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

Photooxygenation mechanisms in naproxen-amino acid linked systems

The photooxygenation of model compounds containing the two enantiomers of naproxen (NPX) covalently linked to histidine (His), tryptophan (Trp) and tyrosine (Tyr) has been investigated by steady state irradiation, fluorescence spectroscopy and laser flash photolysis. The NPX–His systems presented the highest oxygen-mediated photoreactivity. Their fluorescence spectra matched that of isolated NPX and showed a clear quenching by oxygen, leading to a diminished production of the NPX triplet excited state ( 3 NPX*–His). Analysis of the NPX–His and NPX–Trp photolysates by UPLC-MS–MS revealed in both cases the formation of two photoproducts, arising from the reaction of singlet oxygen (1 O2) with the amino acid moiety. The most remarkable feature of NPX–Trp systems was a fast and stereoselective intramolecular fluorescence quenching, which prevented the efficient formation of 3 NPX*–Trp, thus explaining their lower reactivity towards photooxygenation. Finally, the NPX–Tyr systems were nearly unreactive and exhibited photophysical properties essentially coincident with those of the parent NPX. Overall, these results point to a type II photooxygenation mechanism, triggered by generation of 1 O2 from the 3 NPX* chromophoreFinancial support from the Spanish Government (CTQ2010-14882, JCI-2011-09926, Miguel Servet CP11/00154), from the EU (PCIG12-GA-2012-334257), from the Universitat Politecnica de Valencia (SP20120757) and from the Conselleria de Educacio, cultura i Esport (PROMETEOII/2013/005, GV/2013/051) is gratefully acknowledged.Vayá Pérez, I.; Andreu Ros, MI.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Photooxygenation mechanisms in naproxen-amino acid linked systems. Photochemical & Photobiological Sciences Photochemical and Photobiological Sciences. 13:224-230. https://doi.org/10.1039/c3pp50252jS22423013L. I. Grossweiner and K. C.Smith, Photochemistry, in The Science of Photobiology, ed. K. C. Smith, Plenum Press, New York, 2nd edn, 1989, pp. 47–78L. Pretali and A.Albini, in CRC Handbook of Organic Photochemistry and Photobiology, ed. A. Griesbeck, M. Oelgemöller and F. Ghetti, CRC Press, Boca Raton, FL, 3rd edn, 2012, pp. 369–391Foote, C. S. (1991). DEFINITION OF TYPE I and TYPE II PHOTOSENSITIZED OXIDATION. Photochemistry and Photobiology, 54(5), 659-659. doi:10.1111/j.1751-1097.1991.tb02071.xDavies, M. J. (2003). Singlet oxygen-mediated damage to proteins and its consequences. Biochemical and Biophysical Research Communications, 305(3), 761-770. doi:10.1016/s0006-291x(03)00817-9Davies, M. J. (2004). Reactive species formed on proteins exposed to singlet oxygen. Photochemical & Photobiological Sciences, 3(1), 17. doi:10.1039/b307576cGirotti, A. W. (2001). Photosensitized oxidation of membrane lipids: reaction pathways, cytotoxic effects, and cytoprotective mechanisms. Journal of Photochemistry and Photobiology B: Biology, 63(1-3), 103-113. doi:10.1016/s1011-1344(01)00207-xAndreu, I., Morera, I. M., Boscá, F., Sanchez, L., Camps, P., & Miranda, M. A. (2008). Cholesterol–diaryl ketone stereoisomeric dyads as models for «clean» type I and type II photooxygenation mechanisms. Organic & Biomolecular Chemistry, 6(5), 860. doi:10.1039/b718068cStadtman, E. R. (1993). Oxidation of Free Amino Acids and Amino Acid Residues in Proteins by Radiolysis and by Metal-Catalyzed Reactions. Annual Review of Biochemistry, 62(1), 797-821. doi:10.1146/annurev.bi.62.070193.004053Garrison, W. M. (1987). Reaction mechanisms in the radiolysis of peptides, polypeptides, and proteins. Chemical Reviews, 87(2), 381-398. doi:10.1021/cr00078a006P. U. Giacomoni , Sun Protection in Man, Comprehensive Series in Photosciences, Elsevier, Amsterdam, 2001, vol. 3R. C. Straight and J. D.Spikes, Photosensitized oxidation of biomolecules. in Polymers and Biopolymers, ed. A. A. Frimer and O. Singlet, CRC Press, Boca Raton, FL, 1985, pp. 91–143Wright, A., Bubb, W. A., Hawkins, C. L., & Davies, M. J. (2002). Singlet Oxygen–mediated Protein Oxidation: Evidence for the Formation of Reactive Side Chain Peroxides on Tyrosine Residues¶. Photochemistry and Photobiology, 76(1), 35. doi:10.1562/0031-8655(2002)0762.0.co;2Agon, V. V., Bubb, W. A., Wright, A., Hawkins, C. L., & Davies, M. J. (2006). Sensitizer-mediated photooxidation of histidine residues: Evidence for the formation of reactive side-chain peroxides. Free Radical Biology and Medicine, 40(4), 698-710. doi:10.1016/j.freeradbiomed.2005.09.039Huyett, J. E., Doan, P. E., Gurbiel, R., Houseman, A. L. P., Sivaraja, M., Goodin, D. B., & Hoffman, B. M. (1995). Compound ES of Cytochrome c Peroxidase Contains a Trp .pi.-Cation Radical: Characterization by Continuous Wave and Pulsed Q-Band External Nuclear Double Resonance Spectroscopy. 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Drug-Photosensitized Protein Modification:  Identification of the Reactive Sites and Elucidation of the Reaction Mechanisms with Tiaprofenic Acid/Albumin as Model System†. Chemical Research in Toxicology, 11(3), 172-177. doi:10.1021/tx970082dJiménez, M. C., Pischel, U., & Miranda, M. A. (2007). Photoinduced processes in naproxen-based chiral dyads. Journal of Photochemistry and Photobiology C: Photochemistry Reviews, 8(3), 128-142. doi:10.1016/j.jphotochemrev.2007.10.001Catalfo, A., Bracchitta, G., & De Guidi, G. (2009). Role of aromatic amino acid tryptophan UVA-photoproducts in the determination of drug photosensitization mechanism: a comparison between methylene blue and naproxen. Photochemical & Photobiological Sciences, 8(10), 1467. doi:10.1039/b9pp00028cVayá, I., Pérez-Ruiz, R., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2010). Drug–protein interactions assessed by fluorescence measurements in the real complexes and in model dyads. 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Photosensitive drugs: a review on their photoprotection by liposomes and cyclodextrins.

Nowadays, an exciting challenge in the drug chemistry and technology research is represented by the development of methods aimed to protect molecular integrity and therapeutic activity of drugs from effects of light. The photostability characterization is ruled by ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which releases details throughout basic protocols of stability tests to be performed on new medicinal products for human use. The definition of suitable photoprotective systems is fundamental for pharmaceutical manufacturing and for human healthy as well, since light exposure may affect either drugs or drug formulations giving rise even to allergenic or mutagenic by-products. Here, we summarize and discuss the recent studies on the formulation of photosensitive drugs into supramolecular systems, capable of entrapping the molecules in a hollow of their structure by weak noncovalent interactions and protecting them from light. The best known supramolecular matrices belong to the 'auto-assembled' structures, of which liposomes are the most representative, and the 'host-guest' systems, of which cyclodextrins represent the most common 'host' counterpart. A relevant number of papers concerning the use of both liposomes and cyclodextrins as photoprotection systems for drugs has been published over the last 20 years, demonstrating that this topic captures interest in an increasing number of researchers