Difurocoumarins, Psoralen Analogs: Synthesis and DNA Photobinding

A new tetracyclic derivative, difurocoumarin, was synthesized and studied in order to ascertain its possible use as a photochemotherapeutic agent alternative to psoralens. The compound proved able to photobind monofunctionally to DNA on irradiation with UV-A. A photocycloadduct with thymine was isolated and characterized spectroscopically

Effects of UVB light on antiinflammatory corticosteroids in different experimental models

Glucocorticosteroids, natural hormones derived from \uf061-pregnane, are potent therapeutic agents for the treatment of a broad range of inflammatory diseases. Semisynthetic derivatives are widely used systemically mainly for the treatment of rheumatoid diseases and allergic manifestations, and many of them are effective by topical use in dermatoses and other skin diseases. This class of drugs is sensitive to UV radiation. They are a typical example of bichromophoric moiety: all possess an aliphatic ketone in the side chain linked to position 17 of the D ring, which absorbs UVB light. Ring A bears a keto group that is conjugated with either one or two double bonds, depending on the specific drug. In the former case (i.e., hydrocortisone) the chromophore is mainly sensitive to UVB. In the latter (i.e., betamethasone, fluocinolone, triamcinolone, flumethasone) both UVA and UVB effectively induce photolysis. The photodegradation of these drugs was studied in vitro (in the solid state, in organic and aqueous solutions, in commercial formulations) and ex vivo (in the pig skin). Both primary photoprocesses, cyclohexadienone \u2018lumi\u2019 rearrangement (under UV-A) and C-20 ketone homolysis (under UV-B) occur and the main photoproducts formed have been isolated and characterized. Any modification of the structure of corticosteroids, in particular the loss of the side-chain, has profound effect on their anti-inflammatory activity. The drugs are also able to photoreact with biological substrates mainly through radical intermediates and one of them (betamethasone) shows phototoxic effects both ex vivo and in vivo (mice) too. All these results suggest to protect these drugs from light not only during storage but also after in vivo administration to avoid loss of therapeutic activity and potential phototoxic reactions

Drug- photosensitised modifications of proteins

Several topical or systemic drugs may result in some photosensitivity reactions under light exposure. Wavelengths within the UV-A (320-400 nm) range are more likely to cause drug-induced photosensitization, although occasionally UV-B (290-320 nm) can also be responsible for such effects. Proteins are one of the main biological targets of this damage. The mechanisms involved in chemical changes of amino acids and proteins upon irradiation are mediated by radicals (Type I), drug-derived peroxides, singlet oxygen (Type II) and direct binding (Type III), giving rise to drug-protein photoadducts with nucleophilic aminoacids (e.g., serine, tyrosine, lysine), protein photocross-linking (drug-protein or protein-protein), photodegradation or photooxidation of aminoacids (e.g., tryptophan, tyrosine, cysteine/cystine, phenilalanine). The photosensitised modification of proteins and enzymes could lead to loss of their biological functions with damage to some organs and the occurrence of phototoxic side effects as well as to photoallergic reactions when the immune system is involved in the skin. Phenothiazines (fluphenazine, chlorpromazine, promethazine), non selective NSAIDs (tiaprophenic acid) and Coxibs (celecoxib), Diuretics (hydrochlorothiazide), 5-fluorouracil, Corticosteroids (fluocinolone, flumethasone), chlorochresol, are examples of pharmaceutical compounds able to induce protein modifications under UV irradiation. References: H. Alenius, D. W. Roberts, Y.Tokura, A. Lauerma, G. Patlewicz and M. S. Roberts, Skin, drug and chemical reactions Drug Discovery Today: Disease Mechanisms, Vol. 5, No.2, e211-e220 (2008) Miranda M.A. J.V. Castell, D. Hernandez et al., Drug-Photosensitized Protein Modification: Identification of the Reactive Sites and Elucidation Of Reaction Mechanisms with Tiaprofenic Acid/Albumin as Model System Chem.Res. Toxicol., 11, 172-177 (1998) Miranda M.A. J.V. Castell, D. Hernandez et al., Mechanisms of Photosensitizion by Drugs: Involvement of Tyrosines in the Photomodification of Proteins Mediated by Tiaprofenic Acid In Vitro, Toxicol. In Vitro, 11 , 653-659 (1997) Caffieri S., Miolo G., Seraglia S., Dalzoppo D., Toma F.M., van Henegouwen G.M., Photoaddition of fluphenazine to nucleophiles in peptides and proteins. Possible cause of immune system side effects, Chem. Res. Toxicol., 20, 1470-6 (2007

Fluphenazine phototoxicity: a mechanism involving the trifluoromethyl group

Fluphenazine is a neuroleptic drug used for the long-term treatment of mental disorders, in particular in the therapy of various psychoses, including schizophrenia and mania. Occurrence of skin phototoxic and photoallergic reactions is observed when patients expose themselves to sunlight during treatment. In order to identify the mechanism of fluphenazine phototoxicity, the drug was irradiated with UVA in different solvents and in presence of nucleophilic substrates of biological relevance, like serine, lysine and a serine-containing oligopeptide. The photoproducts were characterized by mass spectroscopy and, for three of them, by NMR spectroscopy. A minor product in which N-oxidation occurred was found in all conditions. The major product which formed in water was a carboxylic acid derived from the hydrolytic defluorination of the CF3 group. In methanol and ethanol the main product was the ester of the carboxylic acid. Serine also bound fluphenazine through the same mechanism. Although with low yield, a similar product was identified in a 14-peptide irardiated in presence of the drug. Lysine did not react in the same conditions. These results suggest that photobinding of fluphenazine to serine residues of proteins may occur in vivo, thus initiating the processes leading to photoallergy

Antibacterial sulfonamides: accumulation and effects in barley plants

Abstract: The application of manure to fertilize arable lands is one of the major means through which veterinary sulfonamides (SAs) enter the environment. Little is known about the capacity of woody plants to phytoremediate this class of antibiotics. To this purpose we performed preliminary studies to evaluate Salix Fragilis L. response to sulfadimethoxine (SDM) by investigating both its ability to absorb and tolerate doses of SDM found in fresh faeces of treated calves. Forty cuttings were exposed to either 0, 0.5, 1, or 2 mM of SDM for one month. Decreases in photosynthetic electron transport rate and net CO2 assimilation after 25 days for the higher SDM concentrations were noticed. Moreover, alterations in root morphology of treated plants were observed and further investigated through electron microscopy. However, collected data revealed high root accumulation potential. These preliminary results are promising as they demonstrate that Salix Fragilis L. can both absorb and tolerate high concentrations of SAs