Date of Completion

8-29-2020

Embargo Period

8-29-2023

Major Advisor

Dr. Mark Peczuh

Associate Advisor

Dr. Amy Howell

Associate Advisor

Dr. Christian Brückner

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Macrocycles are currently an important area of investigation in drug design and development. Macrocycles can bind target biomolecules and affect various cellular processes due to their ability to modulate their conformations and their occupation of a unique region of chemical space. Our group has worked on the synthesis, structural properties, and biological activity of a class of [13]-macrodilactones in previous studies. Their key structural components include two ester groups, an alkene, and a hinge atom.

This dissertation takes advantage of the modular approach to the synthesis of [13]-macrodilactones and parlays it for the ability to prepare numerous analogs from a common intermediate. This late stage diversification was applied in two separate projects. In the first, a family of biaryl-decorated [13]-macrodilactones were synthesized via Suzuki couplings using a common C7 bromo-aryl macrocycle starting material. In the second project a C7-amine functionalized [13]-macrodilactone was prepared and acylated with a number of amino acids. These two families of C7-substituted-[13]-macrodilactones have also been evaluated via principal component analysis (PCA), antiproliferation, and antibacterial assays. Additionally, a minor project of an unsubstituted [13]-macrodilactam have been studied as a derivative from the two major projects.

The studies of functionalized [13]-macrodilactones indicated that the unique structural and physiochemical characteristics may allow them to exhibit biological activity. The information obtained can be linked to new bioactive molecules with designed properties.

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