engleski

Synthesis, Photochemical Reaction Mechanisms of Formation, and Biological Activity of Benzene, Naphthalene and Anthracene Quinone Methides

This Thesis comprises synthesis and investigation of photochemical reactivity of three series of quinone methide (QM) precursors, which are derivatives of benzene, naphthalene and anthracene. The photoreactivity of compounds has been studied in solid state at 14 K for 2- hydroxymethylphenol (1), and in solution at room temperature for Mannich derivatives of p-cresol, naphthalene and anthracene derivatives. Mechanisms of photochemical reactions were studied in solution by preparative irradiations, by UV-vis and fluorescence spectroscopy and by laser flash photolysis (LFP). The photodehydratation of compound 1 in solid state at 14 K gave a mixture of o-QM and benzoxete, which were detected by IR spectroscopy. A mechanistic investigation of photodeamination in Mannich derivatives of p- cresol was conducted, demonstrating that the attack of nucleophiles to bifunctional QM2a generates new QM2b. This observation is of particular importance in the biological systems since it could be applied to DNA cross-linking. Naphthalene derivatives were designed to investigate the optimal substitution pattern on the naphthalene chromophore for the most efficient photodehydratation. Derivative 3 underwent the most efficient photodehydration to QM3, indicating that a 2, 6-substitution is optimal. Photogeneration of QMs from anthracenes is interesting because of potential application in biology, given that the chromophore absorbs at wavelengths >400 nm. Anthracene derivatives were prepared by a multistep synthetic procedure starting from 2-aminoanthraquinone. Formation of reactive intermediates from 4 was probed by LFP wherein QM4 was detected. It was shown that QM4 undergoes protonation to give the cation that subsequently reacts with nucleophiles. Antiproliferative investigation on human cancer cell lines was conducted on several series of compounds with and without exposure to irradiation. 3-Hydroxymethyl-2-anthrol (5) was found as a lead molecule which is not toxic without irradiation (IC50 > 100 mM), whereas irradiation significantly increased the antiproliferative activity (for HCT 116, human colon cancer cell line, IC50 is 1 ± 0.4 mM after 3×15 min of irradiation on 420 nm). The observed enhancement of antiproliferative activity upon irradiation can be correlated to the photochemical generation of reactive QMs.

quinone methides ; Mannich derivatives of phenols ; naphthylphenol ; anthrol ; photosolvolyses ; photodehydration ; photodetermination

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