engleski

Enhancement of antiproliferative activity by phototautomerization of anthrylphenols

Antiproliferative investigation has been conducted on 3 human cancer cell lines HCT 116 (colon), MCF-7 (breast), and H 460 (lung), on a series of 4 anthrylphenols in dark, and upon exposure to light (350 nm). 9-(2-Hydroxyphenyl)anthracene (1) moderately inhibits the proliferation, but the irradiation considerably enhances the effect. The other investigated anthracenes 4-6 exhibit antiproliferative activity in dark, which was not enhanced upon irradiation. The enhancement of the antiproliferative effect on irradiation of 1 was rationalized as being due to the formation of quinone methide (QM 2) by excited state proton transfer. QM 2 acts as an electrophilic species capable of reacting with biological molecules. Although QM 2 reacts with nucleotides, adducts could not be isolated. On the contrary, cysteine adduct 8 has been isolated and characterized, whereas adducts with glycine, serine and tripeptide glutathione have been characterized by MS. Non-covalent binding of 1 to DNA and bovine serum albumin was demonstrated by UV-vis, fluorescence and CD spectroscopy. However, straightforward conclusion about the DNA or ptotein alkylating (damaging) ability of 2 could not be drawn. The results obtained by the irradiations of 1 in the presence of DNA, amino acids and peptides, the cell cycle perturbation analysis, and in vitro translation of GFP suggest that the effect is not only due to the damage of DNA but also the impact on the cellular proteins. Considering that up to date all QM agents were assumed to target dominantly DNA, this is an important finding with impact to the further development of anticancer agents based on QMs.

anthracenes ; antiproliferative activity ; excited state proton trasnfer ; quinone methides

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