Synthetic and structural investigations of the novel biologically active cyclodepsipeptides : the didemnins / Joshi Maddela Ramanjulu.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Ramanjulu, Joshi Maddela.

Contributor:

Joullié, Madeleine M., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xxxi, 417 pages : illustrations ; 29 cm

Production:

1996.

Summary:

The didemnins, isolated from a marine tunicate displayed diverse bioactivity namely antiviral, antitumor, and immunosuppressive. Didemnin B, one of the most successful drug candidate of the Didemnidae family has been the target of our investigations. Most didemnins contain a common macrocycle and differ only in the side chains attached to the amino group of threonine (Figure 1.2).

Didemnin B has greater immunosuppressive activity than cyclosporin A. Phase II clinical trials for antitumor activity showed no significant activity yet demonstrated toxicity possibly due to its rapid conversion to a toxic metabolite. In recent years, peptidomimetics have offered great potential to produce compounds with enhanced enzymatic stability and reduced toxicity. In order to arrive at the pharmacophore when little is known regarding the receptor-bound conformation, structure-activity relationships are extensively used. Our preliminary SAR investigations are aimed at confirming the original hypothesis that "$\beta$-turn side chain of the didemnin B is the main if not the only bioactive site and the macrocycle is used only for binding or anchoring to the receptor". The syntheses and biological activities of the $\beta$-turn analogs (14-16, Figure 1.6) that were designed, retaining the residues found in the $\beta$-turn region of the natural compound, are presented in chapter 1. Also shown in chapter 1, is the syntheses of acyclic analogs of didemnins in order to investigate effects of ring-opening on bioactivity.

Introduction of covalent linkers to replace amino acids that are not required for biological activity have produced active analogs. The reduced ring analog (23, Figure 2.1), that we have designed with the aid of molecular modeling, displayed remarkable superimposition with the natural compound. The syntheses of this analog as well as the syntheses of two other analogs are presented in chapter 2. In chapter 3, a bolder approach was taken that is to replace the entire peptide backbone with a suitable scaffolding. We chose 2,3-diaminoglycal as a scaffolding that would keep the pharmacaphores in a presumed bioactive conformation. Progress made toward the synthesis of this analog (89, Figure 3.1) is discussed in chapter 3.

Notes:

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 1996.

Includes bibliographical references and index.

Local Notes:

University Microfilms order no.: 97-12990.

OCLC:

187469418