Synthesis and cytotoxic properties of new N-substituted 4-aminophenol derivatives with a potential as antimelanoma agents

New tyrosinase-targeted compds. based on structural variants of the prototype unit 4-aminophenol have been synthesized and screened for their potential as antitumor agents against malignant melanoma. Cytotoxicity assays showed that N-4-hydroxyphenylglycine (NHPG) and its α-Me derivs. methylphenylglycine and dimethylphenylglycine exhibit significant antiproliferative effects on pigmented human melanoma cell lines (HBL), with inhibitory concns. at 50% (IC50) around 80 μg/mL. A marked increase in cytotoxicity was obsd. with morpholine-contg. 4-aminophenols, e.g. N-(2-morpholinoethyl)-4-aminophenol, which showed an IC50 of 20 μg/mL of HBL cells. Much more pronounced was the effect of the diacetoxy-deriv., DiAcMoAC, which showed an IC50 of 15 μg/mL on HBL cells and as low as 2 μg/mL on tyrosinase contg., non-pigmented human melanoma cells (LND1), with a toxicity response of the same order of magnitude as that of melphalan. These results open interesting perspectives in the design of new targeted pro-drugs against malignant melanoma.