Biological evaluation of complexes of cyclopentadienyl M(CO)3+ (M = Re, 99mTc) with high blood-brain barrier penetration potential as brain cancer agents.

To address the major medical need for effective chemotherapeutics/diagnostics for brain cancer, in this work three cyclopentadienyl M(CO)3+ (M = Re, 99mTc) complexes, which cross the blood-brain barrier (BBB) in high % and are designed to mimic the anticancer agent 2-phenylbenzothiazole, are in vitro and in vivo evaluated for anticancer action. The study includes cytotoxicity and uptake studies in cancer and healthy neuronal cell lines, mechanistic investigation of potential anticancer pathways, and biodistribution studies in mice bearing glioblastoma xenografts. The stable Re complexes exhibit selective uptake and significant antiproliferative effect, particularly against U-251 MG glioblastoma cells, with no significant toxicity in healthy neurons, demonstrating the suitability of this type of complexes to serve as selective therapeutic/imaging agents for brain cancer. Furthermore, they result in the generation of elevated Reactive Oxygen Species (ROS) levels, and lead to significant G2/M arrest followed by apoptosis. Biodistribution studies in U-251 MG xenograft bearing mice with the radioactive 99mTc complex that exhibits the highest BBB penetration, show retention at the tumor-site offering a diagnostic prospect and, in addition, indicating the capability of the Re analogue to accumulate at the tumor site for therapeutic action. Overall, the complexes demonstrate significant anticancer properties that, combined with their high BBB penetration potential, render them strong candidates for further evaluation as brain cancer agents.

Curcumin derivatives as photosensitizers in photodynamic therapy: photophysical properties and in vitro studies with prostate cancer cells.

Photodynamic therapy (PDT) is a minimally invasive approach to treat various forms of cancer, based on the ability of certain non-toxic molecules (photosensitizers) to generate reactive oxygen species (ROS) after excitation by light of a certain wavelength and eventually induce strong phototoxic reactions against malignant cells and other pathogens. Curcumin is one of the most extensively investigated phytochemicals with a wide range of therapeutic properties and has been shown to induce strong photocytotoxic effects in micromolar concentrations against a variety of cancer cell lines. Curcumin (1) is comparatively evaluated with the naturally occurring bisdemethoxy Curcumin (2), which lacks the two methoxy groups, as well as two newly synthesized curcuminoids, the cinnamaldehyde derivative (3) and the dimethylamino one (4), designed to increase the absorption maximum and hence the tissue penetration. The synthetic curcuminoids were successfully synthesized in sufficient amounts and their photophysical properties such as absorption, fluorescence, photobleaching and free radical generation were investigated. Compound 4 exhibited a significant increase in peak absorption (497 nm) and strong fluorescent emission signals were recorded for all curcuminoids. Photobleaching of 4 was comparable to 1 whereas 2 and 3 showed more extended photobleaching but much higher ROS production in very short irradiation times. Compounds 2 and 4 exhibited specific intracellular localization. After dark and light cytotoxicity experiments against LNCaP prostate cancer cell line for all curcuminoids, concentration of 3 µM and irradiance of 6 mW cm-2 were selected for the PDT application which resulted in remarkable results with very short LD50. Curcuminoids 2 and 4 exhibited a significant dose-dependent PDT effect. The biphasic dose-response photodynamic effect observed for 1 and 3 may provide a strategy against prolonged and sustained photosensitivity.

Evaluation of naturally occurring curcuminoids and related compounds against mosquito larvae.

The three curcuminoid components commonly isolated from Curcuma longa, curcumin (1), demethoxycurcumin (2), and bis-demethoxycurcumin (3) were separated and isolated from a commercially available turmeric extract product in high purity and sufficient amounts. Three more derivatives of curcumin, the di-O-demethylcurcumin (4), di-O-methylcurcumin (5) and the di-O-acetylcurcumin (6) were also synthesized and characterized. All six compounds were evaluated for their larvicidal effect against the mosquito Culex pipiens. Curcumin (1) exhibited highly potent larvicidal activity with LC(50) value of 19.07mgL(-1). Moreover, di-O-demethylcurcumin (4), was found to be equally active with LC(50) value of 12.42mgL(-1). Based on the LC(90) values of the two compounds, di-O-demethylcurcumin (4) was the most active of all, resulting in an LC(90) value of 29.40mgL(-1), almost half of the LC(90) value 61.63mgL(-1) found for compound 1. The rest of the compounds were inactive at concentrations even as high as 150mgL(-1) indicating a dependence of the larvicidal activity upon the substitution patent and the presence of aromatic hydroxyl and methoxy moieties. These results show for the first time the potential of this valuable natural product regarding its use as vector control agent.

Biomonitoring with the comet assay of Greek greenhouse workers exposed to pesticides.

The pesticides in use in Greek greenhouses include a number of agents known to be mutagens and carcinogens. In the present study, we evaluated whether occupational exposure of agricultural workers to a complex mixture of pesticides resulted in a significant increase in DNA damage in human peripheral blood lymphocytes (PBLs). A total of 116 healthy individuals were divided into groups based on exposure to pesticides, smoking status, and gender. Alkaline comet assays performed on PBLs from these individuals indicated no statistically significant differences in basal DNA damage between the study groups. In addition, exposure of PBLs to a dose of hydrogen peroxide led to a similar degree of DNA damage and subsequent repair for all the study populations. The results of the study indicate that the agricultural workers who participated in this study had no detectable increase in DNA damage or alteration in the cellular response to DNA damage.

Design and synthesis of novel pyrrolobenzodiazepine (PBD) prodrugs for ADEPT and GDEPT.

Three N10-(4-nitrobenzyl)carbamate-protected PBD prodrugs (9a, 9b and 15) have been synthesized and evaluated for potential use in nitroreductase-based ADEPT and GDEPT therapies. An approximately 100-fold activation was observed for the DC-81 prodrug 9a.

Effects of smoking and aging on oxidative DNA damage of human lymphocytes.

The effects of H2O2-induced oxidative DNA damage in 80 healthy individuals with relation to age (20-25 and 55-60 years old) and smoking has been investigated with the comet assay technique. Both factors have shown a significant effect upon basal DNA damage with smoking appearing to have the most impact. A differentiation of the four groups response to induced oxidative damage was also observed. A distinctly separate behavior of the younger non-smokers group, when compared with the rest of the categories, was found. This is attributed to the lower degree of initial basal damage that occurs in their lymphocytes.