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

Authors

  • Felipe Lombó Dr.,

    1. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo 33006 Oviedo (Spain), Fax: (+34) 985103652
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  • Mohamed S. Abdelfattah Dr.,

    1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 2 Lexington, Kentucky 40536-0082 (USA)
    2. Permanent address: Chemistry Department, Faculty of Science, Helwan University, Ain Helwan, Cairo, 11795 (Egypt)
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  • Alfredo F. Braña Dr.,

    1. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo 33006 Oviedo (Spain), Fax: (+34) 985103652
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  • José A. Salas Dr.,

    1. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo 33006 Oviedo (Spain), Fax: (+34) 985103652
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  • Jürgen Rohr Dr.,

    1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 2 Lexington, Kentucky 40536-0082 (USA)
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  • Carmen Méndez Dr.

    1. Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias (I.U.O.P.A), Universidad de Oviedo 33006 Oviedo (Spain), Fax: (+34) 985103652
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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.

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