I. Total synthesis of a constrained didemnin B analog. II. Total synthesis of sanjoinine A.

Format:

Book

Thesis/Dissertation

Author/Creator:

Xiao, Dong.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Chemistry, Organic.

Biochemistry.

0487.

0490.

Local Subjects:

0487.

0490.

Physical Description:

270 pages

Contained In:

Dissertation Abstracts International 61-03B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The three-dimensional display of a primary chemical structure is the critical factor responsible for the binding of a ligand to a protein. A macrocyclic compound of known primary structure may exist as a group of conformers in rapid equilibrium. The bioactive conformation of a macrocyclic compound is the one assumed when the ligand binds to the receptor and the one that is responsible for the biological activity. Although the bioactive conformation is predetermined by the primary chemical structure, this information alone cannot reliably predict the bioactive conformation. Didemnin B is an antiviral, antitumor and immunosuppressive marine natural product. To explore the possibility of applying a synthetic approach to probe the didemnin B bioactive conformation, an isostatine-constrained analog was designed. The constrained cyclohexane beta-hydroxy-gamma-amino acid was synthesized and incorporated into didemnin B. This analog when tested in the protein synthesis inhibition assay, showed a 20-fold decrease in activity when compared to the natural product. Nuclear magnetic resonance studies in CDCl3 indicated that this analog existed in a somewhat different conformation than didemnin B. Chapter One discusses the background information of didemnins and the research on bioactive conformation, the design and synthesis of an isostatine constrained analog and the results of biological testing. The present synthetic venture demonstrates both the possibilities as well as the limitations of using a synthetic approach to probe the bioactive conformation of macrocyclic compounds.

Chapter Two discusses the total synthesis of a 14-membered cyclopeptide alkaloid sanjoinine A. Sanjoinine A is the major component of sanjoine, a traditional Chinese medicinal plant used for insomnia. The biological activity and unique structure feature of this natural product warranted a synthetic endeavor. Based on the earlier investigations by the Joullie group, the first total synthesis of sanjoinine A was completed. The key manipulations of the end game for the synthesis of sanjoinine A solved some long-standing problems in 14-membered cyclopeptide alkaloid synthesis.

Notes:

Source: Dissertation Abstracts International, Volume: 61-03, Section: B, page: 1422.

Supervisor: Madeleine M. Joullie.

Thesis (Ph.D.)--University of Pennsylvania, 2000.

Local Notes:

School code: 0175.

ISBN:

9780599702110

Access Restriction:

Restricted for use by site license.