The family of oligomeric natural products derived from resveratrol possesses broad pharmacological potential, with the larger members of the class often displaying the most impressive bioactivities and the highest potencies. In particular, the trans-dihydrobenzofuran architectural motif, common to the majority of the natural materials, appears to act as a pharmacophore. Our group proposes controlled stepwise synthesis of the resveratrol derivatives to allow access to the higher-order oligomers, bypassing their inefficient isolation from natural sources. Specifically, this work focused on regioselective installation of the trans-dihydrobenzofuran motif on diverse cores. This goal was achieved by employing electrophilic aromatic substitution and directed lithiation as selective functionalization tools. A robust and broadly applicable method has been developed to allow the elaboration of the resulting functional handles into the desired structural motif.

No description available.

本論文描述了一系列由銅(I)催化-疊氮-端基炔環加成反應（CuAAC）而生成並具有分子内氫鍵的AABB型共聚主鏈（酰胺-三唑）化合物，並以此研究結構上的預組織對這一系列聚合物的聚合效率、物理性質和超分子性質的影響。 / 從衍生自吡啶-2,6-二甲酰胺或對苯二甲酰對苯二胺的二炔單體61或62與具有醌二疊氮化物單體63或64共聚，可獲得一系列重復單元内含兩個分子内氫鍵並具有不同内部結構的聚（酰胺-三唑）化合物。此外，一系列結構相似但重復單元内不含分子内氫鍵的二炔單體65-69也被用於與63或64共聚以作比較。透過核磁共振光譜法，質譜法，和/或尺寸排阻排阻色譜法（SEC）的鑑定能確認所有份子的結構。通過SEC分析結果顯示，只有每個重復單元内含分子内氫鍵的單體61或62得到的相應點擊聚合物才具有較高的DP值。這些結果表示，分子間的氫鍵能增強化合物結構的剛性從而減少環狀聚合物的產生，因而提高聚合度。 / 我們還發現，這些具預組織能猶的骨架的可以提升它們的自組裝能力，並促使它們在芳香溶劑裏形成可逆的有機凝膠。我們採用傅里葉轉換紅外光譜（FTIR）、X-射線粉末衍射（XRD）和掃描電子顯微鏡（SEM）對自組裝機制進行了研究。相比之下，重復單元内不含足夠分子内氫鍵的結構類似物65-69卻不能形成凝膠。 / 最後，我們發現，含有三唑基間苯二甲酰間苯二胺或三唑基吡啶-2,6-二甲酰胺基的聚（酰胺-三唑）化合物可以利用酰胺的NH和三唑的CH形成多個可結合滷素陰離子的位點。我們先用結構更簡單的寡聚類似物113-114和118模仿滷素陰離子(氯、溴、碘)結合強度，模式和機制。結果顯示，寡聚類似物與氯離子的結合強度明顯高於溴陰離子、碘陰離子是最弱的。有趣的是，間苯二甲酰間苯二胺的類似物對滷素陰離子的結合能力比吡啶-2,6-二甲酰胺類似物高得多。表明預組織的酰胺NH和三唑CH並沒有提供明顯對陰離子結合的優勢。相反，含有氮孤對的吡啶-2,6-二甲酰胺系統對滷素陰離子的結合的不穩定性影響更突出。根據此訊息，聚合物對滷素陰離子的結合特性就能得以估計。這研究結果得出一系列少數具有陰離子封裝能力的中性聚合物。 / This thesis described the copper(I)-catalyzed alkyne-azide AABB-type copolymerization of a series of main-chain poly(amide-triazole) compounds containing intramolecular hydrogen bond motifs, with the aim of understanding the effects of hydrogen bond-promoted preorganization on polymerization efficiencies and their physical and supramolecular properties. / A dialkyne monomer, 61 or 62 derived from pyridine-2,6-dicarboxamide or terephthalamide with two intramolecular hydrogen bonds per repeating unit, were synthesized and copolymerized with a diazide monomer, 63 or 64 respectively, to give the corresponding poly(amide-triazole)s (99 and 106) with different internal architecture. For comparison purposes, structurally similar dialkyne monomers 65-69 but with only one or no intramolecular hydrogen bonds per repeating unit were also prepared and copolymerized with the same diazide monomer 63 or 64 to give polymers 100-103 and 107. All compounds were characterized by a combination of nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, and/or size exclusion chromatography (SEC). According to SEC analysis, it was found that monomers 61-62, with two intramolecular hydrogen bonds per repeating unit gave the corresponding click polymers with higher DP values. These results indicated that the imposed structural rigidity created by the intramolecular hydrogen bonds could reduce the amount of cyclic polymers and enhance the propagation growth of the polymerization process. / It was also discovered that such a preorganization along the backbone of poly(amide-triazole)s could enhance their self-assembly process and promote the formation of thermoreversible organogels in aromatic solvents. The assembly mechanisms were investigated by Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (XRD) and scanning electron microscopy (SEM). The organogelating property was not observed in other structural analogues (100-103 and 107) that lack the sufficient number (i.e. 2 per repeating unit) of intramolecular hydrogen bonds. / Finally, it was found that poly(amide-triazole)s that contained repeating triazolyl isophthalamide or triazolyl pyridine-2,6-dicarboxamide motifs could utilize the amide NH and triazole CH groups to form multiple binding sites for halide anions. The halide (Cl⁻, Br⁻, I⁻) binding strengths, modes and mechanisms were first modeled using the structurally simpler oligomeric analogues 113-114 and 118. It was found that the binding strength of the chloride anion was higher than that of the bromide anion, and that of the iodide anion was the weakest. Interestingly, the isophthalamide analogues possessed a much higher binding ability towards anions than the pyridine-2,6-dicarboxamide analogues, suggesting preorganization of the amide NH and triazole CH groups did not offer substantial advantages towards anion binding. Rather, the destabilizing effect of the nitrogen lone pair on the pyridine-2,6-dicarboxamide system was more prominent. Based on this information, the binding properties of the polymeric analogues were then formulated. These results represent one of the few examples of a class of neutral polymers that possessed anion binding ability. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Yim, Sui Lung. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 150-156). / Abstracts also in Chinese.

acase@tulane.edu / In the present study a few approaches are developed for theoretical investigation of vibrational energy propagation in highly ordered polymers and linear atomic chains. Density matrix formalism applied to explain the transition between ballistic and diffusive regimes in polymers, the diffusive and ballistic regimes of energy transport are described in terms of asymptotic limits of exact solution of Liouville-Bloch equation. Energy bands theory is developed for oligomeric structures such as perfluoroalkane and alkane compounds, as an example, practical application for understanding experimental data for alkane is discussed. Also, purely electronic torsional mode in linear atomic chains, such as cumulene, is considered. The speed of up to 1000~km/s for electronic sound is predicted, the spectrum of quanta (torsitons) of torsional electronic mode in cumulene is obtained. / 1 / Arkady Kurnosov

Tau is a protein which regulates microtubule stability and is heavily involved in axonal transport. This stability is dynamically controlled in part by over 40 phosphorylation sites across the tau protein which allows for binding and release from the microtubules. However, if abnormal hyperphosphorylation occurs, tau dissociates from the microtubules. Once released, the microtubules become unstable and the aberrant tau mislocalizes from the axon to the somatodendric compartment, where it aggregates. These aggregates are made of many pathological forms of tau including oligomeric species, paired helical filaments, and neurofibrillary tangles, all of which have associated toxicities. Tau pathology is a hallmark of Alzheimer's disease, one of over 15 diseases known as tauopathies which present with tau pathology, all of which lack effective treatments. Heat shock protein 90 kDa (Hsp90) is a major adenosine triphosphate (ATP)-dependent regulator of non-native proteins, like misfolded tau. Although Hsp90 is able to effectively refold and degrade many aberrant proteins, it has been associated with preserving aberrant tau. In fact, inhibiting the Hsp90 ATPase activity leads to the degradation of tau, which has been demonstrated in a number of models with the use of various Hsp90 inhibitors. However, there are many side-effects associated with the use of these inhibitors including toxicity and heat shock factor 1 (HSF1) activation. Although improvements on Hsp90 inhibitors are still in progress, this study explores targeting Hsp90 through a slightly different mechanism, by targeting Hsp90 co-chaperones. Hsp90 is involved in almost every pathway in each cell throughout the body. Co-chaperone proteins assist Hsp90 in these various processes, but are each only involved in a subset of the total Hsp90 interactome. Therefore, targeting Hsp90 co-chaperones could lead to improved efficacy, potency, and safety of drugs designed toward Hsp90 for the treatment of tauopathies. We previously showed one of these co-chaperones, FK506 binding protein 51 kDa (FKBP51), a tetratricopeptide repeat (TPR) domain containing immunophilin, coordinates with Hsp90 to regulate tau metabolism. More specifically, we found that increases and decreases in FKBP51 levels correlated with increases and decreases in tau levels, respectively. FKBP51 knockout mice have been extensively studied and have shown no negative phenotypes in these characterizations. In this study, we found that this mouse model has decreased endogenous tau levels. Furthermore, this study demonstrates that FKPB51 colocalizes with pathological tau in the AD brain, and synergizes with Hsp90 to preserve tau from proteasomal degradation. Additionally, FKBP51 overexpression in mouse model of tau pathology leads to the preservation of tau. We went on to characterize this accumulated tau as being neurotoxic and oligomeric in nature, while being low in silver positive, β-sheet structure. In the human brain, we found that FKBP51 is strikingly increased with aging and even further in the AD brain. In support of these findings, we also found age-associated decreased methylation in the FKBP5 gene, which encodes FKBP51. Moreover, we found that increasing levels of FKBP51 caused other co-chaperone to have reduced Hsp90 binding and led to tau preservation. This supports a model where age-related increases in FKBP51 lead to the preservation of misfolded tau species and ultimately disease. In order to model the high FKBP51 expression found in the aging brain, we generated the first FKBP5 overexpressing mouse model, which is tet-regulatable. This mouse, rTgFKBP5, was made by targeted, single insertion of the human FKBP5 gene into the HIP11 locus of the mouse genome crossed with CamKIIα tTa mice. We have now confirmed high FKBP51 levels in the forebrain and hippocampus of this mouse, which will serve as a testing platform for FKBP51 regulating drugs. Overall, this work exemplifies FKBP51 as an important regulator of tau metabolism through Hsp90. With the absence of a negative phenotype in mice ablated of FKBP51 and the development of this novel, FKBP51 overexpressing mouse model, strategies designed to decrease FKPB51 levels or to disrupt the FKBP51/Hsp90 complex could be relevant for the treatment of tauopathies, like AD.

Graduation date: 1991

No description available.

The distinct structural properties of heterochromatin accommodate a diverse group of vital chromosome functions, yet we have only rudimentary knowledge about its protein composition. One powerful tool for Drosophila biologists has been a group of genes that reverse the repressive effect of heterochromatin on the expression of a gene placed next to it ectopically. Several of these genes are known to encode proteins enriched in heterochromatin. The best characterized of these is the heterochromatin associated protein, HP1. HP1 has no known DNA-binding activity, hence its incorporation into heterochromatin is likely to be dependent upon other proteins. To examine HP1 interacting proteins, we isolated three distinct oligomeric species of HP1 from the cytoplasm of early Drosophila embryos and analyzed their compositions. The two larger oligomers resemble a fraction of that is tightly associated with the chromatin of interphase nuclei. Like the HP1 in these two cytoplasmic oligomers, this tightly bound nuclear fraction of HP1 is underphosphorylated and is associated with subunits of the origin recognition complex (ORC). We also found the localization of HP1 into heterochromatin to be disrupted in mutants for the ORC2 subunit. This phenotype supports a role for ORC in HP1 targeting and heterochromatin assembly. This proposed role for Drosophila ORC suggests striking similarities to the ability of ORC to recruit the Sir1 protein to silencing nucleation sites at the silent mating type loci in S. cerevisiae.

Thesis (Ph. D.)--University of Hawaii at Manoa, 1994. / Includes bibliographical references (leaves 86-90). / Microfiche. / xiii, 90 leaves, bound 29 cm

Thesis (Ph.D.)--Tufts University, 2001. / Adviser: Clemens Richert. Submitted to the Dept. of Chemistry. Includes bibliographical references (leaves 228-235). Access restricted to members of the Tufts University community. Also available via the World Wide Web;