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Antiproliferative activity of photogenerated naphthalene and antracene bis(quinone methides) derivatives

In chemistry and photochemistry of phenols and related compounds, quinone methides (QMs) are commonly encountered as reactive intermediates [1]. The interest in the chemistry of QMs was initiated by their biological activity since it is known that some classes of anticancer antibiotics exhibit their antiproliferative activity due to metabolic formation of QMs that alkylate DNA. [2] With the on-going interest in our group to investigate anticancer activity of simple QMs [3, 4], we have prepared a series bis(naphthol) and bis(anthrol) QM precursors 1- 7 and investigated their photophysical properties and photochemical reactivity in the photodehydration reactions where QMs are generated. Antiproliferative activity of precursors 1 - 7 was investigated in vitro on a series of three human cancer cell lines H1299 (lung), SUM159 (breast) and MCF7 (breast), where the cells were kept in dark, or irradiated at 350 nm where QM precursors absorb light. All compounds exhibit antiproliferative activity in micromolar concentration range that is upon excitation up to ten times enhanced. We tried to link the observed enhancement of antiproliferative activity to the ability of photogenerated QMs to cross-link DNA molecules. However, irradiations of plasmid DNA in the presence of our compounds and analysis by alkaline agarose electrophoresis suggests that DNA is not the biological target. Furthermore, investigation of non-covalent binding of QM precursors to DNA and bovine serum albumin by fluorescence spectroscopy indicates that non- covalent binding of molecules to DNA or protein does not take place. Consequently, we propose that biological activity stems from the action of QMs that are intracellularly localized in lysosomes, or in perinuclear region, possibly in endoplasmatic reticulum or Golgi apparatus where they destroy the membranes or react with the surrounding proteins, as it has been suggested for the patent 2-hydroxy-3- hydroxymethylanthracene [4].

antiproliferative activity ; quinone methides ; photodehydration ; DNA alkylation

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