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Computational studies of photodynamic drugs, phototoxic reactions and drug design
Örebro University, School of Science and Technology. (Leif Eriksson research group)
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. , 99 p.
Series
Örebro Studies in Life Science, 4
Keyword [en]
NSAIDs, fluoroquinolone, photodegradation, phototoxicity, drug design, DFT, TD-DFT
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-8356ISBN: 978-91-7668-694-2 (print)OAI: oai:DiVA.org:oru-8356DiVA: diva2:273975
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
List of papers
1. Mechanism of Photoinduced Decomposition of Ketoprofen
Open this publication in new window or tab >>Mechanism of Photoinduced Decomposition of Ketoprofen
2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 8, 1735-1743 p.Article in journal (Refereed) Published
Abstract [en]

UV-induced decarboxylation of the NSAID ketoprofen, followed by activation of molecular oxygen or formation of a decarboxylated peroxide adduct, is explored using computational quantum chemistry. The excited energy surfaces reveal that the neutral species will not decarboxylate, whereas the deprotonated acid decarboxylates spontaneously in the triplet state, and with an associated 3-5 kcal/mol barrier from several low-lying excited singlet states. The observed long lifetimes of the decarboxylated anion is explained in terms of the high stability of the triplet benzoyl ethyl species with protonated carbonylic oxygen, from which there is no obvious decay channel. Mechanisms for the generation of singlet oxygen and superoxide are discussed in detail. Addition of molecular oxygen to give the corresponding peroxyl radical capable of initiating propagating lipid peroxidation reactions is also explored. The computed data explains all features of the observed experimental observations made to date on the photodegradation of ketoprofen.

Place, publisher, year, edition, pages
Washington, DC: American Chemical Society, 2007
National Category
Theoretical Chemistry Natural Sciences Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-4100 (URN)10.1021/jm060697k (DOI)
Available from: 2007-11-01 Created: 2007-11-01 Last updated: 2017-10-18Bibliographically approved
2. Theoretical Study of Ibuprofen Phototoxicity
Open this publication in new window or tab >>Theoretical Study of Ibuprofen Phototoxicity
2007 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 46, 13345-13352 p.Article 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
Keyword
ibuprofen, phototoxicity, degradation, decarboxylation, reactive oxygen species, TD-DFT
National Category
Theoretical Chemistry Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-4113 (URN)10.1021/jp076553e (DOI)17958415 (PubMedID)
Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2017-10-18Bibliographically approved
3. Photochemical and photophysical properties, and photodegradation mechanism, of the non-steroid anti-inflammatory drug Flurbiprofen
Open this publication in new window or tab >>Photochemical and photophysical properties, and photodegradation mechanism, of the non-steroid anti-inflammatory drug Flurbiprofen
2009 (English)In: Journal of Photochemistry and Photobiology A: Chemistry, ISSN 1010-6030, E-ISSN 1873-2666, Vol. 202, no 1, 48-56 p.Article in journal (Refereed) Published
Abstract [en]

The photodegradation mechanism of the widely used non-steroidal anti-inflammatory drug 2-(4-phenyl-3-fluorophenyl) propanoic acid, Flurbiprofen, and its photochemical and photophysical properties have been investigated by means of computational quantum chemistry at the DFT-B3LYP/6-31G(d,p) level. Comparison of computed and experimental singlet and triplet–triplet absorption spectra point to that most experiments, using a range of different solvents, are conducted on the neutral, protonated form of Flurbiprofen. The deprotonated acid, which should dominate at physiological pH, shows no sign of decarboxylation from the lowest singlet excited states, whereas from its first excited triplet state this should readily occur by passing over an energy barrier of <0.5 kcal/mol. Further reactions in the proposed photodegradation mechanism, after decarboxylation, as well as the probability for reactive oxygen species formation are discussed in detail. The generation of the corresponding peroxyl radical from the decarboxylated radical and molecular oxygen is strictly exergonic and occurs without barrier under aerobic conditions. The thus formed peroxyl radical will in turn be capable of initiating propagating lipid peroxidation processes.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2009
National Category
Natural Sciences Chemical Sciences Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:oru:diva-6319 (URN)10.1016/j.jphotochem.2008.11.010 (DOI)000263500000007 ()2-s2.0-58249098792 (Scopus ID)
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2017-10-18Bibliographically approved
4. Theoretical Study of the Phototoxicity of Naproxen and the Active Form of Nabumetone
Open this publication in new window or tab >>Theoretical Study of the Phototoxicity of Naproxen and the Active Form of Nabumetone
2008 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 43, 10921-10930 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Washington, DC: American Chemical Society, 2008
National Category
Natural Sciences Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-6318 (URN)10.1021/jp805614y (DOI)
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2017-10-18Bibliographically approved
5. Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct
Open this publication in new window or tab >>Photodegradation mechanism of the common non-steroid anti-inflammatory drug diclofenac and its carbazole photoproduct
2009 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, no 22, 4601-4610 p.Article in journal (Refereed) Published
Abstract [en]

Diclofenac (DF) is a widely used non-steroid anti-inflammatory drug, associated with a range of side effects. The phototoxicity of DF is studied herein employing computational quantum chemistry at the B3LYP/6-31G(d,p) level of theory. The results show that the drug readily absorbs radiation from the UV-region. The deprotonated form spontaneously dechlorinates from its triplet state leading to ring closure and formation of an active photoproduct: chlorocarbazole acetic acid, CCA. The formed CCA is also photodegraded easily from its deprotonated triplet state. Photodegradation routes of deprotonated CCA are decarboxylation (barrier less than 4.5 kcal mol(-1)) and dechlorination (barrier around 6.2 kcal mol(-1)). The energy barrier required for dechlorination to take place from the neutral from is about 20 kcal mol(-1). The differences between the molecular orbitals of the neutral and the deprotonated forms of DF and CCA and spectra obtained using time-dependent density-functional theory (TD-DFT), in addition to the different radical and oxygenated intermediate species formed during the photodegradation mechanism, are discussed in more detail. The theoretical results obtained herein are in line with the experimental results available to date.

National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-13296 (URN)10.1039/b900144a (DOI)000266587300022 ()
Available from: 2011-01-14 Created: 2011-01-11 Last updated: 2017-12-11Bibliographically approved
6. Photodegradation Mechanism of Nonsteroidal Anti-Inflammatory Drugs Containing Thiophene Moieties: Suprofen and Tiaprofenic Acid
Open this publication in new window or tab >>Photodegradation Mechanism of Nonsteroidal Anti-Inflammatory Drugs Containing Thiophene Moieties: Suprofen and Tiaprofenic Acid
2009 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 32, 11306-11313 p.Article in journal (Refereed) Published
Abstract [en]

The photodegradation of nonsteroid anti-inflammatory drugs suprofen, 2-[4-(2-thienoyl)phenyl]propionic acid, and tiaprofenic acid, 2-(5-benzoyl-2-thienyl)propanoic acid, is studied by means of density functional theory. Besides the redox properties of the neutral species, we report on absorption spectra and degradation pathways involving excitation, intersystem crossing to the T-1 state. and spontaneous decarboxylation of the deprotonated species of each drug. The energetics and properties of the suprofen and tiaprofenic acid systems are found to be very similar to those of the highly photolabile benzyl analogue ketoprofen. Mechanisms leading to the formation of a closed-shell decarboxylated ethyl species, as well as peroxyl radicals capable of initiating lipid peroxidation reactions, are discussed.

National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-13254 (URN)10.1021/jp904171p (DOI)000268661100033 ()
Available from: 2011-01-17 Created: 2011-01-11 Last updated: 2017-12-11Bibliographically approved
7. Theoretical assessment of naphazoline redoxchemistry and photochemistry
Open this publication in new window or tab >>Theoretical assessment of naphazoline redoxchemistry and photochemistry
2007 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 15, 3977-3981 p.Article in journal (Refereed) Published
Abstract [en]

The imidazoline derivative naphazoline (2-(1-naphtylmethyl)-2-imidazoline) is an α2-adrenergic agonist used as non-prescription eye and nasal preparations. Besides its functionality in generating vascoconstriction and decongestion in the patient, the toxicity, ROS generating capability, and recently also possible antioxidant capacity of the compound have been reported in the literature. In the current work the structural and electronic features of the drug are explored, using computational chemical tools. Electron affinities, ionization potentials, and excitation energies are reported, as well as charge and spin distributions of various forms of the drug. The difference in photochemical behavior between the protonated and unprotonated (basic) species is explained by the molecular orbital distributions, allowing for efficient excitation quenching in the basic structure but clear naphthalene to imidazolene charge transfer upon HOMO→ LUMO excitation in the protonated form, enabling larger intersystem crossing capability to the imidazole localized excited triplet and a resulting higher singlet oxygen quantum yield.

Place, publisher, year, edition, pages
Washington, DC: American Chemical Society, 2007
Keyword
Molecular Structure, Naphazoline, Oxidation-Reduction, Photochemistry, Density functional theory
National Category
Theoretical Chemistry Natural Sciences Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-4105 (URN)10.1021/jp070207f (DOI)17388561 (PubMedID)
Available from: 2007-11-02 Created: 2007-11-02 Last updated: 2017-10-18Bibliographically approved
8. Theoretical assessment of norfloxacin redox and photochemistry
Open this publication in new window or tab >>Theoretical assessment of norfloxacin redox and photochemistry
2009 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 113, no 40, 10803-10810 p.Article in journal (Refereed) Published
Abstract [en]

Norfloxacin, 1-ethyl-6-fluoro-1,4-dihydo-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxyli c acid, NOR, is an antibiotic drug from the fluoroquinoline family. The different protonation states of this drug formed throughout the pH range is studied by means of density functional theory (DFT) and the spectra of the NOR species computed using time-dependent DFT. Details about their photochemistry are obtained from investigating the highest occupied and lowest unoccupied molecular orbitals. The predominant species under physiological pH, the zwitterion, is the most photoliable one, capable of producing singlet oxygen or/and superoxide radical anions from its triplet state. In addition, the main photodegradation step, defluorination, occurs more easily from this species compared with the other forms. The defluorination from the excited triplet state requires passing a barrier of 16.3 kcal/mol in the case of the zwitterion. The neutral and cationic forms display higher transition barriers, whereas the reaction path of defluorination is completely endothermic for the anionic species. The theoretical results obtained herein are in line with previous experimental data.

National Category
Chemical Sciences
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-13209 (URN)10.1021/jp904671s (DOI)000270362900026 ()
Available from: 2011-01-17 Created: 2011-01-11 Last updated: 2017-12-11Bibliographically approved
9. Photophysical and photochemical properties and photodehalogenation of antibiotic drug lomefloxacin
Open this publication in new window or tab >>Photophysical and photochemical properties and photodehalogenation of antibiotic drug lomefloxacin
(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-15445 (URN)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-10-17Bibliographically approved
10. New non-steroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity
Open this publication in new window or tab >>New non-steroidal anti-inflammatory molecules with reduced photodegradation side effects and enhanced COX-2 selectivity
(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:oru:diva-15446 (URN)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-10-17Bibliographically approved

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