Date of Award

5-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

Duane D. Miller, Ph.D.

Committee

Isaac O. Donkor, Ph.D. Richard E. Lee, Ph.D. Wei Li, Ph.D. Gabor J. Tigyi, M.D., Ph.D.

Abstract

Lysophosphatidic acid (LPA) is a naturally occurring bioactive phospholipid. It has a wide array of biological effects like cell proliferation, survival, migration, apoptosis invasion, wound healing and angiogenesis. Autotaxin (ATX) was identified as an autocrine tumor cell motility factor from A2058 melanoma conditioned medium. ATX has lysophospholipase D enzyme activity and is responsible for the cleavage of lysophophatidylcholine (LPC) leading to the generation of LPA. Antagonists of Autotaxin would have a potential therapeutic application in cancer research. Chapter 1 is an introduction of LPA and autotaxin. It provides the background and significance of the research. Chapter 2 explores the synthesis of the stereoisomers of 3‑CCPA and the pharmacological activites of these isomers. Chapter 3 discusses the design and synthesis of benzyl and naphthalene-methyl phosphonic acid inhibitors of autotaxin with anti‑invasive and anti-metastatic actions. Chapter 4 elaborates on the search for new non‑lipid, drug like LPA analogs. Chapter 5 provides an overview of the work detailed in the dissertation; as well as future directions that will help further the scope of these projects.

DOI

10.21007/etd.cghs.2011.0121

Comments

Two year embargo expired May 2013

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