Controlled synthesis of complex organic molecules and nanomaterials: Engaging chemical properties for biological applications

Kincanon, Maegen M.

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https://hdl.handle.net/2142/124209 Copy

Description

Title

Controlled synthesis of complex organic molecules and nanomaterials: Engaging chemical properties for biological applications

Author(s)

Kincanon, Maegen M.

Issue Date

2024-03-25

Director of Research (if dissertation) or Advisor (if thesis)

Murphy, Catherine J

Doctoral Committee Chair(s)

Murphy, Catherine J

Committee Member(s)

• Burke, Martin D
• Mirica, Liviu M
• Manesis, Anastasia

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• furanocembranoid
• cembranoid
• organic
• total synthesis
• bielschowskysin
• verrillin
• amaryllidaceae
• alkaloids
• pancratistatin
• narciclasine
• lycoricidine
• deoxy-pancratistatin
• self-assembly
• gold
• nanorod
• nanoparticle
• streptavidin
• biotin
• temozolide
• glioblastoma
• MTAB
• MoTAB
• MeTAB
• MiTAB
• mvGlu
• cancer

Abstract

Physiologically, the body requires a specific balance of chemical nutrients to function properly. Any alterations to this balance can create detrimental effects. During cancer, the mutation and quick replication of abnormal or damaged cells causes widespread unbalance within the body, invading healthy tissue, redirecting nutrient pathways, and altering the physiological pH. To combat these changes medicinal chemistry has aimed to create a therapeutic that selectively terminates the tumor cells. The objective of this dissertation is to use a diverse subset of strategies to aid in the discovery of anticancer therapeutics. In Chapter 1, the history of medicine and its chemically synthesized methods for the treatment of cancer will be discussed. Background on the mechanism of cancer, use of organic and nanomaterials, and the biological utility of these materials will be discussed. Insights into the benefits and needs of future development will demonstrate the importance of the research included in this dissertation. Chapter 2 focuses on the use of traditional organic synthesis of bioactive marine nature products. Isolated from the soft octocorals Pseudopterogorgia kallos and Pseudopterogorgia bipinnata, respectively, bielschowskysin and verrillin represent complex, novel carbon skeletons that have stumped chemists for decades. However, the intricate structure and potential cancer treating properties of these structures remain of interest. Herein, synthetic strategies and stereochemical considerations towards the synthesis of each of these highly oxygenated, strained macrocycles will be discussed. Chapter 3 takes an alternative approach to anticancer drug development, derivatizing known cytotoxic Amaryllidaceae alkaloids pancratistatin, (7)-deoxypancratistatin, narciclasine, and lycoricidine in hopes of increasing their solubility, lipophilicity, and metabolic stability. Derivatization consists of three strategies. A prodrug strategy, utilizing amino acids, carbamates, formates, esters, and ether functional groups, aims to alter exposed functional groups while the alkaloids undergo uptake and then cleave in vivo to expose the original alkaloid structure. An analog strategy, as possible through determination of hydroxy functionalization order, aims to undergo decarboxylative photochemical C-C bond formation at the C1 position of pancratistatin and (7)-deoxypancratistain and C2 position of narciclasine and lycoricidine to obtain point modifications of the alkaloids. Lastly, a photoisomerization strategy, altering the stereochemical composition of the alkaloids aims to modify potential hydrogen bonding and decrease the flatness of the alkaloids. Chapter 4 marks a shift from organic based drug development to the use of gold nanoparticles. Exploring the properties of nanoparticle size using nanorods of dimensions 34 ± 7 × 6.3 ± 0.8 nm, 89 ± 8 × 19 ± 2 nm, 112 ± 8 × 26 ± 1 nm, and 151 ± 9 × 39 ± 2 nm, the ability to selectively functionalize the ends v. the sides of the nanorods with organic-based ligands is examined. A streptavidin-biotin self-assembly strategy is taken to examine the selectivity of the end v. side to produce visible proof of the selective functionalization. Based on a combination of ligand-density and surface curvature, it is found that the selectivity of functionalization decreases with nanorod size. Additionally, we see that self-assembly elongation increases with nanorod size. Chapter 5 utilizes nanorods of dimensions 24 ± 3 × 6.0 ± 0.8 nm coated with glioblastoma drug temozolomide, tumor nutrient glutamine, and a mixture of the two. To account for heterogeneity of glioblastoma tumors, nanorods, with a poly(ethylene)glycol chain attaching the treatment molecules at molecular weights of 1 kDa, 1.5 kDa, 4 kDa, and 6 kDa, are exposed to tumor lines T98G, U87MG, and U138MG. Through cell uptake and cytotoxicity assays, the extentiv of how well addition of a glutamine source and use of a nanorod as a drug carrier improve the use of temozolomide as a drug treatment. An additional comparison to free temozolomide, temozolomide ligand without the nanoparticle, glutamic acid, and the glutamic acid ligand without the nanoparticle, the enhanced stability of the drug when attached to nanoparticles will be examined. Future potential of this strategy will then be discussed. Finally, Chapter 6 looks to the development of new ligands to be attached to the gold nanoparticles. The synthesis of hydrocarbon ligand chains MoTAB and MeTAB looks to expand knowledge on how ligand size alters packing density, ligand-ligand interactions, and ligand orientation on nanoparticles. Gaining this knowledge can help strategize future ligand development for various biological applications. The synthesis of a poly(ethylene)glycol containing mvGlu via a triazole attachment aims to increase selectivity and localization to improve mvGlu’s potential towards cancer treatment.

Graduation Semester

2024-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2024 Maegen Kincanon

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