π (polyphenol-superoxide) scavenging activity. These results suggest the possibility of their mimicking superoxide dismutase (SOD) action and help explain the ability of natural polyphenols to assist in lowering superoxide concentrations. The SOD metalloenzymes all dismutate O2•- to H2O2 plus O2 through metal ion redox chemistry whereas these polyphenolic compounds do so through suitable hydrogen bonding and stacking intermolecular interactions. Additionally, docking calculations suggest FMNT can be a partial agonist of the PPARγ domain. Overall, our work confirms the efficacy in combining multidisciplinary approaches to provide insight into the mechanism of action of small molecule polyphenol antioxidants. Our findings promote the further exploration of other natural products, including those known to be effective in traditional Chinese medicine for potential drug design in diabetes research.

Antioxidant properties of bee propolis and an important component, galangin, described by X-ray crystal structure, DFT-D and hydrodynamic voltammetry.

Propolis is produced by honeybees and used to seal their hives for defensive purposes and has been used in ethnopharmacology since ancient times. It is a lipophilic material containing a large collection of naturally produced plant organic molecules, including flavonoids. The flavonoid galangin is consistently found in propolis, independent of the hive geographical location and its X-ray crystal and molecular structure is reported. The antioxidant scavenging of superoxide by galangin and propolis is here presented. Using a cyclic voltammetry technique developed in our lab, we show that galangin is an excellent scavenger of the superoxide radical, perhaps even better than quercetin. Our results show that galangin displays a Superoxide Dismutase (SOD) function. This is described experimentally and theoretically (DFT). Two modes of scavenging superoxide are seen for galangin: (1) superoxide radical extraction of H atom from the hydroxyl moieties located in position 3 and 5 of galangin, which are also associated with proton incorporation defining the SOD action; (2) π-π interaction among several superoxide radicals and the galangin polyphenol ring that evolve towards release of O2 and H2O2. We describe these two actions separately as their relative sequence, and/or combination, cannot be defined; all these processes are thermodynamically spontaneous, or subjected to mild barriers.

X-ray Structure Determination, Antioxidant Voltammetry Studies of Butein and 2',4'-Dihydroxy-3,4-dimethoxychalcone. Computational Studies of 4 Structurally Related 2',4'-diOH Chalcones to Examine Their Antimalarial Activity by Binding to Falcipain-2.

Malaria is a huge global health burden with resistance to currently available medicines resulting in the search for newer antimalarial compounds from traditional medicinal plants in malaria-endemic regions. Previous studies on two chalcones, homobutein and 5-prenylbutein, present in E. abyssinica, have shown moderate antiplasmodial activity. Here, we describe results from experimental and computational investigations of four structurally related chalcones, butein, 2',4'-dihydroxy-3,4-dimethoxychalcone (DHDM), homobutein and 5-prenylbutein to elucidate possible molecular mechanisms by which these compounds clear malaria parasites. The crystal structures of butein and DHDM show that butein engages in more hydrogen bonding and consequently, more intermolecular interactions than DHDM. Rotating ring-disk electrode (RRDE) voltammetry results show that butein has a higher antioxidant activity towards the superoxide radical anion compared to DHDM. Computational docking experiments were conducted to examine the inhibitory potential of all four compounds on falcipain-2, a cysteine protease that is involved in the degradation of hemoglobin in plasmodium-infected red blood cells of the host. Overall, this work suggests butein as a better antimalarial compound due to its structural features which allow it to have greater intermolecular interactions, higher antioxidant activity and to create a covalent complex at the active site of falcipain-2.

Emodin Scavenging of Superoxide Radical Includes π-π Interaction. X-Ray Crystal Structure, Hydrodynamic Voltammetry and Theoretical Studies.

The naturally occurring anthraquinone emodin is found in many plants that have been part of traditional Chinese medicine (TCM) for thousands of years. Recent pharmacological studies suggest that emodin might be a valuable therapeutic option for the treatment of various diseases. We describe the antioxidant effects of emodin on the superoxide radical. Our techniques include X-ray crystallography, density functional theory (DFT), and a recently developed cyclovoltammetry improvement, the rotating ring-disk electrode (RRDE) method. X-ray results show offset π-π stacking of emodin units in the crystal, and this type of interaction is supported by the DFT, which indicates one superoxide interacting via π-π stacking with the quinone moiety, by transferring one electron to the ring, and inducing some quinone aromatization. The second superoxide seems to form a stable complex after interacting with the H(hydroxyl) in position 3 of emodin. We show that one molecule of emodin sequesters two molecules of superoxide: one forming a complex with H(hydroxyl) in position 3, and the other due to π-π oxidation of superoxide and emodin ring reduction. We conclude that emodin is a very strong antioxidant. Color variation in the voltaic cell was observed during the RRDE study. This was analyzed and explained using a mini-grid gold electrode for UV-Vis spectroscopy in the voltaic cell.

beta-sitosterol among other secondary metabolites of Piper galeatum shows inhibition of TNFalpha-induced cell adhesion molecule expression on human endothelial cells.

A phytochemical investigation of the stems of Piper galeatum yielded one novel amide, 1-(3'-hydroxy-5'-methoxycinnamoyl)-piperidine (5) along with four known compounds, i.e. beta-sitosterol (1), cyclostachine-A (2), piperine (3) and piperolein-B (4). The structures of all the five compounds, isolated for the first time from this plant were unambiguously established on the basis of their detailed spectral analysis. The structure of cyclostachine-A (2) was confirmed by X-ray crystallographic studies and structures of known compounds were confirmed by comparison of their physical and/or chemical data with those reported in the literature, which were in complete agreement. Additionally, the crude extracts as well as the isolated pure compounds were screened for their activity to inhibit TNFalpha (tumour necrosis factor-alpha)- induced expression of cell adhesion molecule ICAM-1 (intercellular adhesion molecule-1) on the surface of human umbilical vein endothelial cells (HUVECs). Among all, beta-sitosterol (1) was found to be the most active compound, which was taken for further studies. beta-sitosterol also significantly inhibited the TNFalpha-induced expression of VCAM-1 and E-selectin, which also play key role in various inflammatory diseases. The functional correlation of cell adhesion molecules inhibition was assessed by cell adhesion assay using human neutrophils. We found that beta-sitosterol significantly blocks the adhesion of neutrophils to endothelial monolayer. To elucidate the molecular mechanism of inhibition of cell adhesion molecules, we investigated the status of nuclear transcription factor-kappaB (NF-kappaB) and were able to establish that beta-sitosterol significantly blocked the TNFalpha-induced activation of NF-kappaB.