>Magister Scientiae - MSc / In this work, we describe the synthesis of ferrocenylimine and G1 dendrimeric N,N′ ligands, and their palladium(II) complexes. The ligands L1 – L4 were synthesized following Schiff base condensation reactions. The ferrocenylimine ligands L1 and L2 were prepared from ferrocenecarboxaldehyde and 1,3-diaminopropane or DAB-4-(NH2)4, while the G1 dendrimeric N,N′ ligands L3 and L4 were prepared from DAB-4-amine and 2- pyridinecarboxaldehyde or 2-quinolinecarboxaldehyde. The air and moisture stable ligands were obtained in fairly good yields of over 65 %. All the ligands were observed to be soluble in common organic solvents. They were characterized by FTIR spectroscopy, 1H-NMR spectroscopy, 13C-NMR spectroscopy, micro-analysis and ESImass spectrometry.A reaction of the ligands with PdCl2(COD) or PdCl2(MeCN)2 gave palladium(II) complexes C1 – C4 in good yields of over 70%. The complexes were observed to be stable. However,the complexes did not dissolve in common organic solvents. These were characterized by FTIR spectroscopy and 1H-NMR and 13C-NMR spectroscopy.All the complexes were screened for activity towards Heck coupling model reaction of iodobenzene with styrene. The complexes catalyzed the coupling of styrene with iodobenzene, giving over 60 % conversions. However, complex C3 was found to be the most active catalyst, yielding 75% conversion without formation of palladium black.

The decapeptide, gonadotropin releasing hormone (GnRH), is the central regulator of reproductive function. It binds to receptors on the gonadotrope cells of the pituitary and stimulates release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Eleven different structural forms of GnRH have now been identified in various animal species. Chimaeric analogues of some of the variant forms of GnRH were synthesized in order to study the functional significance of the most common amino acid substitutions, which occur in positions 5, 7 and 8. Peptide binding affinities for sheep and rat GnRH receptors and potencies in stimulating LH and FSH release from cultured sheep pituitary cells and LH release from cultured chicken pituitary cells were measured. Histidine in position 5 decreased LH releasing potency in chicken cells, but slightly increased receptor binding affinity in rat and sheep membranes. Tryptophan in position 7 had minimal effect on GnRH activity in mammals, but increased LH release in chicken cells. Although differences in the structural requirements of mammalian and chicken GnRH receptors were anticipated, it was also found that rat GnRH receptors exhibited higher affinity for analogues with Tryptophan in position 7, than did sheep GnRH receptors. Substitutions in position 8 revealed the most marked differences in the structural requirements of mammalian and chicken GnRH receptors. Arginine was required for high GnRH activity in mammalian systems, but analogues with neutral substitutions in position 8 were more potent in chicken pituitary cells. The tolerance of position 8 substitutions, combined with the relatively small effects, in chicken cells, of incorporating a D-amino acid in position 6, indicate that the chicken GnRH receptor is less stringent than mammalian receptors in its recognition of peptide conformation. To examine how changes in ligand structure cause changes in receptor binding affinity and receptor activation, it was necessary to know the structures of the GnRH receptors. A protocol was developed for the purification of GnRH binding proteins from detergent-solubilized pituitary membranes, by affinity chromatography. This procedure yielded a protein which migrated as a single band on sodium dodecyl sulfate polyacrylamide gel electrophoresis, but was different from the recently cloned GnRH receptor. To test the proposal that the arginine residue in mammalian GnRH interacts with an acidic receptor residue, eight conserved acidic residues of the cloned mouse GnRH receptor were mutated to asparagine or glutamine. Mutant receptors were transiently expressed in COS-1 cells and tested for decreased preference for Arg⁸-containing ligands by ligand binding and inositol phosphate production. One mutant receptor, in which the glutamate residue in position 301 was mutated, exhibited decreased affinity for mammalian GnRH. The mutant receptor also exhibited decreased affinity for [Lys⁸]-GnRH, but unchanged affinity for [Gln⁸]-GnRH compared with the wildtype receptor, and increased affinity for the acidic analogue, [Glu⁸]-GnRH. This loss of affinity was specific for the residue in position 8, because the mutant receptor retained hiszh affinity for analogues with favourable substitutions in positions 5, 6 and 7. Thus, the Glu³⁰¹ residue of the GnRH receptor plays a role in receptor recognition of Arg⁸ in the ligand, consistent with an electrostatic interaction between these two residues. The Glu³⁰¹ and Arg⁸ residues were not required for the high affinity interactions of conformationally constrained peptides. This indicates that an interaction which involves these two residues may induce changes in the conformation of GnRH after it has bound to the receptor.

Nanoparticles (NPs) are the basis of nanotechnology and finding numerous applications in various fields such as health, electronics, environment, personal care products, transportation, and catalysis. To fulfill these functions, the nanoparticles must be synthesized, passivated to control their chemical reactivity, stabilized against aggregation and functionalized to achieve specific performances. The chemistry of metal nanoparticles especially that of noble metals (Gold, Platinum…) is a growing field. The nanoparticles have indeed different properties from those of the corresponding bulk material. These properties are largely influenced by several parameters; the most important are the size, shape, and the local environment of the nanoparticles. One of the most common synthetic methods for the preparation of gold nanoparticles (AuNPs) is based on stabilization by citrate. Since it was reported first by Turkevich et al. in 1951, this synthetic scheme has been widely used, studied and a substantial amount of important information regarding this system has been reported in the literature. The most popular method developed by Frens for controlling the size of the noble gold nanoparticles based on citrate was achieved by varying the concentration of sodium citrate. Despite a large number of investigations focused on utilizing Cit-AuNPs, the structural details of citrate anions adsorbed on the AuNP surface are still unknown. It is known only that citrate anions “coordinate” to the metal surface by inner sphere complexation of the carboxylate groups and there are trace amounts of AuCl4−, Cl−, and OH− on the metal surface. Moreover, it is generally accepted that the ligand shell morphology of Au nanoparticles can be partly responsible for important properties such as oxidation of carbon monoxide. The use of Au-NPs in heterogeneous catalysis started mostly with Haruta who discovered the effect of particle size on the activity for carbon monoxide oxidation at low temperature. The structure of the citrate layer on the AuNP surface may be a key factor in gaining a more detailed understanding of nanoparticle formation and stabilization. This can be affecting the catalytic activity. These thoughts invited us to systematically examine the role of sodium citrate as a stabilizer of gold nanoparticles, which is the main theme of this thesis. This research is focused on three main objectives, controlling the size of the gold nanoparticles based on citrate (and other carboxylate ligands Trisodium citrate dihydrate, Isocitric Acid, Citric acid, Trimesic acid, Succinic Acid, Phthalic acid, Disodium glutarate, Tartaric Acid, Sodium acetate, Acetic Acid and Formic Acid by varying the concentration of Gold/sodium citrate, investigating the interaction of the citrate layer on the AuNP surface, and testing the activity of the Au/TiO2 catalysts for the oxidation of carbon monoxide. This thesis will be divided into five chapters. In Chapter 1, a general literature study on the various applications and methods of synthesis of Au nanoparticles is described. Then we present the main synthetic pathways of Au nanoparticles we selected. A part of the bibliographic study was given to the use of Au nanoparticles in catalysis. In Chapter 2, we give a brief description of the different experimental procedures and characterization techniques utilized over the course of the present work. The study of the size control and the interaction between gold nanoparticles and the stabilizer (carboxylate groups) was achieved by using various characterization techniques such as UV-visible spectroscopy, Transmission Electron Microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Nuclear Magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FTIR). In Chapter 3, we discuss the synthesis and size control of Au nanoparticles by following the growth of these nanoparticles by UV-Visible spectroscopy and TEM. We then describe the effect of the concentrations and of various type of the stabilizer, and the post-synthesis treatment on gold nanoparticles size. In Chapter 4, we focus on determining the nature of the interactions at molecular level between citrate (and other carboxylate-containing ligands) and AuNP in terms of the mode of coordination at the surface, and the formal oxidation state of Au when interacting with these negatively charged carboxylate ligands (i.e., LX- in the Green formalism). We achieve this by combining very advanced 13C CP/MAS, 23Na MAS and low-temperature SSNMR, high-resolution transmission electron microscopy (HRTEM) and density functional theory (DFT) calculations. A particular emphasis will be based on SS-NMR. In Chapter 5, we study the influence of pretreatment of 1% Au/TiO2 catalysts on the resulting activity in the oxidation of carbon monoxide, the effect of the concentration and the type of the ligands on the catalytic activity. The catalysts were characterized by TPO, XRD, and TEM spectroscopy.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, 1977 / Includes bibliographical references. / Ph. D. / Ph. D. Massachusetts Institute of Technology, Department of Chemistry

Serious cardiovascular side effects are reported from synthetic cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs, the most common medication for rheumatoid arthritis (RA) and osteoarthritis (OA). Natural products from herbal medicine are inspirational source of safe and effective remedy due to its distinguished chemical diversity. Nanomagnetic ligand fishing using enzyme-anchored-magnetic nanoparticles (MNPs) is an advanced selective bioseparation strategy based on macromolecular target-ligand binding, which can screen enzyme inhibitors from complex mixtures. "Snow lotus" herbs have been clinically applied as safe and effective treatment for arthritis throughout centuries in Asia. Some major chemicals from the herbs have been found with anti-COX-2 activities. It is therefore hypothesized that novel and safe COX-2 selective inhibitors can be separated from a most representative snow lotus herb via ligand fishing using COX-2-functionalized MNPs (COX-2-MNPs), and that the efficacy and safety of the screened COX-2 ligands can be verified by subsequent evaluation. Saussurea laniceps Hand.-Mazz. (SL), S. medusa Maxim. (SM) and S. involucrata (Kar. et Kir.) Sch.Bip. (SI) are three authenticated sources of "snow lotus" herbs. An ultra-high performance liquid chromatography hyphenated with diode array detector and quadrupole time of flight-mass spectrometry (UPLC-DAD-QTOF-MS) method was developed to analyze 49 herbal samples for species analysis and overall quality evaluation. With 25 simultaneously identified constituents, of which 12 were quantified, the chemical determination, four-dimensional principle component analysis (4D-PCA), and orthogonal hierarchical cluster analysis (2D-HCA) showed a distinctive bioactive component profile of SL from the other two species, and explained the therapeutic potency of SL. As a result, SL has been chosen as a model herb to screen for novel and safe COX-2 selective inhibitors. With systematic uniform experimental designs and statistical modeling, COX-2-MNPs with high magnetic moments and outstanding enzyme activity have been synthesized. Four COX-2-selective compounds, namely, chlorogenic acid, syringin, umbelliferone, and scopoletin, were separated from the herbal extract using fine-tuned fishing protocol and were identified by UPLC-DAD-QTOF-MS. All the four ligands were proved with evidently lower in vitro and in vivo cardiotoxicity than celecoxib, a known selective COX-2 inhibitor. Some of them exerted potent anti-inflammatory activities on cells, and their optimum combination ratios were investigated. Among the ligands, scopoletin showed most evident therapeutic potential in rats with adjuvant-induced arthritis and anterior cruciate ligament transection (ACLT)-induced OA, respectively, by alleviating clinical statuses, immune responses, and joint pathological features. An equal mixture of scopoletin and syringin brought possible synergistic remedial effects on rat OA. Molecular docking results explained the structure-specific enzyme-binding affinities of the ligands; the ligands' inhibition on COX-2 may involve direct interaction as well as upstream signaling pathways. In conclusion, promising candidates of COX-2 selective inibitors, e.g. scopoletin, have been screened and validated on a nanomagnetic ligand fishing platform using COX-2-MNPs from the extract of SL, a most representative snow lotus herb with distinctive chemical composition and outstanding therapeutic efficacies. The quality evaluation strategy of snow lotus herbs combining chemical determination and multidimensional chemometric analysis can be applied in other multi-original herbal medicines. The nanomagnetic ligand fishing platform of compound bio-separation and multi-model bio-evaluation should be equally valuable for uncovering other therapeutic chemicals in different natural sources.

Philosophiae Doctor - PhD / Pneumonia remains the major cause of death in children and the elderly and several efforts have been intensified to reduce the rate of pneumonia infection. The major breakthrough has been the discovery of certain biomarkers for the diagnosis of pneumonia through immunogenic techniques.

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<p> A series of chiral transition metal clusters of the type MCo2(CO)6C-CO2R, where M = Co(CO)3, (C5H5)Mo(CO)2, (i-Pr-C5H4)Mo(CO)2 or (indenyl)Mo(CO)2 and R =menthyl or exo-bornyl have been synthesized and characterized using FAB mass spectrometry and high field NMR techniques. The isopropyl Cp and the indenyl ligands served as NMR probes to detect the chirality created by the incorporation of the terpenoidal capping group.</p> <p> The tricobalt clusters were treated with the bidentate ligands arphos, Ph2AsCH2CH2PPh2 and diphos, Ph2PCH2CH2PPh2. Treatment with arphos yields a pair of diastereomers which are interconverted via the migration of the Ph2As terminus of the arphos ligand from one cobalt vertex to another. This fluxionality was monitored by variable-temperature 31P NMR spectroscopy. The diphos cluster is not a fluxional molecule. However, the Co(CO)2P vertices are diastereotopic and give two signals in the 31P NMR. Thus, diphos serves as a convenient probe for chirality. </p> <p> In the case where M = Co(CO)3 , the two remaining cobalt vertices are diatereotopic and are, in principle, not equally susceptible to attack by an incoming ligand. To test for chiral discrimination, these molecules have been treated with several different phosphines. If the reaction were to proceed with any degree of selectivity, the 31P NMR spectrum ought to show resonances of unequal intensity. Such results have been obtained when a bulky phosphine, such as tricyclohexylphosphine, has been employed.</p> / Thesis / Master of Science (MSc)

<p> An apparatus was designed and built to enable the study of volatilization reactions using a novel variant of thermogravimetry called thermoradiometry. The usefulness of the apparatus was demonstrated by investigating the volatilization of iron from solid samples with the fluorinated ligands 1,1,1-trifluoro-2,4-pentanedione and 1,1,1,5,5,5-hexafluoro-2,4-pentanedione.</p> / Thesis / Master of Science (MSc)