Over the past decades, numerous studies have shown that curcumin has potent biological activities. As a potential chemopreventing agent, curcumin was demonstrated to exert anti-cancer effects in both in vitro and in vivo studies. However, low bioavailability of curcumin limited human clinical trials and its application to be formulated as therapeutics. In this thesis, we will summarize the anti-cancer effects of curcumin in animal studies and clinical trials. In addition, an SAR study will be introduced to elucidate the mechanism of curcumin degradation at physiological pH. We synthesized various curcumin analogues and compared their stability in phosphate buffer using HPLC and colorimetry assay. The results not only demonstrated that the -OH group and the methoxy group play a critical role in stability of curcumin in physiological environment, but also support the proposed mechanism of phenolic radical formation by which curcumin degrades to its major product bicyclopentadione.

<p> The study of proteasome is a rapidly evolving field with multifaceted implications in neuroscience, aging, and cancer. Recent developments structural biology of the proteasome machinery has catapulted the drug discovery and targeted protein degradation. The success of proteasome inhibitors like Bortezomib and Ixazomib has also led to new interests in developing more precise inhibitors for the various proteasome isoforms. Proteasome activation is a relatively new field, and much has to be done in the field. The 20S CP is an emerging target in chemical biology and drug discovery for its implications in maintaining protein homeostasis and immune regulation. The central theme of the thesis is to study the proteasome in cellular contexts to develop new chemical biology tools to study the proteasome and its modulation by small molecules and probes in cellular contexts to ameliorate protein accumulation-mediated neurodegeneration </p>

<p>Natural products, along with natural product derivatives, are known to be at the root of the development of many pharmaceuticals, oftentimes showing unique bioactivity against interesting targets. Specifically, natural products containing furans show activity against a variety of diseases including fungal infections, and cancers. It is hypothesized that unknown natural products containing furans could show more potent or other biological activities. However, it is challenging to discover and isolate these small molecules from cell supernatant. The work described herein showcases the development of a molecular probe that can covalently attach to furan moieties via a [4 + 2] Diels-Alder cycloaddition, making them easily identifiable on liquid chromatography mass spectroscopy (LC-MS). The molecular probe, which undergoes this reaction with a variety of furans, was designed with both a UV-tag and a mass tag to enable easy identification. The probe has been tested with a variety of purified furans, including natural products, methylenomycin furan (MMF) hormones, and MMF derivatives. Moreover, work has begun to test the molecular probe in cell supernatants. </p>

<p>An original palladium-catalyzed ring opening carbonylative lactonization of synthetic available hydroxycyclopropanols was reported to efficiently synthesize tetrahydrofuran (THF) and tetrahydropyran (THP)-fused bicyclic γ-lactones, two unique scaffolds often found in quite a few natural products. This new developed reaction features mild reaction conditions, good functional group tolerability, and the scale-up abilities. The synthetic application was demonstrated in a short total synthesis of (±)-Paeonilide. The THF-fused bicyclic γ-lactone products can be readily diversified into some medicinally important structures, which further broadens the application of this new carbonylation approach.</p> <p>The first total synthesis of Phleghenrine A was reported. This synthesis features an unprecedented inverse electron-demand Diels-Alder reaction and Tiffeneau-Demjanov ring expansion to rapidly construct bicyclo[3,2,2]-nonane core structure of Phleghenrine alkaloids. Two Diels-Alder adducts were synthesized, which were the synthetic precursors for divergent synthesis of Phleghenrine A and B, respectively.</p>

<p>  </p> <p>Quinolines are benzopyridine complexes present in many modern antimalarial, anticancer, anti-inflammatory, antimicrobial, and other useful pharmaceuticals and natural products.1,2 Quinolines form the scaffold for many potent anticancer drugs; this is because quinolines can undergo both nucleophilic and electrophilic substitution reactions, can be ingested and inhaled by humans without any harm, and possess a great deal of biological importance.3 My research has focused on synthesizing 3H-pyrazolo[4,3-f]quinoline analogs. The 3H-pyrazolo[4,3-f]quinoline scaffold was modified using various amine groups to obtain amide analogs as well as see how a change in the scaffold affects the anticancer activity of the synthesized complexes by screening them against kinases such as FLT3, CDK2, CDK4, and CDK9 to see if they are effective inhibitors. The synthesized complexes were then characterized using proton, carbon NMR and FTIR spectroscopy.</p>

<p> Over 40 years since the emergence of the AIDS epidemic and still no cure exists for AIDS or its causative HIV-1 infection. Protease inhibitors are an integral part of the most effective treatment regimen for HIV-1 infected patients known as combination antiretroviral therapy (cART), which is extremely effective at decreasing viral loads to nearly undetectable levels. One of the most alarming issues with current treatments is the emergence of multi-drug resistant strains. Even darunavir, which has shown exceptional activity against drug resistant strains, has experienced this issue. Herein we designed a novel series of heterocyclic based P2 ligand HIV-1 protease inhibitors based on kinase inhibitors such as imatinib and dasatinib. These inhibitors were designed to promote hydrogen bonding with the peptide backbone atoms of HIV-1 protease. Compounds were synthesized, biologically evaluated, and underwent X-ray structural studies. Inhibitors displayed activity as low as sub-nanomolar potency and low nanomolar antiviral activity. Important ligand-binding site interactions were determined through two X-ray crystal structures.</p> <p>Emergence of SARS-CoV-2 at the end of 2019 resulted in a global pandemic that has affected millions. Researchers all over the world turned their attention to developing drug therapies aimed at preventing and treating the viral infection. One such target became the main viral protease, or 3-chymotrypsin like protease (3CLpro). 3CLpro is an essential viral enzyme responsible for polypeptide cleavage during the viral replication cycle to produce 16 nonstructural proteins (nsps). Thus, it has been a highly researched area for effective SARS-CoV-2 drug therapies. Therefore, we designed, synthesized, and biologically evaluated a series of competitive reversible SARS-CoV-2 3CLpro inhibitors. </p>

<p>Radical polymers bearing open-shell moieties at their pendant sites offer potential advantages in processing, stability, and optoelectronic properties compared to conventional doped conjugated polymers. The rapid development of radical-containing polymers has occurred across various applications in energy storage devices and electronic systems. However, significant gaps still exist in understanding the key structure-property-function relationships governing charge transport phenomena in these materials. Most reported radical conductors primarily rely on (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) radicals, which raises fundamental questions about the ultimate limits of charge transport capabilities and the impact of radical chemistry choice on material deficiencies. Moreover, an understanding gap persists when it comes to connecting the computable electronic features of individual units and the charge transport behavior of these materials in condensed phases. This dissertation seeks to address these gaps by developing a molecular understanding of charge transport in radical-bearing materials through a combined computational and experimental approach.</p> <p><br></p> <p>The initial stage of this dissertation investigated the impact of dimeric orientations and interactions on charge transport by conducting a density functional theory (DFT) study on a diverse set of open-shell chemistries relevant to radical conductors. The results revealed the anomalously high reorganization energies of the TEMPO radical due to strong spin-localization, which may result in inefficient charge transfer. Additionally, a significant mismatch was identified between dimeric conformations favored by intermolecular interactions and those maximizing charge transfer. This study provided new insights into the impact of steric hindrance and spin delocalization on elementary charge transfer steps and suggests opportunities for exploiting directing interactions to enhance charge transport in these materials.</p> <p><br></p> <p>Building upon these findings, we established a direct relationship between the molecular architecture and intrinsic charge transport properties. To accomplish this, single-molecule characterization methods (i.e., break junction techniques) were implemented to study the nanoscale charge transport properties of radical-containing oligomeric nonconjugated molecules. Temperature-dependent measurements and molecular modeling revealed that the presence of radicals improves tunneling at the nanoscale. Integrating open-shell moieties into nonconjugated molecular structures significantly enhances charge transport, thereby characterizing charge transport through radicals at the individual level and opening new avenues for implementing molecular engineering in the field of nanoelectronics.</p> <p><br></p> <p>To further connect the electronic properties of repeat units with the condensed-phase charge transport behavior of radical polymers, a quantum chemical study was carried out to explicitly evaluate the interplay between polymer design, open-shell chemistries, and intramolecular charge transport. After comprehensive conformational sampling of the configurational space of radical polymers, we determined their anticipated intrachain charge transport values by utilizing graph-based transport metrics. We show that charge transport in radical polymers primarily hinges on the choice of radical chemistry, which in turn affects the optimal selection of backbone chemistry and spacer group to ensure proper radical alignment and prevent undesired trap states. These findings highlight the potential for a substantial synthetic exploration in radical polymers for radical conductors.</p> <p><br></p> <p>In summary, this dissertation provides compelling evidence of radical-mediated charge transport and suggests potential design guidelines to enhance the charge transfer behavior of radical-containing polymer materials. Furthermore, these findings inform future research directions in fine-tuning molecular engineering and modular design to enable the development of radical-based materials and their end-use applications in organic electronics.</p>

<p dir="ltr">Ring strain is the driving force for numerous ring-opening reactions of three- and four-membered heterocycles. By comparison, five-membered heterocycles lack this thermodynamic driving force. As a result, only a few methods exist for the ring-opening of five-membered heterocycles using transition metal catalysts. For unstrained and unactivated 2,5-dihydrofurans this is achieved via a β-O elimination process, wherein, gaining selectivity over a competing β-H elimination is challenging. We report a novel strategy for the asymmetric ring-opening of 2,5-dihydrofurans with dichloroalkenes utilizing an earth-abundant cobalt catalyst. We propose that the dichloroalkenes form reactive vinylidene intermediates with the chiral catalyst, followed by a [2+2] cycloaddition with the heterocyclic alkene. This cobaltacyclobutane exclusively undergoes an outer-sphere β-O elimination assisted by zinc halide. Alternative inner-sphere β-O and β-H elimination pathways are inaccessible from this four-membered metallacycle. This is followed by a transmetallation step to form a zinc metallacycle, which subsequently gives rise to homoallylic alcohols, upon quenching, with high diastero- and enantioselectivity. Additionally, the organozinc intermediate can be trapped in situ by various electrophiles for further derivatizations. DFT model predicts the origin of the high diastereo- as well as enantioselectivity observed in the reaction.</p><p dir="ltr">Furthermore, the cobaltacyclobutane intermediate serves as a dynamic platform, facilitating access to a diverse array of products depending on the alkene partners employed. Utilizing chiral allylic alcohols as alkene partners leads to the translation of stereochemical information enabling the stereospecific synthesis of both <i>E</i>- and <i>Z</i>-isomers of alkenes. Alkenes are important motifs found in various natural products and bioactive compounds. A catalytic approach for the precise control of the alkene geometry is highly valuable since the stereochemistry of alkenes plays a pivotal role in determining the properties of molecules. Our strategy provides access to organozinc dienes which could be functionalized further to form highly substituted 1,4-skipped dienes. Additionally, meso-diols can undergo a desymmetrizing β-O elimination from the cobaltacyclobutane intermediate yielding chiral cyclopentenols with contiguous stereocenters</p>

<p dir="ltr">A study on the impact of the position of the attachment of the photolabile, backbone amide linker, 4-formyl-3-hydroxy-5-nitrobenzoic acid, on the synthesis of a model cyclic pentapeptide was conducted. The peptide was synthesized on a solid support and cleaved photolytically. The crude product was analyzed for the effect of changing position by LC/MS, 1HNMR, and yield. The target peptide could not be identified convincingly by LC/MS or NMR. It was observed that attachment of the backbone amide linker to the N alpha of tyrosine provided the highest crude product yield.</p>

<p> Dramatic advances over the past decade have occurred in the use of cryogenic electron microscopy (cryoEM) to elucidate the structures of macromolecules at atomic resolution. Unfortunately, the sample preparation process is one of the most time-consuming and empirical methods in the cryoEM workflow. Each sample must be tediously optimized to resolve issues with particle aggregation, ice quality, particle orientation, and particle density to enable high-resolution reconstruction analysis. Post-polymerization modifications of synthetic aqueous bottlebrushes offer a promising approach to streamline the workflow for cryoEM sample preparation. Our approach utilizes synthetic bottlebrush materials comprised of flexible polymer scaffolds bearing grafted side-chains, armed with high affinity ligands at the distal termini of the grafted polymers along the polymer core. Development of water-soluble one-dimensional (1D) synthetic bottlebrush polymers has led to new advancements in the biomaterials, antimicrobial, nanomedicine, and responsive materials fields. These synthetic bottlebrush materials are favorable as they confer properties that linear polymers and small molecules cannot achieve. Moreover, structural manipulations employed during post-polymerization processes can afford bottlebrush polymers with distinguishable topologies for advanced functions. These 1D constructs can be synthesized by atom transfer radical polymerization (ATRP), reversible addition- fragmentation chain-transfer polymerization (RAFT), ring-opening polymerization (ROP), cationic ring-opening polymerization (CROP), anionic ring-opening polymerization (AROP) or ring opening metathesis polymerization (ROMP). The chemical composition of the molecule, number of monomer repeats, grafting density and topology influence the morphology and function of polymer brushes. Elongated, vesicular or micellar morphologies can be specifically tuned for the desired application of the material. The morphology of the polymers can also be manipulated by concentration effects. The morphologies of amphiphilic bottlebrush materials specifically, can typically be influenced by structural topology, solvent choice, or external conditions. ROMP is a living polymerization mechanism that can suffer from catalytic backbiting, causing a loss of livingness. The synthesis of aqueous bottlebrush polymers and the comparison of morphologies via AUC, DLS, AFM and TEM will be presented in this dissertation. The synthetic amphiphilic bottlebrush polymer family presented suffered a loss of livingness and ultimately displayed distinct morphologies, relative to chemical composition, solvent, and ultimately polymerization time. Post-polymerization 11 modifications such as backbone hydrolysis and single-walled carbon nanotube complexation promoted even more unique morphologies of bottlebrushes. These synthetic materials indicate use as promising reagents for cryoEM sample preparation.  </p>