engleski

Antiproliferative activity of photochemically generated quinone methides

Quinone methides (QM) are reactive intermediates in chemistry and photochemistry of phenols. The scientific interest in the chemistry of QMs was initiated by their biological activity, since it is known that some antitumor antibiotics such as mitomycin base their action on metabolic formation of QMs that cross-link DNA molecules [1]. Further investigation of biological activity of QMs was hampered due to the fact that these species are too reactive so to be stored, they have to be generated in situ. However, photochemical reactions of suitably substituted phenols represent mild methods for the QM generation in biological systems [2]. Several classes of phenols 1 [3], hydoxybiphenyls 2 [4], naphthols 3 [5] and anthrol derivatives 4 [6], were synthesized and their photochemical reactivity investigated. Antiproliferative activity of the photogenerated QMs was evaluated on human cancer cell lines, with and without exposure of cells to UV-vis irradiation. The investigation indicated lead molecules that exhibited enhanced activity on exposure to irradiation. The mechanism of the antiproliferative action was studied in more detail for selected anthrol molecules by investigating non-covalent binding to DNA and proteins, aptitude to alkylate DNA upon photoexcitation, influence on the production of reactive oxygen species (ROS) and cell cycle, as well as localization in cells by confocal microscope. The experiments indicated that compounds enter cell and localize in the perinuclear region. Upon photoexcitation, QMs or ROS are formed that do not react with DNA, but react with the cellular membranes and proteins, contrary to previous understanding of the QM antiproliferative activity.

quinone methides ; photochemistry ; antoproliferative activity

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