The Selective Cytotoxicity of New Triazene Compounds to Human Melanoma Cells

Abstract Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t ½  ≥ 48 h), and most of them showed to be slowly hydrolysed in human plasma (1.5 ≤ t ½ (h) ≤ 161). Compounds 3c – n revealed to be excellent tyrosinase substrates (0.74 ≤ t ½ (min) ≤ 6) with the best tyrosinase substrate 3l releasing MMT 45 s after tyrosinase activation. Structure-activity relationship studies allowed the identification of the better structural features for enzyme affinity. Furthermore, the derivatives 3l and 3m showed cell selectivity with significant cytotoxic effects (IC 50 values of 46–65 μM) against melanoma cell lines with tyrosinase overexpression MNT-1 and B16F10.