Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Amos B. Smith

Abstract

ABSTRACT

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION

OF (+)-DISCODERMOLIDE ANALOGS

AND

SYNTHETIC STUDY TOWARDS (–)-PTEROCIDIN

Nan Zhang

Amos B. Smith, III

Chapter one describes the design and synthesis of novel (+)-discodermolide analogs, that featured different saturation degrees of the terminal diene system and various lactone moieties. Biological evaluation via multiparameter dose-response analysis identified analog B2 as lead congener with superior efficacy towards different cancer cell lines. The high-resolution crystal structure of the B2-tubulin complex was obtained, shedding light on future design of new (+)-discodermolide analogs based on a better understanding of binding mechanism at molecular level.

Chapter two describes a “high-risk” synthetic study towards the natural product (–)-pterocidin. Besides cytotoxicity in different cancer cell lines at the low micromolar level, (–)-pterocidin has potent anti-invasive activity at non-cytotoxic concentration. A “high-risk” synthetic strategy was designed as a showcase of Type II Anion Relay Chemistry comprising a multicomponent union involving an aldehyde fragment, a bifunctional linchpin and a dienyl ether moiety. The key union has been demonstrated and the final step of the synthesis is currently under investigation.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS