The solid phase combinatorial method is an excellent tool for the modulation of protein-protein interactions through focused library generations. Nucleophilic aromatic substitution reactions with an iodinated template on solid phase has opened a door for easy and pure libraries of 13-22 membered medium and macrocyclic peptidomimetics. These peptide mimics showed promising activities for tyrosine kinase receptors. Iodine functionality can then be used to modify the products, on the resin, via Sonogashira and Suzuki couplings and presumably through other organometallic catalysis. The coupled products can have conformational biases that differ from the iodinated macrocycles. These coupling reactions also provide a means to introduce additional pharmacophores and to adjust the solubilities of the products. The fluorinated template also gave libraries of cyclic peptidomimetics on solid phase in good yields and purities. These libraries have improved water solubility over the iodinated libraries. The 3-fluorinated template yielded better results than the 5- fluorinated template. Some compounds showed biological activities in cell survival assays providing strong support of our approach to mimic external β-turn sequences in target proteins. Intrasite dimerization with 1,5-hexadiyne gave a homodimer as a byproduct. Solidphase synthesis of bivalent turn mimics with fluorescent tags has been demonstrated. The key feature of this synthetic route is that homo- and hetero-dimers can be formed chemoselectively from unprotected monomeric precursors. The dimerization reaction is very mild and versatile, as only potassium carbonate is required to affect the coupling. Solution phase library synthesis of small molecule mimics is presented. Some monomers of full sequence mimics have been prepared to afford dimer generations. Theses monomers were combined with linker handles to afford diverse length of dimers. Final combination of monomers to make bivalent compounds is in progress.

No description available.

In dieser Arbeit wurde mit Hilfe von small-molecule Inhibitoren die Rolle von clathrin- und dynaminabhängigen Endozytosemechanismen bei der Aufnahme von anti-Amphiphysin-Autoantikörpern am Zellkulturmodell primärer hippocampaler Neurone untersucht. Hierbei konnte eine Beeinflussung der Autoaantikörperaufnahme durch die Intervention gezeigt werden. Außerdem erfolgte der Versuch der Etablierung eines siRNA knockdowns unter Zuhilfenahme unterschiedlicher Traansfektionsreaaagenzien. / This thesis investigated the role of clathrin and dynamin dependent endocytosis in internalisation of anti-amphiphysin-autoantibodies in primary mouse hippocampal neurons by using small molecule inhibitors. An influence in the uptake due to small molecule treatment can be shown. Furthermore an attempt of siRNA knockdown establishment was performed using different transfection reagents.

The versatility of N-heterocyclic carbenes (NHCs) is demonstrated by numerous practical applications in homogeneous transition metal catalysis, organocatalysis and materials science. There remains a paucity of electropositive metal NHC complexes and so this chemistry is poorly developed with respect to that of the late transition metal and main group elements. This thesis describes the synthesis of new alkoxy-tethered NHC proligands, their use in the synthesis of reactive metal amide and metal alkyl complexes, and finally small molecule activation using these complexes. Chapter One introduces NHCs and discusses their use as supporting ligands for early transition metal and f-block complexes. Small molecule activation using organometallic complexes is examined alongside the use of electropositive metal NHC complexes in catalysis. Chapter Two contains the synthesis and characterisation of new alkoxy-tethered NHC proligands and a variety of electropositive MII (M = Mg and Zn), MIII (M = Y, Sc, Ce and U) and MIV (M = Ce and U) amide complexes. X-ray diffraction studies and a DFT study are used to probe the extent of covalency in the bonding of the MIV complexes. Chapter Three investigates the reactivity of the amide complexes prepared in Chapter Two. The MII complexes are shown to be initiators for the polymerisation of raclactide into biodegradable polymers. The MIII complexes are used to demonstrate additionelimination reactivity of polar substrates across the M-Ccarbene bond which allows the formation of new N-E (E = Si, Sn, P or B) bonds. Treatment of the UIII silylamide complex U(N{SiMe3}2)3 with CO results in the reductive coupling and homologation of CO to form an ynediolate core -OC≡CO- and the first example of subsequent reactivity of the ynediolate group. The MIV complexes are used to examine the potential for forming MIV cationic species and alkyl complexes. Chapter Four examines the synthesis of MIII (M = Ce and Sc) aminobenzyl complexes and MIII (M = Y, Sc and U) neosilyl and neopentyl alkyl complexes. The addition-elimination reactivity discussed in Chapter Three is extended to include C-E bond formation (E = Si, Sn, P, B, I or C). Chapter Five provides overall conclusions to the work presented within this thesis. Chapter Six gives experimental and characterising data for all complexes and reactions in this work.

Thesis advisor: Marc L. Snapper / Chapter 1 Review of methodology developments in the area of selective tosylation of alcohols. Chapter 2 Development of a catalytic enantioselective tosylation of alcohols with an amino-acid-based organocatalyst. / Thesis (MS) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Stoichiometric and catalytic small molecule activation reactions are vital for the synthesis of new materials. The activation of phosphorus-hydrogen or phosphorus-phosphorus bonds allows for the facile synthesis of new phosphorus-containing molecules for a wide variety of applications.1 An investigation of the P-H dehydrocoupling reaction was undertaken utilizing two rhodium(I) based catalysts. Over the course of this investigation it was found that the Rh(I) systems were also active catalysts for the reverse reaction: phosphorus-phosphorus bond hydrogenation (and hydrosilylation). This reaction was exploited for the synthesis of novel phosphines from P-P bound species. Molecules with P-P bonds were reacted in a stoichiometric fashion with the catalyst precursor, producing a variety of novel species with interesting bonding features which shed some light on the reaction mechanism. Following the discovery in 2006 that a linked phosphine-borane system could reversibly activate hydrogen2 a tremendous effort has been put forth to understand and expand this unprecedented reactivity.3,4 This new archetype for metal-free small molecule activation, containing a bulky Lewis acid and Lewis base which are unable to bond directly due to steric repulsion, has been termed a “frustrated Lewis pair” (FLP).3,4 The FLP concept is expanded to include bulky P-P bound species, pyridines and P-O bound Lewis bases as partners for B(C6F5)3. In some cases small molecule activation produced ion pairs or zwitterions related to those found for reactions with tertiary phosphines,3,4 but in others novel reaction pathways were discovered including phosphorus-phosphorus bond cleavage, catalytic hydrogenations and the formation of novel intramolecular FLPs. An unexpected situation was observed for the pair of 2,6-lutidine with B(C6F5)3, where adduct formation was observed along with free Lewis acid and base, but H2 activation by the FLP proceeded smoothly. Covalently bound phosphinoboranes of the general formula R2PB(C6F5)2 are synthesized. While systems with small R groups dimerized, monomers existed for cases with bulkier R groups. These monomers were found to exhibit extraordinarily short phosphorus-boron bonds yet were still capable of H2 activation analogous to bimolecular phosphine-borane systems. These systems also showed unique reactivity with Lewis acids and Lewis bases. This work further demonstrates the broad and general utility of the FLP concept in the synthesis of new materials and in catalytic transformations.

Wnt signaling is important in human development and disease, thus dysregulated beta-catenin constitutes an attractive target for drug intervention. The few functional inhibitors currently available target transcriptional activation, therefore, identifying novel upstream modulators would be of tremendous importance to elucidating the mechanisms involved in regulatingbeta-catenin activity. To achieve this, I developed a high-throughput screen to assess beta-catenin stability in mammalian cells using a luciferase tagged beta-catenin molecule. This assay was used to screen three chemical libraries to identify small molecule modulators of the pathway. Identified inhibitors/activators of the pathway were investigated via secondary assays. The most promising inhibitor, 21H7, significantly attenuated activated beta-catenin signaling in colon cancer cells, decreasing beta-catenin stability. The inhibitory effects of 21H7 and a structurally similar compound were shown to not only inhibit Wnt target gene expression in colon cancer cells, but also prostate cancer lines. Thus, 21H7 represents an attractive lead compound for further study.

Cancer accounts for nearly one-quarter of deaths in the United States, exceeded only by heart diseases. In 2006, there were 559,888 cancer deaths in the US. Finding effective treatments for cancer is a major challenge among researchers. In solid tumor, hypoxia increases the progression of malignancy and metastasis by promoting angiogenesis. The transcription factor HIF-1 is responsible for the regulation of cellular processes, including glycolysis and angiogenesis. Clinical evidence has determined that expression of HIF-1 is strongly associated with poor patient prognosis. Also, activation of HIF-1 contributes to malignant behavior and therapeutic resistance. In view of these observations, there is a need for anti-cancer treatments that addresses hypoxic related tumors. HIF-1 presents a viable target for inhibition of tumor growth with small molecules. Herein, we describe the design and synthesis of small molecules that inhibit the HIF-1 pathway, as well as mechanistic studies involved in the investigation of the mode of action of these compounds.

Wnt signaling is important in human development and disease, thus dysregulated beta-catenin constitutes an attractive target for drug intervention. The few functional inhibitors currently available target transcriptional activation, therefore, identifying novel upstream modulators would be of tremendous importance to elucidating the mechanisms involved in regulatingbeta-catenin activity. To achieve this, I developed a high-throughput screen to assess beta-catenin stability in mammalian cells using a luciferase tagged beta-catenin molecule. This assay was used to screen three chemical libraries to identify small molecule modulators of the pathway. Identified inhibitors/activators of the pathway were investigated via secondary assays. The most promising inhibitor, 21H7, significantly attenuated activated beta-catenin signaling in colon cancer cells, decreasing beta-catenin stability. The inhibitory effects of 21H7 and a structurally similar compound were shown to not only inhibit Wnt target gene expression in colon cancer cells, but also prostate cancer lines. Thus, 21H7 represents an attractive lead compound for further study.

Stoichiometric and catalytic small molecule activation reactions are vital for the synthesis of new materials. The activation of phosphorus-hydrogen or phosphorus-phosphorus bonds allows for the facile synthesis of new phosphorus-containing molecules for a wide variety of applications.1 An investigation of the P-H dehydrocoupling reaction was undertaken utilizing two rhodium(I) based catalysts. Over the course of this investigation it was found that the Rh(I) systems were also active catalysts for the reverse reaction: phosphorus-phosphorus bond hydrogenation (and hydrosilylation). This reaction was exploited for the synthesis of novel phosphines from P-P bound species. Molecules with P-P bonds were reacted in a stoichiometric fashion with the catalyst precursor, producing a variety of novel species with interesting bonding features which shed some light on the reaction mechanism. Following the discovery in 2006 that a linked phosphine-borane system could reversibly activate hydrogen2 a tremendous effort has been put forth to understand and expand this unprecedented reactivity.3,4 This new archetype for metal-free small molecule activation, containing a bulky Lewis acid and Lewis base which are unable to bond directly due to steric repulsion, has been termed a “frustrated Lewis pair” (FLP).3,4 The FLP concept is expanded to include bulky P-P bound species, pyridines and P-O bound Lewis bases as partners for B(C6F5)3. In some cases small molecule activation produced ion pairs or zwitterions related to those found for reactions with tertiary phosphines,3,4 but in others novel reaction pathways were discovered including phosphorus-phosphorus bond cleavage, catalytic hydrogenations and the formation of novel intramolecular FLPs. An unexpected situation was observed for the pair of 2,6-lutidine with B(C6F5)3, where adduct formation was observed along with free Lewis acid and base, but H2 activation by the FLP proceeded smoothly. Covalently bound phosphinoboranes of the general formula R2PB(C6F5)2 are synthesized. While systems with small R groups dimerized, monomers existed for cases with bulkier R groups. These monomers were found to exhibit extraordinarily short phosphorus-boron bonds yet were still capable of H2 activation analogous to bimolecular phosphine-borane systems. These systems also showed unique reactivity with Lewis acids and Lewis bases. This work further demonstrates the broad and general utility of the FLP concept in the synthesis of new materials and in catalytic transformations.