Total synthesis of didemnin B analogs
Abstract
The didemnins are a class of depsipeptides which were isolated from a marine tunicate. Most didemnins share a common macrocycle and only differ in the side chains attached to the macrocycle at the threonine amide position. They exhibit a wide variety of biological activity, including antitumor, antiviral and immunosuppressive. Among the members of the didemnin family, didemnin B is one of the most potent and the most investigated. It was the first marine natural product to enter clinical trials against cancer. Unfortunately, it showed poor solubility, serious toxicity and short lifetime which may be related to enzymatic degradation. Very little is known about its mechanism of action and receptor binding sites. Conformational and SAR studies show that three moieties in this molecule may be important: N,O-dimethyl tyrosine, the isostatine hydroxyl group, and the side chain. The didemnin B side chain, in particular, is considered to be an extremely important and sensitive area. It is the only site which differentiates didemnin B from the other didemnin members, ^ Chapter 2 describes our design and synthesis of two side chain analogs: an aminomethylene analog and a γ-turn analog. In the first analog, the amide bond between D-leucine and L-proline in the side chain was replaced by an aminomethylene bond. In the second analog, the original lactyl portion was removed and also the prolyl ring was replaced by a dehydroprolyl ring. ^ Recently, covalent bonds were used to replace unnecessary amino acids to increase resistance to enzymatic degradation and prolong lifetime. By using this strategy, more active analogs have been produced. Chapter 3 discusses the design and synthesis of a reduced ring analog, in which the Leu-Pro portion was replaced by a n-butyl linker in the macrocycle. ^
Subject Area
Chemistry, Organic
Recommended Citation
Amy Xiaobin Ding,
"Total synthesis of didemnin B analogs"
(January 1, 2000).
Dissertations available from ProQuest.
Paper AAI9965469.
http://repository.upenn.edu/dissertations/AAI9965469
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