Structural Requirements for the Antiproliferative Activity of Pre-mRNA Splicing Inhibitor FR901464

Authors

  • Sami Osman,

    1. Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
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  • Brian J. Albert,

    1. Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
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  • Yanping Wang,

    1. Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
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  • Dr. Miaosheng Li,

    1. Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
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  • Nancy L. Czaicki,

    1. Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
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  • Prof. Dr. Kazunori Koide

    Corresponding author
    1. Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
    • Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA, 15260 (USA), Fax: (+1) 412-624-8611
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Abstract

FR901464, a natural product isolated from a bacterium source, activates a reporter gene, inhibits pre-mRNA splicing, and shows antitumor activity. We previously reported the development of a more potent analogue, meayamycin, through the total synthesis of FR901464. Herein, we report detailed structure–activity relationships of FR901464 that revealed the significance of the epoxide, carbon atoms in the tetrahydropyran ring, the Z geometry of the side chain, the 1,3-diene moiety, the C4-hydroxy group, and the C2′′-carbonyl group. Importantly, the methyl group of the acetyl substituent was found to be inessential, leading to a new potent analogue. Additionally, partially based on in vivo data, we synthesized and evaluated potentially more metabolically stable analogues for their antiproliferative activity. These structural insights into FR901464 may contribute to the simplification of the natural product for further drug development.

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