Synthesis and Photochemical Properties of Fluorescent Metabolites Generated from Fluorinated Benzoylmenadiones in Living Cells

Abstract

This work describes the reactivity and properties of fluorinated derivatives (F-PD and F-PDO) of plasmodione (PD) and its metabolite, the plasmodione oxide (PDO). Introduction of a fluorine atom on the 2-methyl group markedly alters the redox properties of the 1,4-naphthoquinone electrophore, making the compound highly oxidizing and particularly photoreactive. A fruitful set of analytical methods (electrochemistry, absorption and emission spectrophotometry, and HRMS-ESI) have been used to highlight the products resulting from UV photoirradiation in the absence or presence of selected nucleophiles. With F-PDO and in the absence of nucleophile, photoreduction generates a highly reactive ortho-quinone methide (o-QM) capable of leading to the formation of a homodimer. In the presence of thiol nucleophiles such as β-mercaptoethanol, which was used as a model, o-QMs are continuously regenerated in sequential photoredox reactions generating mono- or disulfanylation products as well as various unreported sulfanyl products. Besides, these photoreduced adducts derived from F-PDO are characterized by a bright yellowish emission due to an excited-state intramolecular proton transfer (ESIPT) process between the dihydronapthoquinone and benzoyl units. In order to evidence the possibility of an intramolecular coupling of the o-QM intermediate, a synthetic route to the corresponding anthrones is described. Tautomerization of the targeted anthrones occurs and affords highly fluorescent stable hydroxyl-anthraquinones. Although probable to explain the intense visible fluorescence emission also observed in tobacco BY-2 cells used as a cellular model, these coupling products have never been observed during the photochemical reactions performed in this study. Our data suggest that the observed ESIPT-induced fluorescence most likely corresponds to the generation of alkylated products through reduction species, as demonstrated with the β-mercaptoethanol model. In conclusion, F-PDO thus acts as a novel (pro)-fluorescent probe for monitoring redox processes and protein alkylation in living cells.

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3-Benzylmenadione Revealed by High-Content Imaging

“…Based on our previous works, compound 23a was synthesized via a top-down approach based on a modified Friedel–Crafts acylation reaction and a Buchwald–Hartwig coupling. , The protecting group was removed in acidic media, and the reductive amination of salts 23b with aldehydes in the presence of NaBH(OAc) 3 allowed the corresponding 1,4-dimethoxynaphthalene derivatives 24a , b to be obtained in excellent yields. Final demethylation of 24a , b afforded the desired 3-benzoyl derivatives 25a , b .…”

Synthesis and evaluation of photophysical, electrochemical, and ROS generation properties of new chalcogen-naphthoquinones-1,2,3-triazole hybrids

“…2a ). Furthermore, in a study conducted by Trometer et al 14 the authors concentrated on adding fluorine into the 2-methyl group of 1,4-naphthoquinone, which resulted in considerable alterations in the compound's redox characteristics, making it highly oxidizing and photoreactive. Thus, the compound 3 exhibit emission properties in the visible region, making it effective as a fluorescent probe to monitor protein alkylation processes and oxidation state in living cells, such as BY-2 tobacco cells, which demonstrated high fluorescence emission ( Fig.…”