Date of Award

Spring 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Madeleine M. Joullié

Abstract

The tamandarin and didemnins are a class of cyclodepsipeptides that have shown a wide range of biological activity. The didemnins have demonstrated antitumor, antiviral and immunosuppressive activity at low nano- and femtomolar levels. Didemnin B was the first marine natural product to enter clinical trials in humans in the United States. The structures of tamandarins A and B were reported in 2000 and possess almost identical structure and biological activity to didemnin B. These compounds have shown impressive biological activity and some progress has been made in establishing structure-activity relationships. However, their molecular mechanism of action is still unclear. The goal of the present research was to further the understanding of the processes underlying the biological activity through the preparation of designed analogs. Chapter 1 deals with the synthetic background of the tamandarins and the optimization of tamandarin B macrocyle for the preparation of specific analogs.

Chapter 2 describes the development of three tamandarin B/didemnin hybrid analogs. Their synthesis utilized a high-yielding method to form the tamandarin B macrocycle and a concise approach to the three desired side chains that employed common intermediates.

Chapter 3 focuses on the synthesis of Lys3 tamandarin M. This Lys3 modified macrocycle was designed for attachment to a biological probe in order to clarify the mechanism of action. Lys3 tamandarin M was designed so that the attachment to the biological probe would allow for an intact side chain which is known to be the site of the activity.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS