Date of Degree

6-2017

Document Type

Dissertation

Degree Name

Ph.D.

Program

Chemistry

Advisor

Charles Michael Drain

Committee Members

Nancy Greembaum

Shengping Zheng

Alexander Greer

Subject Categories

Chemistry | Medicinal-Pharmaceutical Chemistry | Organic Chemistry | Other Chemistry

Keywords

Chlorin, Porphyrin, Cycloaddition, Third Generation Porphyrin, Photodynamic Therapy, Fluorescence

Abstract

Chlorins are porphyrins missing a double bond. These pigments are optimal platforms for the development of novel dyes that display drug-like attributes such as photodynamic therapy (PDT) agents. More recently, it was demonstrated that chlorins can serve both as a PDT agent and as a modality for fluorescence or PET imaging. Thus, multifunctional chlorins eliminate the differences that may occur in specificity, uptake, and distribution between separate compounds or constructs for imaging and therapy. The overall goal of this dissertation is to take advantage of the reputed intrinsic attributes of chlorins as a viable tool in biomedical applications. In this endeavor, we demonstrate that three successive click reactions yield multifunctional chlorin platforms appended with either S-linked or O-linked polyethyleneglycol chains (S-PEG or O-PEG, respectively) and a carboxylate-linker to a free base of a pyrrolidine ring form from a 1,3-dipolar cycloaddition. This strategy allows rapid conjugation to biological and biotargeting motifs. As a demonstration, the soluble chlorin platforms were conjugated to lysozyme and to an amino terminated tether on a short oligonucleotide. These multi-purpose chlorins possess stability to bleaching and their photophysical properties allow use as biomolecular trackers, photodynamic therapy agents, and for fluorescence diagnostic imaging. Chelation with zinc(II) further modulates the photophysical properties. It is our desire that our studies and findings contribute to the body of knowledge of chemists, clinicians, technicians and physicians in a manner that sets a precedent as a stepping stone to produce the next generation of chlorins that are beneficial for diagnostics and treatment of human disease.

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