Rational design, synthesis and biological evaluation of natural product mimics / Onur Atasoylu.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Atasoylu, Onur.

Contributor:

Smith, Amos B., III, advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xix, 341 pages : illustrations ; 29 cm

Production:

2010.

Summary:

This dissertation describes the design and synthesis of molecules mimicking bioactive portions of peptides, nucleoside bases and bioactive natural products.

Chapter 1 details the design and implementation of catechol based peptidomimetics of urotensin II (U-II), based on the identified 3D pharmacophore. The synthesis describes orthogonal protecting group strategies for phenols.

Chapter 2 summarizes an efficient protocol to annulate the 5,6-fused 2-pyridones, a ring system similar to those found in nucleoside bases. A tandem procedure comprising the condensation of propiolamide and cyclic beta-ketomethyl esters in water, followed by acid or base promoted intramolecular ring closure and decarboxylation was developed.

Chapter 3 provides a strategy for the design of truncated analogs of (+)-spongistatin 1 preserving conformational properties of the natural product. The solution conformers of (+)-spongistatin 1 were studied in detail leading to the design of AB- and ABEF-ring analogs. An ABEF-ring analog with low nanomolar activity was found to act through the same mode of action as (+)-spongistatin 1, proving that the bioactive portion of the molecule comprise a linear version of the ABEF-ring system.

Finally Chapter 4 describes the design and synthesis of novel (+)-discodermolide analogs with improved potency. Detailed investigation of the earlier SAR and photolabeling data, combined with solution structure and docking studies revealed a possible binding mode of (+)-discodermolide that occupies known taxane binding site on beta-tubulin. Attachment of aromatic side-chains mimicking the taxol tail furnished one of the most potent (+)-discodermolide analog series reported to date.

Notes:

Adviser: Amos B. Smith, III.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2010.

Includes bibliographical references.