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The development of dimetallic metal complexes into functional and selective recognition agents for monophosphorylated peptides is described. The development of dimetallic metal complexes into functional and selective phosphopeptide recognition agents is described. Scaffold functionalization was conducted to assess whether binding affinity for phosphate monoesters could be modulated. A protocol for the facile synthesis of symmetric and asymmetric pyridine-functionalized bis-dipicolylamine (BDPA) scaffolds was thus first optimized. Zn(II) complexes were screened for the ability to bind to various phosphate monoesters of biological relevance using isothermal titration calorimetry (ITC). An expanded family of compounds was then screened using a variety of biophysicial and biological techniques for the ability to bind to disrupt Stat3 dimer both in biophysical assays and in whole cells. Several compounds displayed the ability to potently disrupt Stat3 dimer formation at low micromolar doses. Moreover, one compound emerged as having potent anti-cancer activity against MDA468, a solid breast cancer tumor line. Efforts were subsequently redirected towards the development of Zn(II)-BDPA receptors which mimicked the pY, pY+X recognition motif displayed by human SH2 domains. A family of ditopic biphenyl-based receptors, computationally predicted to adopt this binding mode, were synthesized and screened against a family of high-profile pY-containing phosphopeptides. The reported family of mimetics displayed a wide variance in cytotoxicity against common cancer cell lines, supporting our structure-activity hypothesis. Selectivity observed in our fluorescence intensity assay did not hold in a cellular context. We next pursued the development of selective receptors for phosphopeptides containing pS instead of pY. A diverse family of Zn(II)-BDPA receptors featuring a 2’ substituted benzothiazole core were synthesized, and their binding affinities toward model phosphopeptides assessed. A central conclusion of this project is that development of potent, selective receptors for anionic and hydrophobic peptides will likely be possible only by using receptors with cationic or hydrophobic pendants, and by maximizing phosphopeptide-specific interactions. Lastly, investigations into the use of bowl-type receptors as phosphopeptide recognition agents are presented. Synthesis of a prototype bowl receptor and early efforts to characterize the receptor’s binding preferences using ITC are reported. Progress-to-date in the development of a FRET system, which will be used to measure the receptor’s affinity for different dephosphorylation motifs, is also reported.

The development of dimetallic metal complexes into functional and selective recognition agents for monophosphorylated peptides is described. The development of dimetallic metal complexes into functional and selective phosphopeptide recognition agents is described. Scaffold functionalization was conducted to assess whether binding affinity for phosphate monoesters could be modulated. A protocol for the facile synthesis of symmetric and asymmetric pyridine-functionalized bis-dipicolylamine (BDPA) scaffolds was thus first optimized. Zn(II) complexes were screened for the ability to bind to various phosphate monoesters of biological relevance using isothermal titration calorimetry (ITC). An expanded family of compounds was then screened using a variety of biophysicial and biological techniques for the ability to bind to disrupt Stat3 dimer both in biophysical assays and in whole cells. Several compounds displayed the ability to potently disrupt Stat3 dimer formation at low micromolar doses. Moreover, one compound emerged as having potent anti-cancer activity against MDA468, a solid breast cancer tumor line. Efforts were subsequently redirected towards the development of Zn(II)-BDPA receptors which mimicked the pY, pY+X recognition motif displayed by human SH2 domains. A family of ditopic biphenyl-based receptors, computationally predicted to adopt this binding mode, were synthesized and screened against a family of high-profile pY-containing phosphopeptides. The reported family of mimetics displayed a wide variance in cytotoxicity against common cancer cell lines, supporting our structure-activity hypothesis. Selectivity observed in our fluorescence intensity assay did not hold in a cellular context. We next pursued the development of selective receptors for phosphopeptides containing pS instead of pY. A diverse family of Zn(II)-BDPA receptors featuring a 2’ substituted benzothiazole core were synthesized, and their binding affinities toward model phosphopeptides assessed. A central conclusion of this project is that development of potent, selective receptors for anionic and hydrophobic peptides will likely be possible only by using receptors with cationic or hydrophobic pendants, and by maximizing phosphopeptide-specific interactions. Lastly, investigations into the use of bowl-type receptors as phosphopeptide recognition agents are presented. Synthesis of a prototype bowl receptor and early efforts to characterize the receptor’s binding preferences using ITC are reported. Progress-to-date in the development of a FRET system, which will be used to measure the receptor’s affinity for different dephosphorylation motifs, is also reported.

No description available.

With the blend of addressing issues of sustainable energy with the environmental worries regarding emission of greenhouse gases, there is a motivation to target the efficient chemical reduction of CO2. Re(I) integrated photosensitizers and catalysts, synthesized from commercially available ligands, are introduced with the selective CO2 reduction of formic acid, making for a unique class of Re(I) catalysts typically selective for CO as a reduction product. Furthermore, synthesized Zn(II) phosphino aminopyridine complexes are structurally and computationally characterized as well as observed to function as unprecedented electrocatalysts for the reduction of CO2 to formic acid and CO. Lastly, with the importance and popularity of N-heterocyclic carbenes (NHCs) as a class of ligands in the field of organometallic catalysis, six-membered perimidine based carbenes are further explored. Synthesis of a chelating pyridyl-perimidine NHC in addition to potential transition metal catalysts are also attempted.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第23021号 / 理博第4698号 / 新制||理||1674(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)准教授 齊藤 尚平, 教授 時任 宣博, 教授 依光 英樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Doctor of Philosophy / Department of Chemistry / Christopher J. Levy / The helix is an important chiral motif in nature, there is increasing development in field of helical transition metal complexes and related supramolecular structures. Hence, the goals of this work are to apply the principles of helicity in order to produce metal complexes with predictable molecular shapes and to study their properties as asymmetric catalysts. Computational studies suggest that the (1R,2R)-cyclobutyldiamine unit can produce highly twisted salen complexes with a large energy barrier between the M and P helical forms. To test this prediction, the tartrate salt of (1R,2R)-cyclobutyldiamine was synthesized and condensed with a series of saliclaldehydes to produce novel salen ligands. The salicylaldehydes chosen have extended phenanthryl or benz[a]anthryl sidearms to encourage formation of helical coordination complexes. These ligands were metallated with zinc, iron and manganese salts to produce salen metal complexes which were characterized by NMR analysis, high-resolution mass spectrometry, and IR spectroscopy. A second ligand type, neutral bis(pyridine-imine) has also been synthesized from (1R,2R)-cyclobutyldiamine and quinolylaldehydes. The synthesis of bis(pyridine-imine) ligands was conducted using greener method, solvent assisted grinding. These ligands, in-situ with nickel metal salts, showed good catalytic activity for asymmetric Diels-Alder reactions. The third ligand type studied was chiral acid-functionalized Schiff-base ligands. These were synthesized by the condensation of 3-formyl-5-methyl salicylic acid and (1R,2R)-cyclobutyldiamine. With this type of ligand, there is possibility of producing both mono and dinuclear metal complexes. In our studies, we were only able to synthesize mononuclear complexs. These were tested as catalysts for asymmetric direct Mannich-type reaction, but were found to be ineffective.

Doctor of Philosophy / Department of Chemistry / Christopher J. Levy / A series of chiral titanium and manganese complexes with helix-directing salen ligands have been prepared, characterized and studied. Their structures displayed as a chiral helical motif as expected. And it was also found that all M(salen) units were exclusively M-helimeric in the solid state, except Ti(cyclohexyl-benz[a]anthryl) as P-helix. This may be due to the energy difference between P and M helice, which enables crystal packing forces to control and drive the molecular structure. This is also in agreement with the previous computational studies that the M configuration predominates in THF solution. All metal centers adopt a cis-β octahedral geometry except in Mn(binapthyl-phenanthryl-salen). Most of M(salen) complexes in this work afforded μ–oxo dinuclear helicates, instead of the expected monohelicate, except Mn(binapthyl-phenanthryl-salen), which is bridged by a third salen ligand. The titanium salt affected the complex solution behavior. In the presence of Cl[superscript]-, only mononuclear species was found by ESI-MS, while both di- and mononuclear species was found in MeOH in the presence of –O[superscript]iPr. The NMR spectra of Ti(salen) indicated one major species with cis-β geometry exist in most solution, which could be monomer or dimer, except Ti(binapthyl-salen). No counterions have been found in the solid state of Mn(salen) complexes in this work, but they affected the ligand decomposition in the solution in Mn(binapthyl-phenanthryl-salen). The Mn(salen) complexes could effectively and enatioselectively catalyze the asymmetric epoxidation of somoe trans, cis and terminal olefin, and various oxidants were employed.