The development of new englerin-inspired chemotherapeutic drug candidates and tool compounds & the synthesis of an acyldepsipeptide fluorescent probe
Date
2024
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Publisher
University of Delaware
Abstract
Chapter 1 outlines the discovery, biological mechanistic investigations, syntheses, and derivatization of (–)-englerin A, a guaiane sesquiterpene natural product exhibiting potent and selective renal cancer cell growth inhibition first described in 2009. The cellular mechanism by which the compound kills renal cancer cells is the subject of intense and ongoing study. The synthesis of new englerin tool compounds and analogues have been and continue to be used to investigate the mechanism(s) of action against renal cancer cells. The synthesis of analogues have also supported advancement of an englerin-derived compound to therapeutic candidacy. ☐ Chapter 2, the first project herein, describes synthesis and development of a next generation series of analogues addressing the inherent therapeutic liabilities present within the natural product. This series of analogues is informed by a compendium of structure–function data and improved biological activities. The various substituents being incorporated into these analogues address the lethality observed in mice as well as the stability of the compound when administered orally. The goal of this project is to construct an analogue that may proceed through therapeutic candidacy ultimately leading to the development of an anti-cancer treatment. ☐ Chapter 3 describes the efforts towards the synthesis and development of a new series of englerin-inspired proteomic tool compounds to aid in the elucidation of an unambiguous mechanism of action of (–)-englerin A against cancer cells. The tool compounds will integrate covalent modifiers and clickable moieties for the purposes of cellular target identification and other mechanism studies in order to support the development of new drugs toward renal carcinoma based on englerins. Determining the mechanism of action is extremely important in the development of (–)-englerin A as a cancer therapeutic. Although there have been tool compounds developed in the past, the mechanism of action is still largely unknown. There is still a need for further development of tool compounds to probe this biological mechanism of action. ☐ Chapter 4 describes the synthesis of an acyldepsipeptide fragment fluorescent tool compound used by the Karl Schmitz group to investigate the biological mechanism of action of acyldepsipeptide fragments towards tuberculosis. This tool compound was developed in a collaboration with Karl Schmitz and Joseph Fox of the University of Delaware.
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Keywords
Analogues, Chain, Hudson, Biological mechanism, Cancer cells