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Title page for ETD etd-08172017-143439

Type of Document Dissertation
Author Chong, Katherine Melissa
URN etd-08172017-143439
Title Studies toward a unified synthesis of apoptolidinone C and glycosylated variants
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Gary Sulikowski Committee Chair
Brian Bachmann Committee Member
Lawrence Marnett Committee Member
Steven Townsend Committee Member
  • mutasynthesis
  • precursor directed biosynthesis
  • glycosylation state
  • natural products
  • apoptolidin
  • apoptolidinone C
  • total synthesis
Date of Defense 2017-08-11
Availability restricted
The fully glycosylated apoptolidins have been shown to exert nanomolar activity against several cancer cell types (e.g. human lung cancer and glioblastoma cells). This activity is directly correlated with glycosylation state with the aglycone losing its parent activity (> 10 μM, H292 cells, human lung cancer). In order to understand the connection between apoptolidin glycosylation state and observed cytotoxicity profile, access to the free macrolide and its glycovariants is essential. Past work allowed ready access to the fully glycosylated microbial metabolite apoptolidin A and the corresponding mono-glycosylated aglycone (apoptolidin H) using the methods of fermentation and mutasynthesis. Access to the aglycone apoptolidinone C, has been enabled through a convergent and robust chemical synthesis. Selective C27- glycosylation of the synthetic macrolide could then be achieved using double knockout strain of the natural producing organism, Nocardiopsis sp. FU40 ΔS8 to reach apoptolidin C disaccharide, completing our set of apoptolidin glycovariants.

We aimed to use this unique toolbox of apoptolidin glycovariants to understand the mechanism of selective cellular uptake, localization, and response as a function of apoptolidin glycosylation state. Model studies using fluorescent apoptolidin A and H (fully glycosylated and C9- monoglycosylated) have been conducted to initiate understanding of cellular uptake and response via cell microscopy imaging and single cell phospho- specific flow cytometry. However, comprehensive analysis necessitates access to the apoptolidin aglycone and C27- glycosylated apoptolidin disaccharide. The work described herein details our process to reach large quantities of apoptolidinone C by a modular, convergent, and efficient synthetic plan, having divided the aglycone into four quadrants for increased synthetic efficiency and late stage modifications.

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