Elucidation of oxygenation steps during oviedomycin biosynthesis and generation of derivatives with increased antitumor activity

Abstract

Eight different angucyclinones have been produced in Streptomyces albus by combining three oxygenase genes together with the polyketide synthase and cyclases genes from the oviedomycin biosynthetic gene cluster from Streptomyces antibioticus ATCC 11891. Four of these compounds were fully characterized for the first time. Three of these angucyclinones-prejadomycin-2-carboxylate (2), 4a,12b-dehydro-UWM6 (5), and prejadomycin (3)-show a significant increase in their in vitro antitumor activity relative to oviedomycin (1). 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.