Progress toward the synthesis of the complestatins, novel HIV-1 entry inhibitors from soil bacteria / Jason Joseph Chruma.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Chruma, Jason Joseph.

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:

xxiv, 340 pages : illustrations, (some color) ; 29 cm

Production:

2002.

Summary:

The binding of human cluster determinant 4 (CD4) to the human immunodefeciency virus type 1 (HIV-1) envelope glycoprotein gp120 represents the first step in viral entry and, thus, HIV infection. The binding of CD4 to gp120 induces major conformational alterations in the viral protein, unveiling a secondary binding epitope, which then binds with either CCR5 or CXCR4 chemokine receptors. The vital role of CD4-gp120 binding in HIV infection has marked this interaction as a target for pharmaceutical intervention. Through a combination of literature review and collaborative studies, the first chapter of this dissertation presents a working hypothesis for the future development of CD4-gp120 binding agonists and antagonists.

The second chapter focuses on progress toward the synthesis of a family of known CD4-gp120 inhibitors, the complestatins. In particular, a stereodivergent synthesis of four diastereomers of the complestatin western (BCD) macrocycle, including the natural configuration, is described. The strategy takes advantage of a ruthenium-activated intramolecular SNAr diaryletherification. Also, novel methods for constructing various substituted phenylglycines in enantiopure form are described. The configuration of the two phenylglycine units of the BCD macrocycle were found to have a remarkable effect in directing the overall peptide backbone conformation.

Notes:

Supervisor: Amos B. Smith, III.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2002.

Includes bibliographical references and index.

Local Notes:

University Microfilms order no.: 3072984.

OCLC:

244972835