Structure-Activity Relationship of the Myriaporones and Biosynthetic Study of Tedanolide

Doctoral Dissertation

Abstract

The myriaporones and the tedanolides are two distinct classes of polyketide natural products that exhibit strong structural similarities as well as interesting antitumor activities. Although the latter was isolated in 1984, the complexity of its architecture proved to be a great challenge; the first synthesis was only reported in 2006. Conversely, the myriaporones represent a much simpler target. Isolated from a different source in 1995 by Rinehart et al., the first total synthesis was achieved simultaneously by our group and Cuevas et al. in 2004. Our highly efficient synthesis allowed us to prepare enough material to investigate the mode of action, which is herein disclosed. Additionally, it placed us in excellent position for undertaking a structure-activity relationship study of these compounds.

The efforts to identify the pharmacophore of the myriaporones also are presented in this thesis. The most potent compounds in the myriaporone family, namely myriaporone 3 and myriaporone 4, exist in a dynamic equilibrium due to the lability of myriaporone 3’s hemiketal moiety. It is possible that only one of the components of myriaporone ¾ equilibrium is active. If so, the other component may diminish the activity and destabilize the binding of the biological target. Several analogues were designed to lock either of the two conformations in an attempt to find the biological active one; however, all of them exhibited a significant decrease in biological activity.

Myriaporone ¾ and the southern hemisphere (C10-C23 portion) of tedanolide are structurally closely related. We hypothesized that myriaporone ¾ is a naturally occurring analogue of tedanolide, and, thus, shared an identical pharmacophore. Considering the complexity and the difficulties associated with tedanolide, the study of myriaporone’s analogues would then provide useful information on both families, thereby, ultimately providing better drug candidates. Simple modifications of the myriaporone ¾ synthesis allowed access to the southern hemisphere of tedanolide. 13-deoxytedanolide is a natural product possessing the same activity as tedanolide and differing from the latter only by one hydroxyl group at the 13 position. Some analogues of myriaporone were designed without the corresponding hydroxyl group to determine if the myriaporones and the tedanolides followed similar trends. Additionally, analogues of myriaporone possessing a simpler structure were generated. Again, all of the analogues synthesized exhibited a significant decrease in biological activity.

A fortiori, based on biosynthetic considerations, we propose that the unique macrolactone linkage of tedanolide arise from a skeleton rearrangement. The synthesis of the potential biosynthetic precursor, isotedanolide, was undertaken in order to study the proposed rearrangement and to validate our hypothesis. Progress toward the synthesis of isotedanolide is also presented.

Attributes

Attribute NameValues
URN
  • etd-09122008-140910

Author Myriam Patricia Roy
Advisor Richard Taylor
Contributor Marya Lieberman, Committee Member
Contributor Richard Taylor, Committee Chair
Contributor Shahriar Mobashery, Committee Member
Contributor Bradley Smith, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Chemistry and Biochemistry
Degree Name PhD
Defense Date
  • 2008-09-02

Submission Date 2008-09-12
Country
  • United States of America

Subject
  • myriaporone

  • structure-activity relationship

  • total synthesis

  • tedanolide

  • protein synthesis inhibitor

Publisher
  • University of Notre Dame

Language
  • English

Record Visibility and Access Public
Content License
  • All rights reserved

Departments and Units

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