Chemistry & Biochemistry

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Research from the Department of Chemistry & Biochemistry. The department website may be found at https://www.ndsu.edu/chemistry/

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Diastereoselective Conjugate Radical Additions to ~-Pyrones
(North Dakota State University, 2009) Yu, Arvin Zillion
A convenient protocol for functionalization of ~-pyrones has been developed. Conjugate radical addition and tandem addition-trapping protocols allowed accessing highly substituted pyrones in a single operation with high selectivity. Different radical sources were utilized in the reaction. nOe experiments were performed to confirm the relative stereochemistry of the substituents in the conjugate addition products. Initial studies on the enantioselectivity of the reaction were carried out. Unfortunately, the catalysts chosen for the initial studies did not show any promise regarding enantioselectivity.
Differential Modulation of the Structural and Functional Characteristics of Human Matrix Metalloproteinase Isozymes upon Binding to Different Ligands
(North Dakota State University, 2010) Ganguly, Bratati
Matrix metalloproteinases (MMPs) are a family of Zn2 + -dependent, Ca2 + -containing endoproteinases involved in tissue remodeling and degradation of the extracellular matrix (ECM). Human MMP isozymes are known to be involved in the progression and metastasis of many diseases like cancer, Alzheimer's, and etc. The different nanoparticles (e.g. gold nanoparticles, liposomes, and charged quantum dots) used in this study provides insights into nanoparticle-induced differential modulation in the structural-functional characteristics of MMP 7, 9 and 10 for better therapeutic intervention. To demonstrate the relationship between the rigid and flexible surfaces on the differential modulation of functional and structural characteristics of MMP-7, polylysine (PLL) and cationic gold nanoparticles (Au-CNP) were selected as representative examples. These cationic nano-structures were expected to serve as "soft" (flexible) and ''rigid" (hard) ligands, respectively. Steady-state kinetic analysis demonstrated that PLL induces activation and inhibition of MMP-7 at stoichiometric and super-stoichiometric concentrations respectively. Circular Dichroism spectroscopy was used to confirm that binding of Au-CNP to MMP-7 induces denaturation of the protein. In pursuit of understanding the molecular origin of the intrinsic selectivity in binding of human MMP isozymes to differently charged lipid membranes, steady-state kinetic studies and intrinsic tryptophan quenching studies were carried out. Results demonstrated that differently charged lipid membranes bind to all three MMPs; phosphotidylserine (POPS) liposomes are selective for MMP-7. The bipolar distribution of negative and positive charges on the surface of this enzyme dictates the binding of liposomes and perturbation of catalytic activity. An attempt to explain the molecular rationale for alternative binding modes of differently charged quantum dots (QDs) to the three MMPs, steady-state tryptophan quenching, steady-state kinetics, and time-resolved fluorescence measurements were carried out. Differently charged QDs bind to all the three MMP isozymes. Enzyme activity of these MMPs was perturbed upon binding to cationic and anionic QDs. Binding of MMPs to the differently charged QDs is reversible and is mediated via electrostatic interactions. Analysis of time-resolved fluorescence data indicates that the protein expenences different micro-environments, due to different distribution of intrinsic tryptophan residues (buried and exposed) on MMP isozymes or the existence of two distinct conformations of the protein. Binding to charged QDs perturbs enzyme activity of MMPs either by restricting the access of the substrate to the active-site or through allosteric modulation. In order to develop new isozyme-selective inhibitors, small molecule inhibitors (SMis) were designed, synthesized and screened for MMP-7, 9 and 10. Results indicate that hydroxamates and carboxylates are preferred SMis. Binding preference is based on either the micro-environments of the active-site pockets.
Examining Thieno[3,4-b]pyrazine Through a Multifaceted Lens: From Extended Ring Functionalization to Ambipolar-Acceptor Copolymers
(North Dakota State University, 2022) Culver, Evan
A class of materials known as conjugated polymers (CPs) has been shown to integrate the physical properties of organic plastics such as low-weight, flexibility, and synthetic modularity with electronic semiconducting properties typically found in inorganic materials. While a variety of parameters determine the resultant material’s conductivity, a crucial factor is the bandgap (Eg). Specifically, thieno[3,4-b]pyrazine (TP) has found success in generating low Eg CPs (i.e. Eg < 1.5 eV), largely in part due to its ambipolar identity. Two strategies to achieve Eg values < 1 eV include extending the conjugation of TP through ring fusion and pairing TP with strong electron accepting moieties. The investigation into extended ring TPs as low bandgap homopolymers was initially pursued with the synthesis of poly(acenaphtho[1,2-b]thieno[3,4-e]pyrazine), a record setting low Eg homopolymer. Upon this realization of driving Eg¬ values down through ring fusion on the pyrazine portion of TP, additional analogues were considered with 2λ4δ2-dithieno[3,4-b:3’,4’-e]pyrazine as one of the most promising candidates due to its predicted Eg of 0.14 eV. Efforts into this research have produced a variety of precursors and analogues, adding to the family of TPs for further study. A second strategy for Eg reduction is through the pairing of electronically mismatched units known as donors and acceptors. While this does reduce Eg, the underlying principles of the cause is disputed. Thus, to further understand the interactions in these types of copolymer systems, a small molecule study was designed with a strong donor, a strong acceptor, and the ambipolar unit TP in which six possible dimer configurations were synthesized and analyzed to determine the extent of donor-acceptor interactions. Lastly, an investigation into TP-acceptor alternating copolymers was carried out by pairing TP with two acceptors of varying accepting strength and contributions to polymer solubility. Because of the atypical design of these copolymers, a relatively new cross-coupling method known as direct arylation polymerization was used in their synthesis. The optimization of which produced a CP with an Eg of 0.93 eV. These results thus provide evidence for a new design motif for low bandgap CPs that further refines our understanding of donor-acceptor relationships.
Influence of Active Site Ligands and Nanoparticle Surfaces on Human Carbonic Anhydrase Isozymes
(North Dakota State University, 2010) Manokaran, Sumathra
Carbonic anhydrase (CA) is an ubiquitously distributed zinc containing metallo enzyme that catalyzes the reversible hydration of carbon dioxide to form bicarbonate and a proton. Existence of 16 isoenzymes of CA in the animal kingdom has been known so far with varying subcellular and tissue distributions. Due to their involvement in many physiological and pathological processes, these isozymes have been the target for drug designing for the past 6 decades. The present study was designed with the aim of understanding the effect of active site ligands and nanoparticle surfaces on human carbonic anhydrase isozymes. In an effort to identify a fluorescent probe for carbonic anhydrases, the quantum yields and binding affinities of a variety of naphthalenesulfonamide derivatives with human carbonic anhydrase isozymes (hCAs) were determined. In this pursuit, a highly sensitive fluorescent probe, JB2-48 was identified. Experiments involving the above flurophore with hCA I unraveled the contributions of the sulfonamide moiety and the hydrophobic regions of the ligand structure on the spectral, kinetic, and thermodynamic properties of the enzyme-ligand complex. The fluorescence data revealed that the deprotonation of the sulfonamide moiety of the enzyme-bound ligand increases the fluorescence emission intensity as well as the lifetime of the ligand. This is manifested via the electrostatic interaction between the active site resident Zn2 + cofactor and the negatively charged sulfonamide group of the ligand. Evidence was provided that the anionic and neutral forms of JB2-48 are stabilized by the complementary microscopic/conformational states of the enzyme. Investigations on the binding of the sulfonamide inhibitor, benzene sulfonamide (BS), with hCA isozymes II and VII, revealed that the binding is stabilized by polar interactions in the former case and hydrophobic interactions in the latter case. In addition, it was found that the binding of BS with hCA II is enthalpically driven at low temperatures, whereas it is entropically driven for its binding with hCA VII. Due to the prevalence of bipolar distribution of charges on hCA XII, the effects of the interaction of differently charged quantum dots, liposomes and polylysine on hCA XII were investigated. These charged particles were found to differently modulate the active site of the enzyme. The data revealed that whereas poly lysine and liposomes exhibited no influence on the binding and catalytic features of the enzyme, quantum dots had significant influence on the above features. Arguments were presented that the above differential feature exhibited by quantum dots, liposomes and poly lysine is encoded in the rigidity versus flexibility of the charged molecules. Studies on the denaturation of hCA isozymes II and XII unraveled their unfolding mechanism. It was found that the unfolding ofhCA XII followed a simple two state model from native to unfolded state; however hCA II unfolded with the formation of a stable intermediate.
Mechanistic Investigation of Catalytic Chlorite Decomposition by Chlorite Dismutase
(North Dakota State University, 2021) Geeraerts, Zachary
Water purification processes often involve chlorine-based disinfectants which consequently leads to formation of chloro oxyanions (ClOx−), potent water-soluble oxidizing agents. These chlorine species are kinetically stable in water which allows them to persist and buildup to hazardous concentrations. Chlorite (ClO2−), a common contaminant in water purification processes, has been labeled as a top ten major water contaminant by the United States Environmental Protection Agency. Therefore, there is pressing interest in developing methods for removal of ClOx− species from water. Chlorite dismutases are heme b dependent enzymes that catalyze the unimolecular decomposition of ClO2− into chloride (Cl−) and molecular oxygen (O2) with remarkable efficiency. Catalytic O−O bond formation is a rare process in Nature as the only other well characterized example occurs in photosystems II. Clds are great candidates for bioremediation purposes and an excellent model for investigating catalytic O−O bond formation as the catalyzed reaction is not hindered by the need to pump protons. The goal of this work is to gain mechanistic insight into catalytic ClO2− decomposition by Cld and to investigate the structural features that tune the reaction pathway for productive O2 evolution. Cld from Klebsiella pneumoniae and Dechloromonas aromatica are the representatives used in this work. Since heme is the cofactor in these enzymes, a variety of spectroscopic tools have been utilized to probe the electrostatic landscape of the active site. Vibrational (resonance Raman and infrared), optical absorbance, and electron paramagnetic resonance spectroscopies were used to characterize the heme environment. Various ligand complexes were prepared to probe non-reactionary states of the enzymes while reactionary states were directly observed through use of stopped-flow spectrophotometry and freeze-quenched methods. Site directed mutagenesis studies of key amino acids were performed in combination with the above techniques to elucidate how changes in the electronics of the heme pocket alter catalytic activity. These studies have allowed for development of a proposed mechanism that describes the sequential steps and identification of the reactive intermediates leading to catalytic O2 production that accounts for the pH dependency of the reaction that was previously not understood.
New Insights into Apoptosis-Inducing Factor Mediated Pro-Survival Activity
(North Dakota State University, 2022) Birua, Sujata
Cancer is a group of diseases characterized by the uncontrolled growth of cells and is caused by the accumulation of genetic mutations that contribute to cell division, cell growth, and the DNA repair system. According to the American Cancer Society, more than 1.9 million new cancer cases will be diagnosed in 2022, hence there is a need to study new molecular mechanisms leading to tumorigenesis and develop novel treatment options.While significant research has been done to understand the underlying mechanisms, cancer still poses challenges as it 1) resists cell death, 2) activates metastasis, 3) sustains proliferative signaling, and 4) deregulates cellular metabolism. The present work explores the cancer-supporting role of apoptosis-inducing factor (AIF), a mitochondrial flavoprotein positioned at the convergence of the four hallmarks of cancer. AIF was initially characterized as an effector of caspase-independent death; however, increasing evidence has identified the physiological role of AIF in a variety of cancer, including colorectal, prostate, and pancreatic cancer. Expanding AIF activity studies in additional cancers, such as breast cancer, revealed the capability of AIF to modulate the consumption of biochemical substrates other than glucose, thus deregulating cellular metabolism. These alterations suggest the role of AIF in controlling a switch from metabolic flexibility to metabolic dependency, which can be exploited for therapeutic interventions. Moreover, AIF might be involved in mitochondrial biogenesis of breast cancer, unreported in cancer tested so far. In addition to their metabolic function, AIF serves as a signaling molecule that promotes cadherin switching in a 3-dimensional cell culture model of pancreatic ductal adenocarcinoma, which is associated with tumor growth. Finally. When grown in 3-dimensional culture conditions, pancreatic cancer cells were sensitized to a metabolic inhibitor in an AIF-dependent manner. Altogether, these AIF activities are functionally dissociable and demonstrate that AIF-mediated therapy has promise as a next-generations cancer treatment strategy.
Regioselective and Enantioselective Nitrone Cycloadditions to Alkynones.
(North Dakota State University, 2010) Dunkle, Kelsey Lynn
There has been a need in agriculture, medicine, and organic chemistry for enantiopure isoxazolines. A direct method for their synthesis is from the cycloaddition of 1,3-dipoles and alkynes. Alkynones are difficult substrates to use in cycloadditions due to their high reactivity and sometimes instability. Due to their high reactivity it is often difficult to control regio- endo/exo, and enantioselectivities in dipolar cycloadditions of alkynones. This thesis details the cycloadditions of nitrones and alkynones using chiral Lewis acids leading to isoxazolines with high regio-and enantiocontrol. A chiral bisoxazoline-zinc(II) complex successfully catalyzed the enantioselective 1,3-dipolar cycloaddition reaction of nitrone and alkynone derivatives. This is the second successful reported method for the catalytic enantioselective 1,3- dipolar cycloaddition of nitrones and alkynone derivatives. Yields for the cycloadducts were good to near quantitative and enantioselectivities were generally good reaching a high of 86 % ee. The 4-isoxazolines were isolated as single reg101somers.
Synthesis and Photophysics of Platinum(II) Terdentate and Bidentate Complexes.
(North Dakota State University, 2010) Yi, Jing
Platinum(ll) terdentate and bidentate complexes possess square-planar d8 configuration. The moderate metal-to-ligand charge-transfer (1MLCT) absorption, 3MLCT emission, and broadband excited-state absorption are the unique spectroscopic features for these complexes. In my thesis work, two series of terdentate platinum(II) complexes and one bidentate platinum(II) complex were designed and synthesized. The photophysical properties, such as the electronic absorption, photoluminescence, and triplet excited-state absorption, are investigated systematically. Chapter I introduced the representative work on the synthesis and photophysical studies of the terdentate and bidentate platinum(II) complexes reported in the literature. The motivation for my thesis project was briefly discussed. In Chapter 2, the synthesis and photophysical properties of two platinum 6-phenyl-4- (9,9-dihcxylfluoren-2-yl)-2,2 '-bipyridine complexes with phenothiazinyl (PTZ) acetylide ligand were discussed. Their UV-vis absorption and emission characteristics in solutions and LB films were systematically investigated. The triplet transient difference absorption and reverse saturablc absorption were also studied for these complexes. Both complexes exhibit a broad metal-to-ligand charge-transfer / ligand-to-ligand charge-transfer / intraligand charge-transfer (1MLCTi1LLCTi11LCT) absorption band between 400 and 500 nm and a 'MLCT/'ILClill",ll"' emission band at -594 nm at room temperature, which blue shifts at 77 K. Both UV-vis absorption and emission spectra show negative solvatochromic effect. Both of the complexes also exhibit broad and moderately strong triplet transient absorption from the near-UV to the near-IR spectral region. In addition, LB films of them were prepared and characterized by AFM technique. The UV-vis absorption and emission spectra of the LB films of them were also investigated and compared with those obtained in solutions. In Chapter 3, the synthesis and photophysical studies of a series of platinum 6-phenyl- 4-(7-benzothiazolyl-9, 9-diethyltluoren-2-yl)-2,2' -bi pyridine complexes with different acetylides ligands, such as, nitrophenyl acetylide, tluorenyl acetylide, and benzothiazolyltluorenyl acetylide, were discussed. The complex bearing nitrophenyl acetylide ligand exhibited quite distinct photophysical properties compared to the other two complexes. In Chapter 4, one platinum bis(mesitylimino)acenaphthene complex was synthesized. The lowest-energy absorption band was attributed to 1MLCT transitions, which was much broader and red-shifted (extending from 490 nm to 800 nm) compared to those reported for other diiminc Pt(II) complexes.
Synthesis of Novel Biomass-derived Diol and Epoxide Monomers for Coatings Applications
(North Dakota State University, 2022) Sutton, Catherine
There are few monomers or precursors in the polymer industry that are more ubiquitous than bisphenol A (BPA). According to the CDC, about 5-6 billion pounds of BPA are produced worldwide annually. For the synthesis of coatings and polymeric materials, BPA is polymerized directly as a diol into polycarbonates or, to a lesser extent, glycidated into an epoxy monomer or resin. For coatings applications, BPA epoxy resins are utilized in protecting metal cans from acidic foods and beverages to heavy machinery like farm equipment from weather-related corrosion. In part, this popularity has led to scrutiny of the popular monomer from a few different perspectives. Since BPA is petroleum-derived, there is an effort to find a renewably sourced alternative from a sustainability perspective. Additionally, the structural similarity of BPA and the hormone estradiol make BPA an endocrine disruptor. This combined with its widespread applications, means BPA could be a larger issue than previously understood. To meet that challenge, many researchers, Sibi group included, have turned to biomass-derived “building-block” chemicals. Biomass feedstocks contain unique structures not easily obtained from petroleum sources. While avoiding detrimental structure-activity relationships associated with BPA, the newly synthesized compound would need to retain or mimic the structure-property relationships of BPA-containing polymers for coatings applications. The cellulosic monomer, 2,5-furandicarboxylic acid (FDCA), with exciting similarities to and some improvements upon petroleum-derived terephthalic acid was known, and its oxidative family of furans was being explored at the start of this project. A collection of furan diols was synthesized from 5-hydroxymethylfurfural (HMF), 2, 5-diformylfuran (DFF) and FDCA were synthesized by alkylation with various alkyl groups resulting in mono-, di-, and tetraalkylated diols, respectively. Depending on the alkyl group, certain materials properties were anticipated from these furanic diols. The diols were screened for estrogenic, androgenic, anti-thyroid activity via CALUX assays. The cytotoxicity of the diols were also determined via cell death studies. From those results, few low molecular weight furan diols do not exhibit any observable activity as endocrine disruptors or an observable cytotoxicity. Subsequently, a selection of furanic diols were glycidated for use in epoxy coating synthesis.

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