Date of Completion

5-4-2018

Embargo Period

5-4-2018

Keywords

macrocycles, macrodilactones, shape, topology, chirality, stereogenic centers, acinetobacter baumannii, bacteria, siderophore, iron

Major Advisor

Dr. Mark Peczuh

Associate Advisor

Dr. Amy Howell

Associate Advisor

Dr. Alfredo Angeles-Boza

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Macrocycles are attractive scaffolds for the development of new bioactive compounds. Central to this behavior is the shape of a macrocycle; it is a fundamental parameter that makes a macrocycle able to bind its target. This thesis is geared at understanding the factors that dictate the shape and topology of macrocycles, especially the relationship between the configuration of individual stereogenic centers and planar chirality. We previously evaluated stereogenic centers associated with the ester units, both on the chain attached to the ester oxygen and the carbon α - to the carbonyl. Here we evaluate using X-ray crystallography the consequences of substitution at the positions allylic to the E-alkene.

Acinetobacter baumanni, one of the ESKAPE multi-drug resistant pathogens, is responsible for the rising outbreak infections in hospital settings around the world. Pre-acinetobactin is one of the siderophores that A.baumannii produces during iron deficiency. It is a mixed siderophore containing a catecholate and hydroxamate moiety. It is unique and unlike many other siderophores, in that it can isomerize to acinetobactin when pH levels change, allowing it to be a more versatile iron chelator and in turn be transported down the BauA pathway.The overall goal of this project is to synthesize pre-acinetobactin analogs that link the siderophore and a warhead through a covalent linker. We posit that the analogs will inhibit A. baumanii bacterial cells, thus killing the bacteria.

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