Date on Master's Thesis/Doctoral Dissertation

8-2021

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Degree Program

Chemistry, PhD

Committee Chair

Luzzio, Frederick

Committee Member

Handa, Sachin

Committee Member

Wilson, Andrew

Committee Member

Perlin, Michael

Author's Keywords

Organic; natural product; synthesis; anticancer; nucleoside antibiotic

Abstract

Medicinal chemistry interfaces synthetic organic chemistry, natural product chemistry and chemical biology, with a goal of yielding therapeutic agents. Natural products or compounds derived from natural sources such as plants, animals, and microorganisms, are often biologically active and render that compound a likely drug lead. For thousands of years humankind has utilized natural products for medicinal purposes and consequently scientists take advantage of both these compounds’ core structural characteristics and their modes of actions on selected targets as inspiration to develop therapeutics. Because the total synthesis of such complex molecules can be cumbersome and expensive, semi-synthetic methods on isolated natural products is preferred when diversifying specific structural components. A semi-synthetic strategy involving the derivatization of the naturally occurring neurotoxin annonacin, isolated from locally grown Asimina triloba, and the antiangiogenic activities of such derivatives is reported.1 Annonacin is a member of the annonaceous acetogenin group of compounds and is a potent inhibitor of the mitochondrial Complex I.2 As a confirmed neurotoxin, annonacin causes neuronal cell death and induces the redistribution of tau proteins from axons to cell bodies, leading to neurological diseases termed tauopathies.3 Annonacin has also been studied for its role in inhibiting angiogenesis, specifically through inhibition of the hypoxia-inducible factor-1/vascular endothelial growth factor pathway.4 The syntheses of two deoxytetraazido analogues of annonacin is reported with the late-stage azidation introducing the possibility of reactive nitrogen-based analogue synthesis. Annonacin and the tetraazido analogues were submitted to the rat aortic ring (RAR) bioassay to evaluate antiangiogenic activity and annonacin was found to inhibit angiogenesis with an IC50 of 3 μM. Annonacin was also submitted to a parallel artificial membrane permeability assay (PAMPA) to assess membrane penetration compared to benchmark compounds. The efficient access and extraction processes of natural annonacin allows for further derivatizations to evaluate a variety of potential analogues for further biological studies in cancer and neuroscience. The serious threat posed by multi-drug resistant bacteria has gained interest and there is a need to discover new antibacterial therapies with novel mechanisms of action.5 Crucial for bacterial survival are the glycoconjugates that constitute the bacterial cell walls. Phosphoglycosyl transferases (PGTs) catalyze the first membrane-committed steps of glycoconjugate biosynthesis and represent ideal targets for novel antibacterial therapeutics.6 Naturally occurring nucleoside antibiotics are inhibitors of PGTs but unfortunately their structures are complex, and their total synthesis require large multi-step syntheses. Therefore, a synthetic approach implementing the design of simpler, more accessible nucleoside analogues is advantageous. Utilizing a modular approach, the synthesis of a diverse group of compounds can be performed via a connecting scaffold linked to the uridine moiety native to the natural structures. The synthetic evolution of this design is provided, whereby the use of a Henry reaction to provide the desired carbon-carbon bond-forming step was initially applied to allow for the coupling of various structures to the uridine moiety. The developments that arose from such studies lead to synthetic reports involving the selective reduction of nitroarenes with aluminum amalgam and the chemoenzymatic preparation of chiral oxazolines.7,8 Both of which provide access to the inclusion of heterocycles for potential uses in drug developments. Inspired by both our work with heterocycles and the growing incorporation of such in drug leads, we designed and synthesized a new class of nucleoside analogues incorporating an oxazole ring system attached to both the uridine core and functionalized aryl-substituents. The oxazole structure is considered a prime scaffold for medicinal molecules as it offers diverse interactions such as hydrogen bonding, metal coordination, p-p stacking and more. Furthermore, the functionalization of the aryl-substituents offers the ability to include additional moieties including various lipids, sugars, and amino acids to increase the structural diversity of the target compounds. The antibacterial activity of the novel uridine-derived analogues will offer insight into the structural features required and synthetic modifications can be performed.

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