I. Bioorthogonal transition metal catalysis for prodrug and proprobe release, II. step-economical synthesis of molecular transporters and evaluation of their uptake across cell membrane and cell wall barriers [electronic resource]

The ability of organic chemists to design and synthesize functional molecules has revolutionized the ways in which we can probe biological systems. From catalysts capable of releasing bioactive molecules from bioinactive precursors to oligomers that enable or enhance the uptake of molecules across cell membrane and cell wall barriers, the work described herein emphasizes the power of designing for function. These new tools allow for control over the location of many biologically relevant molecules, including drugs, probes, imaging agents, metabolic modulators, and pesticides, with ramifications for a variety of biochemical, agricultural, and medicinal applications. Chapter 1 reviews the development of selective catalysts designed for use in biological systems. The catalysts have primarily been used for bioconjugations, expanding the classical repertoire of bioconjugation techniques to allow for selective chemistries at many more functional groups than was traditionally possible. Emerging strategies for imaging in biological systems using transition metal catalysis are also reviewed, as are transition metal-based catalytic therapeutics. The synthesis and evaluation of a novel bioorthogonal ruthenium catalyst designed for release of biologically active molecules from inactive precursors is the focus of Chapter 2. Although the challenges associated with using transition metals in biological systems are apparent, creative design ultimately led to the development of a useful bioorthogonal catalyst / substrate pair. This system allows for real-time visualization of transition metal catalysis to generate a biologically active compound that releases photons when it encounters its intracellular enzyme target. Chapters 3 and 4 detail the synthesis and application of molecular transporter scaffolds. Chapter 3 introduces a novel organocatalytic ring-opening oligomerization of guanidinylated cyclic carbonates to access molecular transporter scaffolds in 1 step. This strategy allows for rapid access to molecular transporters of varying lengths. In addition, the synthesis allows for concomitant probe or drug attachment and the carbonate-based backbones of the resulting transporters are biodegradable on a timescale allowing for cellular uptake and intracellular degradation. The ability of molecular transporters to cross not only cell membranes, but also cell walls, is discussed in Chapter 4. These studies focused on the delivery of small molecules and proteins across the algal cell wall and cell membrane barriers using D-octaarginine-based molecular transporters. With this method, it was shown that fluorescein-octaarginine conjugates were able to cross these barriers in a variety of algal species from the class Chlorophyceae, although several species showed no uptake or only cell surface staining. It was also shown in the algal model organism Chlamydomonas reinhardtii that octaarginine-protein conjugates could cross the cell wall and cell membrane barriers to deliver a functional protein to the intracellular algal space.

Keywords: Chemistry
Advisor: Wender Paul A. primary advisor. Thesis advisor
Trost Barry M. advisor. Thesis advisor
Waymouth Robert M. advisor. Thesis advisor