Francesco Dall'Acqua

Angelicins, angular analogs of psoralens: Chemistry, photochemical, photobiological and phototherapeutic properties

Angelicin and some of its derivatives are naturally occuring compounds which show interesting photobiological properties. In this review various aspects of angelicin and its derivatives have been reported. The natural occurrence and the chemical synthesis both of naturally occurring and synthetic angelicins have been reviewed. Photochemical and photophysical properties of angelicins have been considered with particular reference to the capacity to generate active forms of oxygen, photoreactions with nucleic acids, proteins and unsaturated fatty acids. Photobiological effects have been considered: skin phototoxicity, antiproliferative effects, genotoxicity, ability to induce hemolysis in erythrocytes, inactivation of prokaryotic and eukaryotic microorganism and of viruses. The ability of some angelicins to induce photocarcinogenesis has been reviewed as well as in the activity as photochemotherapeutic agents.

Investigation on the dark interaction between furocoumarins and DNA

Abstract The complexes between some furocoumarins and DNA have been studied using various physicochemical techniques. Flow-dichroism measurements data strongly support the intercalation of the planar furocoumarin molecules between two base pairs of duplex DNA. The equilibrium dialysis and spectrophotometric data show relatively low values of the association constants of the complexes and a small number of molecules able to intercalate in DNA, thus indicating that furocoumarins have a relatively low affinity for DNA in the complex formation. The biological and photobiological consequences connected with these results are discussed. The binding curves obtained using some polynucleotides and various DNA samples having different composition with regard to base pairs, have shown that the regions of the macromolecule having alternate sequences of purine and pyrimidine represent sites useful for intercalation. No preference has been observed for A-T or G-C.

Intercalation of Organic Dye Molecules into Double‐stranded DNA. Part 2: The Annelated Quinolizinium Ion as a Structural Motif in DNA Intercalators†

Abstract DNA intercalators represent an important class of compounds with a high potential as DNA-targeting drugs. In this review it is demonstrated that annelated quinolizinium derivatives such as coralyne and derivatives thereof intercalate into DNA and that this structural motif allows several variations of the substitution pattern without loss of intercalating properties. The commonly applied methods for the evaluation of the DNA association, mainly spectroscopic studies, are pointed out. In addition, studies on the biological activities of annelated quinolizinium derivatives, such as topoisomerase poisoning or cell toxicity, are highlighted.

Mechanism of skin photosensitization by forucoumarins: Photoreactivity of various furocoumarins with native DNA and with ribosomal RNA

Abstract The photoreactions (by irradiation at 365 nm) between several furocoumarins and native DNA or rRNA have been studied. The initial rates of the photoreactions and the quantum yields were determined. Moreover some experiments have been performed in a manner suitable to give data of photoreactivity which could be directly compared with those previously obtained in determining the skin-photosensitizing activity of the same substances by irradiation at 365 nm. The results showing a close correlation between the capacity of the substances to photoreact with native DNA and that to produce skin photosensitization, offer valid evidence for the mechanism of action of furocoumarins on the skin. By contrast, the photoreactions with rRNA seem to be less (or not) connected with skin photosensitization.

Photosensitizing action of furocoumarins on membrane components and consequent intracellular events.

The photodamage induced in membrane components by furocoumarins is reviewed. The oxygen-dependent photoreactions between furocoumarins and cell membrane constituents lead mainly to lipid peroxidation and the formation of cross-linking in ghost proteins, whereas the oxygen-independent photoreactions lead essentially to a C4 cycloaddition between the furocoumarin and the unsaturated fatty acids. In the latter, cycloadducts are formed between the 3,4 double bond of the furocoumarin and the olefinic double bond of the unsaturated fatty acid. The stereochemical structures of these cycloadducts and the reaction mechanism of the cycloaddition are discussed. Finally, the modulation of several membrane systems by furocoumarins and the consequent intracellular events are reviewed.

PUVA‐induced apoptosis involves mitochondrial dysfunction caused by the opening of the permeability transition pore

The mechanism of cell death was investigated in Jurkat cells exposed to the combination of psoralen and UVA irradiation (PUVA). Apoptosis was by far prevailing over necrosis and involved mitochondrial dysfunction. The collapse of mitochondrial membrane potential, appears to be caused by the opening of the mitochondrial permeability transition pore since its inhibitor, cyclosporin A, prevented mitochondrial dysfunction and largely attenuated apoptosis. Apoptosis also occurred in cells treated with the photoproducts generated by irradiating psoralen in vitro with an oxygen‐dependent process. Thus, the involvement of reactive oxygen species in the onset of PUVA‐induced apoptosis appears mostly related to psoralen photooxidation.

Excited state properties and in vitro phototoxicity studies of three phenothiazine derivatives

Abstract This work concerns a combined photophysical, photochemical and photobiological study of three drugs (psychotherapeutic agents) of the phenothiazine series: perphenazine, fluphenazine hydrochloride and thioridazine hydrochloride. The excited-state properties were first investigated by stationary and time-resolved fluorimetry and by laser flash photolysis. The spectral description was assisted by quantum-mechanical calculations with the INDO/1-CI method. In organic media the lowest excited singlet state was found to decay by fluorescence (small quantum yield) and mainly by intersystem crossing to the lowest triplet state, which is responsible for oxygen photosensitization (high yields of singlet oxygen production) and photodegradation. A further decay pathway in aqueous solutions was the photoionization process, which led to the formation of the phenothiazine radical cations and the solvated electron. After the preliminary study of the photobehavior in organic solvents and in water, the phototoxicity of the three drugs was investigated on various biological substrates through a series of in vitro assays under UVA irradiation. Photohemolysis of mouse erythrocytes and phototoxicity on cultured murine fibroblasts were observed for all three compounds. Lipid photoperoxidation was then investigated using linoleic acid as the unsaturated lipid model and isolated red blood cell membranes. The drug-induced photodamage was also evaluated on proteins by measuring the photosensitizing cross-linking in erythrocyte ghosts. The combined approach proved to be useful in understanding the mechanism by which these phenothiazine derivatives induce skin photosensitization. In particular, the photophysical properties of the compounds under investigation and the results of the study on their phototoxicity are in agreement with a mechanism that involves the radical cation of the drugs as a main intermediate.

Estimation of the effect of increasing UVB exposure on the human immune system and related resistance to infectious diseases and tumours

Exposure to UV light has, besides some beneficial effects (vitamin D production), many harmful effects on human health. UVB irradiation has been shown to suppress both systemic and local immune responses to a variety of antigens, including some microorganisms. However, it is still not known whether such immunomodulating effects may lead to an increase in the number and severity of certain tumours and/or infections in humans. We report herein the data provided by a project that was funded by the European Union (Programme Environment), and that was aimed at the estimation of the risk associated with increased UVB exposure due to ozone depletion regarding the deleterious effects on the immune system and related resistance to tumours and infections in humans. The data, obtained by the different research groups involved, were assembled and used to calculate for the first time a risk assessment for increased environmental exposure to UVB in human subjects.

New geiparvarin analogues from 7-(2-oxoethoxy)coumarins as efficient in vitro antitumoral agents

A new class of compounds analogues of geiparvarin is described: aldolic condensation of 3(2H)-furanones and 7-(2-oxoethoxy)coumarins followed by a very efficient dehydration protocol led to the title compounds which show good antitumoral activity against several human cell lines.

Studies on the photoreactions (365 nm) between DNA and some methylpsoralens

Abstract While many methyl derivatives of psoralen are very active as skin-photosensitizers, some others have a small activity or are practically inactive. This difference is not explicable in terms of different capacity of photobinding to DNA. Other factors are important, especially the ability to form cross-linkings in DNA. In fact, as a result of a comparison of a group of methylpsoralen derivatives, a good correlation has been found between the skin-photosensitizing potencies of the various compounds, as evaluated by determining the minimum irradiation time necessary for the production of erythema on guinea pig skin, and the amounts of cross-linking formed in DNA as a function of the time of irradiation.