Inaug.-diss.--Rostock. / Cover title. "Lebenslauf": p. 103.

Thesis (M.S.)--Virginia Polytechnic Institute, 1953. / Vita. Includes bibliographical references (leaves 55-57). Also available via the Internet.

by Mabel Siu-Man Yuen. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (p. 146-161). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

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Conventional xanthene dyes (eg: fluorescein and rhodamine) have their absorptions and emissions in the visible region, which limits their use in cellular imaging. Absorptions and emissions at longer wavelengths allow for low background cellular autofluorescence, deep tissue penetration, and minimum cell damage. Chapter I discusses the background of fluorescent dyes and the importance of near-infrared (NIR) emissive dyes for biological applications. Chapter II is based on the design and synthesis of new xanthene-based NIR I dyes using simple and short synthetic routes. This study used pyrrole and indole as donor molecules and combined them to the xanthene core by the Suzuki cross-coupling reaction to prepare the new dyes. After the treatment with trifluoroacetic acid, these new dyes transformed from their non-fluorescent to fluorescent forms and exhibited excellent red shifts in their maximum absorption and emission wavelengths. The novel pyrrole-based xanthene dye was used to investigate the efficacy of the dye as a probe for fluoride ions. We were able to modify this dye with a silyl ester receptor and develop a probe as a colorimetric turn-off fluoride ion sensor. In chapter III, we describe the synthesis of different NIR emissive xanthene dyes using the donor-acceptor-donor concept. New xanthene-based dyes were designed with five-membered heterocycles and fused heteronuclear molecules. Additionally, xanthene-based dyes containing an alkyne spacer were synthesized using the D-pi-A model to extend the pi-conjugation through the alkyne spacer. All of the dyes exhibited absorption and emission maxima in the visible to NIR I region, between 500-850 nm. In chapter IV, we discussed the synthesis of xanthene-based electrochromic materials. These compounds used xanthene as the chromophore and ferrocene as the electrophore units. Novel rhodamine-based symmetric and unsymmetric dyes were synthesized by attaching the ferrocene unit through the lactam ring. The compounds were then investigated as an electrochromic probe using UV-Vis, cyclic voltammetry, and spectroelectrochemical analysis.

The carbazole and 2-isopropenyl-2,3-dihydrobenzofuran structures are widely found in many naturally occurring compounds. For example, the naturally occurring anti-cancer compound, rebeccamycin, contains an indolocarbazole core. Rotenone, which contains an (R)-2-isopropenyl-2,3-dihydrobenzofuran moiety, is widely used today as an effective naturally occurring pesticide. In the carbazole section of this thesis, the synthesis of the naturally occurring furanocarbazole, furostifoline is described. As key steps in this sequence, a Suzuki coupling reaction is utilised to couple appropriately functionalised indole and furan moieties. After further functional group transformations, a metathesis reaction is employed to construct the carbazole system, leading to furostifoline. The synthesis of the unnatural thio-analogue of furostifoline was similarly conducted and is described. Finally, in a somewhat different approach, the synthesis of the indolocarbazole core is described, utilising a Madelung approach initially to form the bis-indole system, 2,2’-biindolyl. After several functional group transformations, a metathesis reaction was once again successfully employed to form the carbazole system, thereby synthesising di(tert-butyl) indolo[2,3-a]carbazole-11,12-dicarboxylate. In the benzofuran section of this thesis, the successful chiral synthesis of two 2- isopropenyl-2,3-dihydrobenzofuran systems is described. As a precursor to rotenone, the synthesis of (R)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol is described starting from resorcinol. The key step in this synthesis is a stereoselective intramolecular Pd π-allyl mediated cyclisation utilising the R,R’-Trost ligand, thereby forming (R)-2-isopropenyl- 2,3-dihydrobenzofuran-4-ol in excellent yield and enantiomeric excess. The alternative enantiomer, (S)-2-isopropenyl-2,3-dihydrobenzofuran-4-ol, was similarly synthesised. Finally, a similar approach was utilised to synthesise both (S)- and (R)-2-isopropenyl-2,3- dihydrobenzofuran, starting from 2-allyl-phenol, and thereby completing a formal synthesis of the naturally occurring compounds, (S)-fomannoxin and (R)-trematone, respectively.

A review of the more important methods of synthesis of 1,3-diarylisobenzofurans (III) and o-diaroylbenzenes (II) was made. These were compared with the possibilities involved in the type of synthesis in which substituted o-benzylbenzophenones (I) are oxidized to o-diaroylbenzenes (II) and subsequently reduced to 1,3-diarylisobenzofurans (III). It is seen that this latter method affords a greater variety of substituents for these types of compounds than the other methods. The possible orientations of substituents are also greater. Two o-benzylbenzophenones (I), 2’-methyl-2-benzylbenzophenone (LIII) and 2'-methoxy-2-benzylbenzophenone (LVI), were prepared by the action of the appropriate Grignard reagent on o-benzylbenzonitrile (LII) and subsequent hydrolysis of the intermediate ketimine. These were oxidized to the corresponding o-dibenzoylbenzenes (II), 2’-methyl-2-benzoy1 benzophenone (LIV), and 2'-methoxy-2- benzoylbenzophenone (LVII), by the use of sodium dichromate and sulfuric acid, Reduction of these with zinc dust in acetic acid gave the corresponding 1,3-diarylisobenzofurans (III), 1-(2‘-methylpheny1)-3-phenylisobenzofuran (LV) and 1-2" -methoxyphenyl)-3-phenyl isobenzofuran (LVIII). Attempts were made to prepare 2'-chloro-2-benzylbenzophenone (I; Reo-Cl and R'=R) by the same method as that in the above-mentioned paragraph. None of the ketone could be obtained. A small amount of a hydrocarbon was obtained in one case which was analyzed as C₂₀H₁₄. The action of the Grignard reagent of 4-iodo-1, 3-dimethylbenzene on o-chlorobenzaldehyde gave 2-chloro-2', 4'-dimethylbenzohydrol (LI). New compounds synthesized are 2‘-methy1-2~benzoylbenzophenone (LIV), 2'-methoxy-2-benzoyl benzophenone (LVII), 1-(2'-methylphenyl)-3-phenylisobenzofuran (LV), 1-(2'-methoxyphenyl1)-3-phenylisobenzofuran (LVIII), and 2-chloro-2! ,4'-dimethylbenzohydrol (LI). / Master of Science

Thrombin is a key enzyme of the coagulation cascade exhibiting important roles in both pro-coagulation and anti-coagulation processes. Most clinically used anticoagulant drugs, including polymeric heparin, warfarin, hirudin, argatroban and the recently approved dabigatran, aim to reduce thrombin activity. There are several binding domains on thrombin including the active site, anion-binding exosites I and II, and the sodium binding site. We hypothesized that thrombin may be better regulated through an allosteric process mediated by small molecules binding to either exosite I or II. An appropriately designed allosteric regulator that reduces the procoagulant signal in a finely tuned manner may maintain a delicate balance between procoagulant and anticoagulant signals in blood resulting reduced bleeding complications. In this work, we synthesized and studied a library of potent, small, aromatic molecules as allosteric inhibitors of thrombin. Of the 28 potential inhibitors, 11 molecules inhibited thrombin with reasonable potency. Structure activity relationship studies showed that sulfation at the 5-position of the benzofuran scaffold was essential for targeting thrombin. Michaelis-Menten kinetic studies indicated a non-competitive, allosteric mechanism of inhibition. Site-directed mutagenesis, competitive binding and molecular modeling studies led to the identification of the most plausible binding pose for a potent sulfated dimer. To further improve the potency, a small library of sulfated benzofuran trimers was synthesized and studied for thrombin inhibition. Further, to find new scaffold to inhibit thrombin allosterically, docking-based virtual screening approach was used. All these molecules were found to be moderately potent thrombin inhibitors and can serve as lead to develop allosteric inhibitor. Overall, this work presents the first small, synthetic, sulfated aromatic molecules as potent allosteric modulators of thrombin. Finally, this work also highlights the opportunity of exploring allosteric modulators of other coagulation enzymes, e.g., factors Xa, IXa and XIa, based on the sulfated benzofuran scaffold.

Neste trabalho, as fragmentações de 2-aroilbenzofuranos e de neolignanas diidrobenzofurânicas (NDB) foram investigadas empregando espectrometria de massas sequencial com ionização por eletrospray (ESI-MS/MS). Os compostos estudados foram sintetizados e, em seguida, suas vias de fragmentação em condições de dissociação induzida por colisão (CID) foram associadas às suas respectivas estruturas. Além das relações estrutura-fragmentação, espectrometria de massas de múltiplos estágios (MSn) e dados termoquímicos, obtidos por Química Quântica Computacional, foram também utilizados para a elucidação das vias de fragmentação. Para os 2-aroilbenzofuranos protonados, os resultados demonstraram que dois íons acílios, provenientes de rearranjos de hidrogênio competitivos, são os mais intensos nos espectros de íons produtos. O íon acílio [M+HC6H6]+ foi o mais intenso para todos os 2-aroilbenzofuranos investigados devido ao fato de que sua decomposição requerer energia crítica maior que a de outras vias de fragmentação competitivas. No caso das NDBs, os resultados indicaram que perdas de CH3OH e CO são comuns aos compostos analisados, tanto na forma protonada como na forma desprotonada. Entretanto, as perdas de CH3OH a partir de NDB protonadas envolvem migração de carga, enquanto que para moléculas desprotonadas, a perda de metanol é um processo remoto à carga. A perda de ceteno (C2H2O) diretamente da molécula protonada é uma via diagnóstica das NDB acetiladas, enquanto que os íons produtos [M+HC3H6O2]+ ou [M+HC6H6O]+ são diagnósticos das NDB que apresentam saturação entre C7 e C8. Para NDBs desprotonadas, íons produtos formados por perdas de CH3 são diagnósticos de grupos metoxila ligados ao anel aromático. A presença do grupo acetil também levou à formação de alguns íons diagnósticos devido à mudança no sítio de desprotonação. Por sua vez, clivagens da cadeia lateral remotas à carga são fragmentações diagnósticas de NDBs que apresentam saturação entre C-7 e C-8. As estruturas dos íons propostos foram suportadas por dados termoquímicos (entalpia e energia de Gibbs). Os resultados deste trabalho contribuem para o conhecimento da química em fase gasosa desses compostos e auxiliarão na identificação dos mesmos diretamente de misturas. / In this work, the fragmentation of 2-aroylbenzofuran and dihydrobenzofuran neolignans (DBN) was investigated using electrospray ionization tandem mass spectrometry (ESI-MS/MS). The studies compounds were synthesized and their fragmentation pathways under collision-induced dissociation (CID) were associated with their respective structures. Besides the structure-fragmentation correlations, multiple-stage mass spectrometry (MSn) and thermochemical data, which were estimated by Quantum Computational Chemistry, were also employed in the elucidation of the fragmentation pathways. For protonated 2-aroylbenzofuran, the results demonstrated that two acylium ions, which arises from two competitive hydrogen rearrangements, are the most intense in the product ion spectra. The acylium ion [M+HC6H6]+ was the most intense for all the investigated 2-aroylbenzofuran, since its decomposition requires a higher critical energy as compared to other competitive fragmentation processes. In the case of DBNs, our results indicated that eliminations of CH3OH e CO are common to the analyzed compounds in their protonated and deprotonated forms. However, eliminations of CH3OH from protonated DBNs involve charge migration, whereas elimination of CH3OH from deprotonated DBNs is a fragmentation remote to the charge site. Elimination of ketene (C2H2O) directly from the protonated molecule is diagnostic for acetylated DBNs, whereas the product ions [M+HC3H6O2]+ or [M+HC6H6O]+ are diagnostic for DBNs displaying a saturated bond between C7 and C8. For deprotonated DBNs, product ions resulting of CH3 losses are diagnostic for methoxyl groups attached to the aromatic ring. The presence of the acetyl group also led to the formation of some diagnostic ions due to the change of the deprotonation site. For compounds that display a saturated bond between C-7 and C-8, cleavages of the side chain of DBNs are also diagnostic. The structures of the proposed ions were supported by thermochemical data (enthalpy and Gibbs energy). The results of this work will contribute to the knowledge of the gas-phase ion chemistry of these compounds and will aid in their identification directly from mixtures.