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Title page for ETD etd-10192009-163254


Type of Document Dissertation
Author Wang, Jingqi
URN etd-10192009-163254
Title Synthetic Studies on Apoptolidin Congeners in Support of Target Identification of A Cell Selective Cytotoxic Agent
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Gary A. Sulikowski Committee Chair
Brian O. Bachmann Committee Member
Daniel C. Liebler Committee Member
Eva Harth Committee Member
Keywords
  • Target identification
  • Apoptosis
  • Apoptolidin
  • Apoptolidinone
  • Biological activity
Date of Defense 2009-10-13
Availability unrestricted
Abstract
As a selective apoptosis inducer, apoptolidin A was isolated from Nocardiopsis Sp. by Japanese chemists in 1997. Khosla and coworkers have demonstrated that apoptolidin A could inhibit the activity of mitochondrial F0F1-ATP synthase. However, in Wender’s SAR study, it was clearly pointed out that there might be a new and more relevant cellular target of apoptolidin’s biological action. The goal of this project is to identify the cellular target of apoptolidin by applying advanced proteomic technologies and molecular imaging methods. Chapter I of this dissertation described the isolation of apoptolidin A, isoapoptolidin A, three minor metabolites (apoptolidin B-D) and their biological activities. Chapter II described the previous successful synthesis of apoptolidin A and apoptolidinone A. Chapter III described the latest studies on the action mechanism of apoptolidin A and application of photo-affinity probes derived from apoptolidin A to target identification. Chapter IV described the total synthesis of three unnatural apoptolidinones, and its use in the development of a biological probe for target identification. Chapter V described the successful precursor-directed bioglycosylation of synthetic apoptolidines using whole cell apoptolidin-producing bacteria (Nocardiopsis Sp.). Chapter VI described our recent findings on apoptolidins biological effects against human lung cancer H292 cells, utilization of this cell assay for SAR studies of sugar units of apoptolidin A and future directions for apoptolidin probe syntheses guided by these biological results.

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