rdf-syntax-grammar
mods:
  schema location: http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
  title info:
    title: Synthetic Studies of Iriomoteolide-1A Total Synthesis of Alotaketal A and an Antifungal O-Hydroxy-P-Quinone Methide Diterpenoid
  name:
    name part: Huang, Jinhua
    role:
      role term: creator
    role:
      role term: author.
  name:
    name part: Yang, Jiong
    role:
      role term: thesis advisor.
  name:
    name part: Texas A & M University
    role:
      role term: degree granting institution.
  type of resource: text
  genre: bibliography
  origin info:
    place:
      place term: txu
    date issued: 2014
    issuance: monographic
  language:
    language term: eng
  physical description:
    form: remote
    extent: 1 online resource (373 pages)
  abstract: Natural products are a rich source of compounds with interesting structures and biological activities. Three bioactive natural products, iriomoteolide-1a, alotaketal A, and an unnamed quinone methide diterpenoid, attracted our attention during our course of exploring natural products as potential leads for biomedical discovery. The structure of iriomoteolide-1a had been misassigned, but the potent cytotoxicity reported for this natural product warranted further studies to elucidate its true structure. As part of our effort toward this goal, we finished the total synthesis of a diastereomer of iriomoteolide-1a. Our total synthesis featured a lithium acetylide-chloroformate coupling to assemble the alkyne and chloroformate fragments, the ring closing metathesis to exclusively generate the 15E-macrocyclic diolide, and a SmI_(2)-mediated intramolecular reductive allylation to form the cyclic hemiketal. The bioactivities of this diastereomer were evaluated, but only weak inhibition of cell proliferation was observed at 10 [mu]M toward HeLa and PC3 cell lines. Alotaketal A was reported to potently (EC₅₀ = 18 nM) activate the cAMP (cyclic adenosine monophosphate) signaling pathway in HEK293 cells transformed with the pHTS-CRE plasmid. Our synthetic efforts toward this natural product culminated in the first enantioselective total synthesis of (-)-alotaketal A. Our total synthesis employed both intra- and inter-molecular reductive allylation of esters for assembling the bicyclic lactone and coupling the fragments. A Hg(OAc)₂-mediated allylic mercuration was used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process was revealed. The synthesis confirmed the relative and absolute stereochemistry of (-)-alotaketal A and allowed verification of alotaketal A's effect over cAMP signaling using reporter-based FRET imaging assays with HEK293 cells. Our studies also revealed alotaketal A's unique activity in select…
  note: by Jinhua Huang.
  note: "Major Subject: Chemistry"
  note: Includes vita.
  note: Doctor of Philosophy Texas A & M University 2013 http://hdl.handle.net/1969.1/151798
  note: Includes bibliographical references.
  note: Text (Dissertation)
  subject:
    topic: Major Chemistry
  subject:
    topic: Total Synthesis
  subject:
    topic: Drug Discovery
  subject:
    topic: Iriomoteolide-1a
  subject:
    topic: Alotaketal A
  subject:
    topic: Quinone Methide Diterpenoid
  identifier: http://hdl.handle.net/1969.1/151798
  record info:
    record content source: TXA
    record creation date: 140618
    record change date: 20151206101802.0
    record identifier: in00003478575
    language of cataloging:
      language term: eng