Electronic Theses and Dissertations

Date of Award

1-1-2022

Document Type

Dissertation

Degree Name

Ph.D. in Chemistry

Department

Chemistry and Biochemistry

First Advisor

Davita L. Watkins

Second Advisor

Daniell L. Mattern

Third Advisor

James V. Cizdziel

Relational Format

dissertation/thesis

Abstract

It is difficult to overstate the importance of heterocycles in many fields of science (including organic, inorganic, pharmaceutical, medicinal, and material science). Due to their remarkable potential for being involved in a vast array of reactions, heterocyclic molecules make up the majority of pharmaceuticals as well as more than half of all natural products. Moreover, nature widely uses heterocycles, and scientists learned to imitate nature by incorporating them into drug molecules to enhance their biological activity. In this research work emphasize the use of heterocycles in biomedical applications.

The first study presents the design, synthesis, and computational evaluation of four novel diazine-based histone deacetylase inhibitors (HDACis), anticancer agents that inhibit histone deacetylases during DNA expression regulation. The targets of interest (TOI) are analogues of panobinostat, one of the most potent and versatile HDACi reported. By simply replacing the phenyl core of panobinostat with that of a diazine derivative (pyridazines, pyrimidines and pyrazines). Docking studies against HDAC2 and HDAC8 revealed that the four analogues exhibit inhibition activities comparable to that of panobinostat and may have increased interactions at the binding pockets, thus leading to better therapeutic activity.

The next study incorporates heterocycles into fluorophore scaffolds for NIR bio imaging applications. Here we designed four symmetrical donor-acceptor-donor (DAD) molecules based on isoindigo: II-EDOT-TPA, II-FURAN-TPA, II-THIO-TPA, and II-MePyr-TPA. Photophysical, electrochemical, and computational analysis was conducted to investigate the effect of heterocyclic donor units on the II-X-TPA derivatives. Electron density distribution maps indicated intramolecular charge transfer (ICT). Theoretical studies confirmed the experimental HOMO energies trend and demonstrated their importance in understanding each heterocycles’ donor ability. Stokes shifts of up to ∼178 nm were observed, whereas absorptions and emissions were shifted deeper into the NIR region resulting from ICT. Results demonstrate the importance of heterocyclic donors in the development of efficient fluorescence imaging (FI) agents.

In our final study, we evaluate the effects of heterocycles on the molecular structure of dye-polymer conjugates for NIR bioimaging. Here we use II-EDOT-TPA as a preliminary candidate for biological evaluations and highlight its exceptional photophysical properties that can be tuned via aggregation behavior. II-EDOT-TPA is encapsulated using a linear dendritic block copolymer (LDBC). In parallel, a polyethylene glycol derivative (PEG-II-EDOT-TPA) was synthesized. The self-assembly and colloidal properties of both nanoaggregates were comparatively assessed. Photophysical and morphological characterization of the LDBC encapsulated II-EDOT-TPA and PEG-II-EDOT-TPA nanoaggregates was performed, which showed the photophysical and morphological properties differed greatly when comparing the two. Both nanoaggregate types were incubated with HEK-293 cells in order to measure cell viability and perform confocal fluorescence microscopy. This work provides fascinating insights into NIR fluorophore design and methods to effectively alter the photophysical and morphological properties of the nanoaggregates for bio-imaging purposes. Overall, this dissertation describes the effects of heterocycles on biologically relevant molecules and provides design strategies for next-generation NIR materials.

Available for download on Wednesday, August 16, 2023

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