Photobinding of Flutamide to Phospholipid Vesicles: Additional Evidence for Photoprocesses Unexpectedly Triggered by Conformational Changes in the Bilayer

Abstract

It is demonstrated that irradiation of the anticancer drug flutamide (FM) in the presence of unilamellar phospholipid bilayer vesicles, chosen as a model for cell membranes, leads to an efficient photobinding process. This pathway is triggered by an unexpected hydrogen-abstraction reaction of the excited drug by the lipid chain and provides additional evidence that the overall photochemical scenario observed in the vesicles is unusually triggered by conformational change of the drug×s molecular structure upon incarceration in the −close-packed× bilayer. The present investigation, beyond contributing to the general picture concerning fundamental aspects of the light-induced processes in self-organized assemblies, may also provide important insights for a more satisfactory understanding of the recently reported adverse photoallergic and phototoxic phenomena displayed by this anticancer drug.

Comparison of photoreactions of flutamide in acetonitrile and 2-propanol solvents in the absence of cage-forming compounds

“…Flutamide has been reported to undergo nitro-nitrite rearrangement [21][22][23][24][25]. It is used as an endocrine-system therapy for advanced prostate cancer, and it is converted into the more pharmacologically active metabolite 2-hydroxyflutamide by first pass metabolism in the human liver.…”

“…Therefore, studying the photochemistry of flutamide is expected to be useful for elucidating the mechanism involved in the pathogenesis of photodermatosis. From a photochemical and photophysical viewpoint, it has been shown in some studies that flutamide photodecomposes at the nitro group when exposed to UV irradiation under various experimental conditions [21][22][23][24][25]. Sortino et al conducted irradiation experiments in inhomogeneous aqueous solutions using cage-forming products such as b-cyclodextrin.…”

“…In their studies, irradiation experiments were conducted in aqueous solutions, such as a phosphate buffer, meaning that cage-forming compounds were required to increase the solubility of flutamide in the water. Both Sortino et al and Udagawa et al suggested that photoreduction reactions will occur only in inhomogeneous solutions, that is, photoreduction is a bimolecular reaction between flutamide and the cage-forming compound via a hydrogen abstraction reaction [23][24][25]. Moreover, Udagawa et al found that the photoreduction process occurred in the excited triplet state of flutamide and suggested that only a nitro-nitrite rearrangement product was found when flutamide was irradiated in a phosphate buffer in the absence of a cageforming compound.…”