Microbial Transformations of Natural Antitumor Agents XVIII: Conversions of Vindoline with Copper Oxidases

Vindoline occurs structurally intact in the clinically important Vinca alkaloids vinblastine and vincristine. It is oxidized by human ceruloplasmin and fungal and plant laccases into a reactive intermediate which undergoes intramolecular cyclization to an enamine which ultimately dimerizes. Transformations of vindoline by these copper oxidases are enhanced when enzyme incubations are performed with cofactors such as chlorpromazine. The role of copper oxidases in alkaloid metabolic interconversions and the possible implications of these reactions in Vinca alkaloid toxicity are discussed.