To enhance their therapeutic effectiveness, and decrease cardiotoxicity and other side effects, we intend to conjugate the quinone chelators with monoclonal antibodies and peptide hormones that are specifically targeted to receptors on the cancer cell surface. Some such candidates have already been synthesized. An alternative approach for delivery of our compounds involves the use of specific peptide-based nanoparticles. In addition, our novel approach for treating malignancies is also suitable for photodynamic therapy. Antioxid. Redox Signal. 28, 1394-1403.

The risk of chronic oxidative stress in the retinal pigment epithelium (RPE) increases with age due to accumulation of the photoreactive age pigment lipofuscin (LFG). Here, we asked whether sublethal and weakly lethal photic stress, induced by irradiation of ARPE-19 cells containing phagocytised LFG, affected the cell specific phagocytic activity, which is critically important for proper functioning and survival of the retina, and if natural antioxidants could modify the observed outcomes. ARPE-19 cells preloaded with LFG isolated from human donors of different age or containing LFG enriched with zeaxanthin and α-tocopherol (LFG-A), were irradiated with blue light. Phagocytosis of fluorescein-5-isothiocyanate (FITC)-labelled photoreceptor outer segments was determined by flow cytometry. Photoreactivity of LFG and LFG-A was analysed by measuring photoconsumption of oxygen and photogeneration of singlet oxygen mediated by the granules. LFG-mediated photic stress in ARPE-19 cells induced significant inhibition of their specific phagocytosis. The inhibitory effect increased with age of LFG donors and was reduced by enrichment of the granules with antioxidants. Oxygen consumption and generation of singlet oxygen induced by the photoexcited LFG increased with donor's age and was partially quenched by antioxidants. Although the phototoxic potential of lipofuscin increased with age, natural antioxidants reduced photoreactivity of LFG and their efficiency to induce oxidative stress. This study has demonstrated, for the first time, that mild oxidative stress, mediated by the age pigment lipofuscin, impairs specific phagocytic activity of RPE, and that natural antioxidants can protect this important cellular function by reducing lipofuscin photoreactivity.

Three novel 1,3,4-tiadiazole-derived compounds with biological-activity, i.e., 4-(5-(methylamino)-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (MDFT), 4-(5-(phenylamino)-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (PhATB), and 4-(5-(4-chlorophenylamino)-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (4-CIPhATB) were characterized with the use of several spectroscopic methods. Detailed UV-vis studies revealed keto/enol tautomerism of the examined compounds. The absorption spectra recorded in nonpolar solvents exhibited bands that were characteristic of keto tautomers, while in polar solvents the enol form is predominant. A number of spectra revealed the presence of both tautomeric forms in the solution. The keto/enol equilibria observed were both solvent- and temperature-dependent. The keto/enol equilibrium was also observed using FTIR spectroscopy. A detailed analysis of the spectroscopic data leads to a conclusion that the solvent-induced tautomerism of the selected compounds from the 1,3,4-thiadiazole group does not depend on the electric dipole moment of the solvent but more likely on its average electric polarizability. Additionally, a clear effect of the substituent present in the molecule on the tautomeric equilibrium in the selected 1,3,4-thiadiazole analogues was noted.

Practical applications of photosynthesis-inspired processes depend on a thorough understanding of the structures and physiochemical features of pigment molecules such as chlorophylls and bacteriochlorophylls. Consequently, the major structural features of these pigments have been systematically examined as to how they influence the S 1 state energy, lifetimes, quantum yields, and pigment photostability. In particular, the effects of the macrocyclic π-electron system, central metal ion (CMI), peripheral substituents, and pigment aggregation, on these critical parameters are discussed. The results obtained confirm that the π-electron system of the chromophore has the greatest influence on the light energy conversion capacity of porphyrinoids. Its modifications lead to changes in molecular symmetry, which determine the energy levels of frontier orbitals and hence affect the S 1 state properties. In the case of bacteriochlorophylls aggregation can also strongly decrease the S 1 energy. The CMI may OPEN ACCESSMolecules 2014, 19 15939 be considered as another influential structural feature which only moderately influences the ground-state properties of bacteriochlorophylls but strongly affects the singlet excitedstate. An introduction of CMIs heavier than Mg 2+ significantly improves pigments' photostabilities, however, at the expense of S 1 state lifetime. Modifications of the peripheral substituents may also influence the S 1 energy, and pigments' redox potentials, which in turn influence their photostability.

The bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E) is formed as a byproduct of visual cycle in retinal pigment epithelium (RPE). It contributes to golden-yellow fluorescence of the age pigment lipofuscin, which accumulates in RPE. Lipofuscin can generate a variety of reactive oxygen species (ROS) upon blue-light excitation. Although in model systems photoreactivity of A2E has been determined to be low, this bis-retinoid exhibited significant phototoxicity in RPE cells in vitro. Although the mechanism of A2E-mediated phototoxicity remains mostly unknown, we hypothesize that formation of A2E-adducts with different biomolecules may play an important role. In this study, we investigated the photochemical reactivity of A2E and its complex with bovine serum albumin (BSA) using UV–Vis absorption and emission spectroscopy, EPR-spin trapping, EPR-oximetry, time-resolved singlet oxygen phosphorescence, and the fluorogenic CBA probe. Our data show that A2E after complexation with this model protein photogenerated an increased level of ROS, particularly singlet oxygen. We also demonstrated the ability of A2E to oxidize BSA upon excitation with blue light in aqueous model systems. The data suggest that pyridinium bis-retinoid could oxidatively modify cellular proteins under physiological conditions.