The previously described 2-aryl-4-chloro-3-iodoquinolines were prepared following literature procedure and in turn converted to the corresponding hitherto unknown 2-aryl-3-iodo-4-(phenylamino)quinoline derivatives using aniline in refluxing ethanol. These 2-aryl-3-iodo-4-(phenylamino)quinolines were reacted with allybromide in ethanol at room temperature to afford 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives. The 2-aryl-3-iodo-4-(phenylamino)quinoline and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were subjected to metal-catalysed carbon-carbon bond formations. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinoline with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single step operation. On the other hand, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo palladium-catalysed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines. All new compounds were characterized by using a combination of NMR (1H and 13C), IR, mass spectroscopic techniques as well as elemental analysis. / Chemistry / MSc. (Chemistry)

The 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were prepared in a single-pot operation by condensing 6,8-dibromoanthranilamide and aryl aldehydes in the presence of molecular iodine in ethanol. Treatment of the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones with thionylchloride in the presence of dimethylformamide afforded the corresponding 2-aryl-4-chloro-6,8-dibromoquinazolines. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling reaction of 2-aryl-4-chloro-6,8-dibromoquinazolines with terminal alkynes at room temperature afforded series of 2-aryl-6,8-dibromo-4-(alkynyl)quinazolines. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as well as mass spectrometry. The absorption and emission properties of 2,6,8-triaryl-4-(phenylethynyl)quinazolines were determined in solution. / Chemistry / M.Sc. (Chemistry)

The previously described 2-aryl-4-chloro-3-iodoquinolines were prepared following literature procedure and in turn converted to the corresponding hitherto unknown 2-aryl-3-iodo-4-(phenylamino)quinoline derivatives using aniline in refluxing ethanol. These 2-aryl-3-iodo-4-(phenylamino)quinolines were reacted with allybromide in ethanol at room temperature to afford 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives. The 2-aryl-3-iodo-4-(phenylamino)quinoline and 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were subjected to metal-catalysed carbon-carbon bond formations. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling of 2-aryl-3-iodo-4-(phenylamino)quinoline with terminal alkynes afforded series of 1,2,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines in a single step operation. On the other hand, the 4-(N,N-allylphenylamino)-2-aryl-3-iodoquinoline derivatives were found to undergo palladium-catalysed intramolecular Heck reaction to yield the corresponding 1,3,4-trisubstituted 1H-pyrrolo[3,2-c]quinolines. All new compounds were characterized by using a combination of NMR (1H and 13C), IR, mass spectroscopic techniques as well as elemental analysis. / Chemistry / MSc. (Chemistry)

The 2-aryl-6,8-dibromoquinazolin-4(3H)-ones were prepared in a single-pot operation by condensing 6,8-dibromoanthranilamide and aryl aldehydes in the presence of molecular iodine in ethanol. Treatment of the 2-aryl-6,8-dibromoquinazolin-4(3H)-ones with thionylchloride in the presence of dimethylformamide afforded the corresponding 2-aryl-4-chloro-6,8-dibromoquinazolines. Palladium(0)-copper iodide catalysed Sonogashira cross-coupling reaction of 2-aryl-4-chloro-6,8-dibromoquinazolines with terminal alkynes at room temperature afforded series of 2-aryl-6,8-dibromo-4-(alkynyl)quinazolines. Further transformation of the 2-aryl-6,8-dibromo-4-(phenylethynyl)quinazolines via Suzuki-Miyaura cross-coupling with arylboronic acids occurred without selectivity to afford the corresponding 2,6,8-triaryl-4-(phenylethynyl)quinazolines. The compounds were characterized using a combination of NMR (1H and 13C) and IR spectroscopic techniques as well as mass spectrometry. The absorption and emission properties of 2,6,8-triaryl-4-(phenylethynyl)quinazolines were determined in solution. / Chemistry / M.Sc. (Chemistry)

Indiana University-Purdue University Indianapolis (IUPUI) / Carbon nanotubes (CNTs) are one of the most common nanoparticles (NP) found in workplace air. Therefore, there is a strong chance that these NP will enter the human body. They have similar physical properties to asbestos, a known toxic material, yet there is limited evidence showing that CNTs may be hazardous to human barrier epithelia. In previous studies done in our laboratory, the effects of CNTs on the barrier function in the human airway epithelial cell line (Calu-3) were measured. Measurements were done using electrophysiology, a technique which measures both transepithelial electrical resistance (TEER), a measure of monolayer integrity, and short circuit current (SCC) which is a measure of vectorial ion transport across the cell monolayer. The research findings showed that select physiologically relevant concentrations of long single-wall (SW) and multi-wall (MW) CNTs significantly decreased the stimulated SCC of the Calu-3 cells compared to untreated cultures. Calu-3 cells showed decreases in TEER when incubated for 48 hours (h) with concentrations of MWCNT ranging from 4µg/cm2 to 0.4ng/cm2 and SWCNT ranging from 4µg/cm2 to 0.04ng/cm2. The impaired cellular function, despite sustained cell viability, led us to investigate the mechanism by which the CNTs were affecting the cell membrane. We investigated the interaction of short MWCNTs with model lipid membranes using an ion channel amplifier, Planar Bilayer Workstation. Membranes were synthesized using neutral diphytanoylphosphatidylcholine (DPhPC) and negatively charged diphytanoylphosphatidylserine (DPhPS) lipids. Gramicidin A (GA), an ion channel reporter protein, was used to measure changes in ion channel conductance due to CNT exposures. Synthetic membranes exposed to CNTs allowed bursts of currents to cross the membrane when they were added to the membrane buffer system. When added to the membrane in the presence of GA, they distorted channel formation and reduced membrane stability.

Indiana University-Purdue University Indianapolis (IUPUI) / The modification of brucine derivatives as chiral ligands and the use of a multifaceted chiral ligand, brucine diol, under different reaction conditions to produce various optical isomers is described. In Chapter 1, the generation of a number of brucine derivatives is described. Taking the advantage of brucine-diol’s excellent molecular recognition capability for multiple organic functional groups, we focused on the synthetic modifications of brucine-diol and the synthesis of brucine N-oxide. We also produced various brucine derivatives with different functional moieties in good yields and selectivities. In Chapter 2, we described the investigation of brucine N-oxide catalyzed Morita-Baylis-Hillman (MBH) reaction of alkyl/aryl ketones. Brucine N-oxide was used as a nucleophilic organic catalyst in the MBH reaction of alkyl vinyl ketone. In addition, asymmetric MBH reactions of alkyl vinyl ketones with aldehydes were investigated using a dual catalysis of brucine N-oxide and proline. In this dual catalyst system, proline was found to form iminium intermediates with electron-deficient aryl aldehydes, while the N-oxide activated vinyl ketones provided enolates through the conjugate addition. Our dual catalysis approach also allowed the development of MBH reaction of aryl vinyl ketones. In Chapter 3, brucine diol-copper complex catalyzed asymmetric conjugate addition of glycine (ket)imines to nitroalkenes is discussed. Stereodivergent catalytic asymmetric conjugate reactions for glycine (ket)imines with nitroalkenes were achieved using various chiral catalysts derived from a single chiral source, brucine diol. Both syn- and anti-conjugate addition products were obtained with high diastereoselectivity and enantioselectivity. In Chapter 4, enantiodivergent production of endo-pyrrolidines from glycine (ket)imines using brucine diol-copper complex is described. The [3+2] cycloaddition reaction of glycine imines and activated alkenes was performed to produce endo-pyrrolidines. The reversal of enantioselectivity was observed for endo-pyrrolidines between concerted and stepwise reaction pathways. The three new brucine derivatives produced in this study would potentially work as organocatalysts and chiral ligands with metal ion in asymmetric synthesis. The brucine diol-metal complex catalyzed reactions laid a good foundation for catalytic asymmetric reactions, where a single chiral source was used to control the absolute and the relative stereochemical outcomes of reactions. Understanding the molecular-level interactions between catalyst and substrates will provide insightful mechanistic details for the stereodivergent approaches in asymmetric catalysis.

Indiana University-Purdue University Indianapolis (IUPUI) / Carbon nanomaterials are widely produced and used in industry, medicine and scientific research. To examine the impact of exposure to nanoparticles on human health, the human airway epithelial cell line, Calu-3, was used to evaluate changes in the cellular proteome that could account for alterations in cellular function of airway epithelia after 24 h exposure to 10 μg/mL and 100 ng/mL of two common carbon nanoparticles, singleand multi-wall carbon nanotubes (SWCNT, MWCNT). After exposure to the nanoparticles, label-free quantitative mass spectrometry (LFQMS) was used to study differential protein expression. Ingenuity Pathway Analysis (IPA) was used to conduct a bioinformatics analysis of proteins identified by LFQMS. Interestingly, after exposure to a high concentration (10 μg/mL; 0.4 μg/cm2) of MWCNT or SWCNT, only 8 and 13 proteins, respectively, exhibited changes in abundance. In contrast, the abundance of hundreds of proteins was altered in response to a low concentration (100 ng/mL; 4 ng/cm2) of either CNT. Of the 281 and 282 proteins that were significantly altered in response to MWCNT or SWCNT, respectively, 231 proteins were the same. Bioinformatic analyses found that the proteins common to both kinds of nanotubes are associated with the cellular functions of cell death and survival, cell-to-cell signaling and interaction, cellular assembly and organization, cellular growth and proliferation, infectious disease, molecular transport and protein synthesis. The decrease in expression of the majority proteins suggests a general stress response to protect cells. The STRING database was used to analyze the various functional protein networks. Interestingly, some proteins like cadherin 1 (CDH1), signal transducer and activator of transcription 1 (STAT1), junction plakoglobin (JUP), and apoptosis-associated speck-like protein containing a CARD (PYCARD), appear in several functional categories and tend to be in the center of the networks. This central positioning suggests they may play important roles in multiple cellular functions and activities that are altered in response to carbon nanotube exposure. To examine the effect of nanotubes on the plasma membrane, we investigated the interaction of short purified MWCNT with model lipid membranes using a planar bilayer workstation. Bilayer lipid membranes were synthesized using neutral 1, 2-diphytanoylsn-glycero-3-phosphocholine (DPhPC) in 1 M KCl. The ion channel model protein, Gramicidin A (gA), was incorporated into the bilayers and used to measure the effect of MWCNT on ion transport. The opening and closing of ion channels, amplitude of current, and open probability and lifetime of ion channels were measured and analyzed by Clampfit. The presence of an intermediate concentration of MWCNT (2 μg/ml) could be related to a statistically significant decrease of the open probability and lifetime of gA channels. The proteomic studies revealed changes in response to CNT exposure. An analysis of the changes using multiple databases revealed alterations in pathways, which were consistent with the physiological changes that were observed in cultured cells exposed to very low concentrations of CNT. The physiological changes included the break down of the barrier function and the inhibition of the mucocillary clearance, both of which could increase the risk of CNT’s toxicity to human health. The biophysical studies indicate MWCNTs have an effect on single channel kinetics of Gramicidin A model cation channel. These changes are consistent with the inhibitory effect of nanoparticles on hormone stimulated transepithelial ion flux, but additional experiments will be necessary to substantiate this correlation.

The known 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 were dehydrogenated using thallium(III) p-tolylsulfonate in dimethoxyethane under reflux to afford the 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136. Palladium-catalyzed Sonogashira cross-coupling of the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones with terminal alkynes in the presence of PdCl2(PPh3)2-CuI (as homogeneous catalyst source) and 10% Pd/C-PPh3-CuI (as heterogeneous catalyst source) catalyst mixture and NEt3 as a base and co-solvent in ethanol under reflux afforded the corresponding 6,8-dialkynyl-2-aryl-2,3-dihydroquinolin-4(1H)-ones 138 and 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones 137, respectively. PdCl2-catalyzed electrophilic cyclization of the 8-alkynyl-2-aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones in acetonitrile under reflux afforded the 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 or the 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)-ones 140 from the 4-phenylethynyl-substituted or 4-alkylethynyl-substituted precursors, respectively. The 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 wturn, subjected to similar homogeneous and heterogeneous palladium catalyst sources using NEt3 as a base in DMF-water mixture under reflux and K2CO3 as a base in dioxane under reflux afforded 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 143 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142, respectively. The monoalkynylated 4-aryl-8-bromo-2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 139 and 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines 142 were subsequently transformed using palladium-catalyzed Suzuki-Miyaura cross-coupling with arylboronic acids in the presence of PdCl2(PPh3)2-PCy3 catalyst mixture and K2CO3 as a base in dioxane-water mixture to afford the corresponding novel 8-substituted 2-phenyl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones 141 and 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinolines 144, respectively. All the new compounds were characterized using a combination of 1H NMR, 13C NMR, IR, mass spectroscopic techniques and X-ray crystallography. / Chemistry / D. Phil. (Chemistry)