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Access Type

WSU Access

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

YOUNG-HOON AHN

Second Advisor

JOHN SANTALUCIA

Abstract

ABSTRACT

CARBOHYDRATE-BASED INDUCERS OF CELLULAR STRESS FOR TARGETING CANCER CELL METABOLISM

by

FIDELIS TOLOYI NDOMBERA

May 2018

Advisor: Dr. Young-Hoon Ahn

Major: Chemistry (Biochemistry)

Degree: Doctor of Philosophy

Metabolic reprogramming and redox control of cancer cells is vital for their proliferation, but also provides selective strategies for treating cancer. Increased generation of reactive oxygen species (ROS) and an intricate control of redox status in cancer cells relative to normal cells provide a basis for designing ROS-inducing anticancer agents. In my work, I designed, synthesized and evaluated carbohydrate-based small molecules for ROS-generation, cytotoxicity and redox signaling and stress response. Our data from assays, including cell viability assays, enzyme inhibition studies, Western blot studies, click chemistry, and metabolomics, reveal that our compound (K8A) is more potent than 2-DG, a well-known carbohydrate-derived inhibitor of glycolysis. We reported discovery of carbohydrate-based small molecules with the property of blocking altered metabolic activity and enhancing ROS with potential therapeutic benefits for targeting cancer cells. Importantly, we investigated the mechanism of action of our potent compound that involve disruption of protein glycosylation in cancer with downstream effects on cancer metabolism.

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