Substituted phenolic compounds were previously shown to exhibit cytotoxicity towards epithelial cells in the presence of the
enzyme tyrosinase as a result of the formation of their
quinone products. Seventeen of these compounds were tested for cytotoxic properties towards three different
melanoma cell lines. The compounds were split into four groups of
phenol derivatives, A; alkoxyethers, including
4-hydroxyanisole (4HA), B; oxyethers derivatized at the acyl side chain, C; oxyethers derivatized at the
phenol, and D; acyl
thioethers. Toxicity was determined by total cell counts after 3 days exposure to the compounds. Large reductions in cell numbers were observed with 4HA (the methoxy-), ethoxy-, propoxy and iso-butoxyethers of group A and the methyl- and propyl
thioethers of
phenol of group D. Derivatization of the ethoxy- and propoxy side chains (group B) did not seem to increase the cytotoxic effects, as determined by cell counts. Compounds of group C, which need intracellular
esterase activity to release the
phenols, showed moderate toxicities. Toxicity of certain compounds was confirmed by LDH release into the culture medium and by increased
trypan blue uptake of cells exposed to the compounds. Flow cytometric investigations of cells after exposure for 24 h revealed that most compounds caused an increase in the proportion of cells in G1 phase. A complete accumulation of cells in S-phase was observed after exposure to 4-ethoxyphenol. Inhibition of
DNA synthesis was also shown by inhibition of
bromodeoxyuridine incorporation. The results presented show that phenolic compounds exhibit cytotoxic properties towards
melanoma cells some of which may be mediated by
tyrosinase activity. Toxicity of the compounds was shown to be exerted during DNA replication but their
toxic action may also be due to membrane damage and inhibition of cell metabolism.