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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2017)

This dissertation describes the development of synthesis strategies for the lissoclimide natural product syntheses starting from either sclareolide or geranyl acetate. Chapter 1 focuses on the isolation and biological activity of lissoclimide terpenoid natural products. Previous synthesis efforts from the Vanderwal lab and other groups are described.

Chapter 2 focuses on the semi-synthesis of chlorolissoclimide, haterumaimide N, and haterumaimide Q from sclareolide. Development of a reliable Evans auxiliary based aldol approach to the hydroxysuccinimide moiety common to all lissoclimide natural products is described. The C–H chlorination of sclareolide is vastly improved with the use of a new chlorinating protocol co-developed with the Alexanian lab, enabling the first synthesis of chlorolissoclimide in 9 steps and 14% overall yield.

Chapter 3 focuses on a fully synthetic route towards the lissoclimides from geranyl acetate featuring an epoxide-initiated bicyclization. This strategy provides access to a readily diversifiable intermediate that is converted to haterumaimide Q and key analogues. A key finding was that the preference for Fürst–Plattner addition of chlorine across an alkene on a rigid decalin system is partially reversed in the presence of a homoallylic trifluoroacetate. The resulting diequatorial dichlorides are found in several of the most potent lissoclimides.

Chapter 4 focuses on four key biological investigations our syntheses have enabled: (1) the Yusupov group elucidated the biological mode of action via a co-crystal structure of chlorolissoclimide in the E-site of the eukaryotic large ribosomal subunit (2); our synthetic lissoclimide natural products and analogues were screened against several cell lines to determine structure activity relationships (SAR); (3) the structural information was used to computationally rationalize the observed SAR; and (4) these compounds were evaluated for their ability to eradicate several viral infections, including Ebola, exhibiting EC50 values of 20 nM.

Chapter 5 focuses on the exploration of 2,2-disubstituted epoxide-initiated bicyclizations to access haterumaimide J. A Ti(III) radical cyclization strategy is first explored using several cyclization precursors. Lewis-acid-catalyzed bicyclizations are described for our efforts towards both haterumaimide J and hydroxytotarol.

    Cover page: Synthesis and Translation Inhibition of the Lissoclimides
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2019)
    Natural products that target the eukaryotic ribosome are promising therapeutics to treat a variety of cancers. It is therefore essential to determine their molecular mechanism of action to fully understand their mode of interaction with the target and to inform the development of new synthetic compounds with improved potency and reduced cytotoxicity. Toward this goal, we have previously established a short synthesis pathway that grants access to multiple congeners of the lissoclimide family. Here we present the X-ray co-crystal structure at 3.1 Å resolution of C45, a potent congener with two A-ring chlorine-bearing stereogenic centers with 'unnatural' configurations, with the yeast 80S ribosome, intermolecular interaction energies of the C45/ribosome complex, and single-molecule FRET data quantifying the impact of C45 on both human and yeast ribosomes. Together, these data provide new insights into the role of unusual non-covalent halogen bonding interactions involved in the binding of this synthetic compound to the 80S ribosome.
      Cover page: Understanding the role of intermolecular interactions between lissoclimides and the eukaryotic ribosome
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2017)
      The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.
        Cover page: Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides
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