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Development of Cobalt and Rhenium An...

King, Arthur Paden.

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Development of Cobalt and Rhenium Anticancer Agents Targeting the Tumor Microenvironment.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Development of Cobalt and Rhenium Anticancer Agents Targeting the Tumor Microenvironment./
Author:	King, Arthur Paden.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
Description:	434 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
Subject:	Inorganic chemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27963674
ISBN:	9798617033467

Development of Cobalt and Rhenium Anticancer Agents Targeting the Tumor Microenvironment.
King, Arthur Paden.

Development of Cobalt and Rhenium Anticancer Agents Targeting the Tumor Microenvironment. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 434 p.

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--Cornell University, 2020.

This item must not be sold to any third party vendors.

This work details the development of metal-based anticancer agents specifically tailored to target aspects of the tumor microenvironment. Cancerous tumors receive decreased blood and nutrient supplies relative to healthy tissues, which leads to low O2 content, decreased pH, and increased levels of protein misfolding and DNA damage. Therapeutics may be designed to target these aspects of the tumor microenvironment, leading to increased selectivity for cancer cells over healthy cells. In particular, this work describes efforts to target two aspects of the tumor microenvironment: decreased O2 content and higher levels of endoplasmic reticulum (ER) stress. The first chapter outlines recent advances in complexes that exploit the increased rates of protein misfolding in tumors by disrupting ER function. This chapter includes a description of the relevant pathways involved in ER stress, a summary of metal complexes that kill cancer cells via ER stress, and a wholistic analysis of trends and similarities in metal complexes that share this mechanistic feature. Chapters 2 and 3 describe the development of Co(III) complexes of biologically active ligands that may be selectively reduced to yield cytotoxic species. Chapter 2 focuses on the development of Co(III)-bis(thiosemicarbazone) complexes with powerful anticancer activity. Chapter 3 details the synthesis of Co(III) complexes bearing Schiff base ligands, and itincludes a thorough study of the ligand exchange pathways and redox reactions that lead to activation of these compounds. Chapter 4 describes the development and mechanistic investigation of the first rhenium complex that kills cancer cells via ER stress. Chapter 5 details the expansion of the original lead complex from Chapter 4 into a library of derivatives with variable activity and the investigation of the lead compound's activity in vivo. Finally, Chapter 6 describes ongoing efforts to develop conjugated rhenium complexes for molecular targeting and pull-down experiments. Together, these results provide a description of metal complexes that target the tumor microenvironment and outline a template for the development of anticancer metal complexes from synthesis to physical characterization to mechanistic studies of their anticancer activity.

ISBN: 9798617033467Subjects--Topical Terms:

3173556
Inorganic chemistry.
Subjects--Index Terms:

Anticancer

Development of Cobalt and Rhenium Anticancer Agents Targeting the Tumor Microenvironment.
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245 1 0 $a Development of Cobalt and Rhenium Anticancer Agents Targeting the Tumor Microenvironment.
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300 $a 434 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
500 $a Advisor: Wilson, Justin J.
502 $a Thesis (Ph.D.)--Cornell University, 2020.
506 $a This item must not be sold to any third party vendors.
520 $a This work details the development of metal-based anticancer agents specifically tailored to target aspects of the tumor microenvironment. Cancerous tumors receive decreased blood and nutrient supplies relative to healthy tissues, which leads to low O2 content, decreased pH, and increased levels of protein misfolding and DNA damage. Therapeutics may be designed to target these aspects of the tumor microenvironment, leading to increased selectivity for cancer cells over healthy cells. In particular, this work describes efforts to target two aspects of the tumor microenvironment: decreased O2 content and higher levels of endoplasmic reticulum (ER) stress. The first chapter outlines recent advances in complexes that exploit the increased rates of protein misfolding in tumors by disrupting ER function. This chapter includes a description of the relevant pathways involved in ER stress, a summary of metal complexes that kill cancer cells via ER stress, and a wholistic analysis of trends and similarities in metal complexes that share this mechanistic feature. Chapters 2 and 3 describe the development of Co(III) complexes of biologically active ligands that may be selectively reduced to yield cytotoxic species. Chapter 2 focuses on the development of Co(III)-bis(thiosemicarbazone) complexes with powerful anticancer activity. Chapter 3 details the synthesis of Co(III) complexes bearing Schiff base ligands, and itincludes a thorough study of the ligand exchange pathways and redox reactions that lead to activation of these compounds. Chapter 4 describes the development and mechanistic investigation of the first rhenium complex that kills cancer cells via ER stress. Chapter 5 details the expansion of the original lead complex from Chapter 4 into a library of derivatives with variable activity and the investigation of the lead compound's activity in vivo. Finally, Chapter 6 describes ongoing efforts to develop conjugated rhenium complexes for molecular targeting and pull-down experiments. Together, these results provide a description of metal complexes that target the tumor microenvironment and outline a template for the development of anticancer metal complexes from synthesis to physical characterization to mechanistic studies of their anticancer activity.
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653 $a Hypoxia
653 $a Microenvironment
653 $a Rhenium
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