Tyrosinase is an enzyme widely distributed in nature, catalyzing two initial reactions in the melanogenesis pathway: hydroxylation of monophenols to o-diphenols and oxidation of o-diphenols to o-quinones. In mammals it is present only in melanocytes and its principal substrates are L-tyrosine and L-dopa. Transformation of melanocytes leads to malignant melanoma, one of the most aggressive tumors with steadily increasing incidence. Despite over 30 years of development of chemotherapy, there is currently no efficient drug against this tumor in advanced stages and new therapeutic agents are urgently needed.

We have recently demonstrated that amino acid phenylhydrazides can be oxidized by o-quinones and therefore indirectly by tyrosinase¹. Since oxidation of the hydrazide group to diazene leads to its cleavage, we concluded that a hydrazine linker may be used for construction of antimelanoma prodrugs activated preferentially by tyrosinase in melanocytes. Such prodrugs might have reduced non-specific toxicity and improved efficacy. We have therefore performed reactions of tyrosinase with an anticancer drug containing a hydrazine group – procarbazine, used primarily against lymphoid malignancies, particularly Hodgkin’s lymphomas and certain brain tumors. We have shown that in the presence of the enzyme’s natural substrates this compound is oxidized indirectly to azoprocarbazine – the primary therapeutically-active derivative. We have designed several classes of hydrazine linker-containing prodrugs. Reactions of the first of these compounds with tyrosinase demonstrated oxidation of both the aromatic ring and the hydrazine linker. Their in vivo activation is therefore likely and will be tested in the near future.

1. B. Gąsowska, B. Frąckowiak, H. Wojtasek (2006) Indirect oxidation of amino acid phenylhydrazides by mushroom tyrosinase. Biochim. Biophys. Acta, 1760, 1373-1379.

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