Elucidation of Oxygenation Steps during Oviedomycin Biosynthesis and Generation of Derivatives with Increased Antitumor Activity

Abstract

<jats:title>Abstract</jats:title><jats:p>Eight different angucyclinones have been produced in <jats:italic>Streptomyces albus</jats:italic> by combining three oxygenase genes together with the polyketide synthase and cyclases genes from the oviedomycin biosynthetic gene cluster from <jats:italic>Streptomyces antibioticus</jats:italic> ATCC 11891. Four of these compounds were fully characterized for the first time. Three of these angucyclinones—prejadomycin‐2‐carboxylate (<jats:bold>2</jats:bold>), 4a,12b‐dehydro‐UWM6 (<jats:bold>5</jats:bold>), and prejadomycin (<jats:bold>3</jats:bold>)—show a significant increase in their in vitro antitumor activity relative to oviedomycin (<jats:bold>1</jats:bold>). A hypothesis for the sequence of tailoring events catalyzed by these three oxygenases during oviedomycin biosynthesis is proposed. In this hypothesis OvmOII acts as a bifunctional oxygenase/dehydratase.