Generation of reactive aryl radical intermediates in the reductive photodehalogenation of itraconazole

Abstract

The photochemical properties of itraconazole (1), a broad-spectrum antifungal agent, have been investigated in connection with reported skin photosensitivity disorders. Steady state photolysis, fluorescence and phosphorescence experiments have been performed to understand photoreactivity of 1 in biological media. The drug is unstable under UVB irradiation, suffering a primary dehalogenation of the 2,4-dichlorophenyl moiety that occurs mainly at the ortho-position. In poorly H-donating solvents, such as acetonitrile, the major photoproduct arises from intramolecular attack of the initially generated aryl radical towards the triazole ring. In addition, reduced compounds resulting from homolytic cleavage of the C-Cl bond in ortho or para positions and subsequent H-abstraction from the medium are obtained to a lesser extent. In good H-donating solvents, such as ethanol, the main photoproducts are formed by reductive dehalogenation. Furthermore, irradiation of a model dyad containing a tryptophan unit and the reactive 2,4-dichlorophenyl moiety of itraconazole leads to formation of a new covalent link between these two substructures revealing that homolysis of the C-Cl bond of 1 can result in alkylation of reactive amino acid residues of proteins, leading to formation of covalent photoadducts. Therefore, it has been established that the key process in the photosensitization by itraconazole is cleavage of the carbon-halogen bond, which leads to aryl radicals and chlorine atoms. These highly reactive species might be responsible for extensive free radical-mediated biological damage, including lipid peroxidation or photobinding to proteins.

Determination of itraconazole and its photodegradation products with kinetic evaluation by ultra‐performance liquid chromatography/tandem mass spectrometry

“…The structure of IP‐7 was assigned on the basis of the molecular ion obtained at m / z 669.3, which corresponds to the loss of HCl from the parent drug and was also described by Nardi et al . (). It is also worth noting that, contrary to the findings of Nardi et al ., we have detected new products (IP‐1 to IP‐3) which are a result of breakdown of the C–N bond.…”

“…Another two derivatives of ITZ without one chloride atom in the phenyl ring, one in the ortho (IP-6) and the second in the para position (IP-5), were previously described (Dettlaff et al, 2015). Dettlaff et al studied the ionizing radiation effects, in the form of an electron beam, on ITZ in the solid phase, and Nardi et al (2014) showed that ITZ is unstable under UV-B irradiation suffering from a primary dehalogenation of the 2,4-dichlorophenyl moiety. The structure of IP-7 was assigned on the basis of the molecular ion obtained at m/z 669.3, which corresponds to the loss of HCl from the parent drug and was also described by Nardi et al (2014).…”

“…() investigated the photochemical properties of ITZ in connection with skin photosensitivity. The drug turned out to be unstable under UV‐B irradiation, suffering a primary dehalogenation of the 2,4‐dichlorophenyl moiety that occurs mainly at the ortho‐ position (Nardi et al ., ). Parikh et al .…”

“…ITZ is considered as a photostable drug but it might cause photosensitivity as skin responses upon exposure to sunlight (Ramos-e-Silva et al, 1998). Nardi et al (2014) investigated the photochemical properties of ITZ in connection with skin photosensitivity. The drug turned out to be unstable under UV-B irradiation, suffering a primary dehalogenation of the 2,4-dichlorophenyl moiety that occurs mainly at the ortho-position (Nardi et al, 2014).…”

“…Nardi et al (2014) investigated the photochemical properties of ITZ in connection with skin photosensitivity. The drug turned out to be unstable under UV-B irradiation, suffering a primary dehalogenation of the 2,4-dichlorophenyl moiety that occurs mainly at the ortho-position (Nardi et al, 2014). Parikh et al (2011) performed forced degradation studies of ITZ in a capsule dosage form using highperformance thin-layer chromatographic method.…”