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Theoretical Study of Ibuprofen Phototoxicity
Örebro University, Department of Natural Sciences. (Biophysical Chemistry)
Örebro University, Department of Natural Sciences. (Biophysical Chemistry)
2007 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 46, p. 13345-13352Article in journal (Refereed) Published
Abstract [en]

The photochemical properties and degradation of the common nonsteroid anti-inflammatory drug ibuprofen is studied by means of hybrid density functional theory. Computed energies and properties of various species show that the deprotonated form dominates at physiological pH, and that the species will not be able to decarboxylate from a singlet excited state. Instead, decarboxylation will occur, with very high efficiency, provided the deprotonated compound can undergo intersystem crossing from an excited singlet to its excited triplet state. In the triplet state, the C−C bond connecting the carboxyl group is elongated, and the CO2 moiety detaches with a free energy barrier of less than 0.5 kcal/mol. Depending on the local environment, the decarboxylated product can then either be quenched through intersystem crossing (involving the possible formation of singlet oxygen) and protonation, or serve as an efficient source for superoxide anions and the formation of a peroxyl radical that will initiate lipid peroxidation.

Place, publisher, year, edition, pages
Washington, DC: American Chemical Society , 2007. Vol. 111, no 46, p. 13345-13352
Keyword [en]
ibuprofen, phototoxicity, degradation, decarboxylation, reactive oxygen species, TD-DFT
National Category
Theoretical Chemistry Chemical Sciences
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-4113DOI: 10.1021/jp076553ePubMedID: 17958415OAI: oai:DiVA.org:oru-4113DiVA, id: diva2:138412
Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Computational studies of photodynamic drugs, phototoxic reactions and drug design
Open this publication in new window or tab >>Computational studies of photodynamic drugs, phototoxic reactions and drug design
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The most important criterion when designing new drugs or improving old ones in order to prevent side effects or at least diminish them is drug safety. Treatment of all diseases generally needs use of either topical application or systemic medications (transported in the blood) during a certain period of time. These treatments are associated with a number of adverse effects. Photosensitivity is one of those side effects, with phototoxicity as one of the photosensitivity disorders. This adverse side effect arises because of a reaction between UV or visible-light and the drug molecule, its active form or photoproduct(s). Due to phototoxic side effect, unexpected symptoms varying from just a simple rash to severe cutaneous affectations can appear. Furthermore, biomolecular damage occurs once the drug-light interaction takes place persistently and ends with cell death.

Several drug families, such as over-the-counter drugs in the non-steroidal anti-inflammatory drug family of 2-arylpropionic acid derivatives, or prescription required fluoroquinolone drugs, have the capability to absorb mainly UV light radiation which in turn causes different phototoxic reactions by forming radical derivatives, reactive oxygen species or both. These may effect DNA, protein and lipid cell components leading to photogenotoxicity, photoallergy and lipid peroxidation, respectively. The photodegradation mechanisms of drugs belonging to the above mentioned families including ketoprofen, ibuprofen, flurbiprofen, naproxen, the active form of nabumetone, diclofenac and its main photoproduct, suprofen, tiaprofenic acid, naphazoline, norfloxacin and lomefloxacin are investigated in more detail in this thesis.

The results obtained by computational density functional theory (DFT) and time-dependent-DFT (TD-DFT) are in line with experimental data available to date. The studies provide detailed insight into the molecular basis and understanding of the full photodegradation mechanisms of drugs mentioned above. This also plays an important role in preventing or at least reducing the phototoxic adverse effects by enabling the development of safe drugs in this area. Hence, new modified non-steroid anti-inflammatory molecules were designed by computational techniques. Obtained results suggest possibility of their future usage as pharmaceuticals with reduced photodegradation and cyclooxygenase 1 induced adverse side effects compared to the parent compounds.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2009. p. 99
Series
Örebro Studies in Life Science ; 4
Keyword
NSAIDs, fluoroquinolone, photodegradation, phototoxicity, drug design, DFT, TD-DFT
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-8356 (URN)978-91-7668-694-2 (ISBN)
Public defence
2009-11-26, Hörsal M, Örebro universitet, Örebro, 13:15 (English)
Opponent
Supervisors
Available from: 2009-10-26 Created: 2009-10-26 Last updated: 2017-10-18Bibliographically approved

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Musa, Klefah A. K.Eriksson, Leif A.

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