Date on Master's Thesis/Doctoral Dissertation

8-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Degree Program

Chemistry, PhD

Committee Chair

Luzzio, Frederick

Committee Member

Buchanan, Robert

Committee Member

Thompson, Lee

Committee Member

Onorata, Amber

Author's Keywords

Reactions; nitrogen and sulfur; heterocyclic; pharmacophores; medicinal; isoindolinones

Abstract

Nitrogen and sulfur-containing heterocycles remain significant classes of compounds in the field of medicinal and organic chemistry due to their unique structural features and diverse biological activities which make them of considerable interest for drug discovery and development. Notable examples of the nitrogen containing heterocycles include the phthalimide and glutarimide rings present in thalidomide. Thalidomide, a potent small-molecule therapeutic agent, precipitated a significant global drug crisis due to its teratogenicity, causing congenital malformations in phocomelia infants, which remains unrivaled over half a century ago. Currently, thalidomide derivatives are extensively utilized in the therapeutic management of various hematological malignancies. Recent investigations have elucidated that both thalidomide and its immunomodulatory imide drugs (IMiDs), function as protein degraders, interacting with cereblon (CRBN), the substrate-recognition receptor within a complex-type E3 ubiquitin ligase system. This interaction leads to the degradation of neo-substrates that do not originally belong to their substrate profile. Additionally, thalidomide and its analogs are being employed in the development of proteolysis-targeting chimeras (PROTACs), which represent a novel class of chimeric protein degraders. The mechanism of action mediated by protein degraders facilitates a groundbreaking approach to drug function and proteolysis, with the potential to selectively target a range of therapeutic proteins, including those previously deemed undruggable. This complex history illustrates the duality of thalidomide as both a cautionary tale and a beacon for future advancements in drug therapy. The synthesis of bioactive molecules as potential therapeutic agents to fulfill the broader theme of medicinal chemistry and drug discovery effort is reported. Most of these bioactive molecules mimic compounds that derive their source from natural products such as plants, animals and microorganisms. A chemoselective reduction protocol developed in these laboratories led to the late-stage acylation which introduces the possibility of accessing intermediate molecules that could serve as substrates for the assembly of PROTACs. Mother Nature is not able to supply from her repertoire all the compounds which have found use in addressing the challenges of biomedicine. As a result, Synthetic organic chemists are prompted to design and synthesize various pharmaceutical leads to mimic what nature provides through a non-biogenic merger to access interesting scaffolds in the arena of pseudo-natural products. Inspired by our ongoing interest in the synthesis of heterocyclic compounds, we utilized N-acyliminium ion chemistry to access such pseudo-natural products from the isoindolinone scaffold, which originates from the corresponding phthalimides through a Gabriel type synthesis. Throughout such exploratory scientific studies have arisen the development of three oxidation protocols involving the use of nickel peroxide and the eco-friendlier iron-based oxidants and copper (II) acetate for the oxidation of selected substituted 3-hydroxylactams to their corresponding imide products. Both studies led to approaches to accessing C-N, and C-S bond forming reactions in making a series of phthalimide isoindolinone - derived isothiouronium salts and their corresponding sulfides which constitutes privileged scaffolds in the furtherance of drug discovery.

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