The derivatives of boradiazaindacene (BODIPY) are highly fluorescent dyes which have quantum yields near 1.0. These dyes that have exceptional spectral and photophysical stability as compared to other fluorescent groups are used for several different applications. The fluorescent sensor molecules for the detection of cations with PET (photoinduced-electron transfer) mechanism in general have been obtained by the differentiation of the BODIPY core. The extension of conjugation over the pyrrole ring shifts the absorption and emission at longer wavelength. Moreover, it is seen that red emission occurs from an ICT (intramolecular-charge transfer) state. iii In this study, we designed and synthesized an unsymetrically substituted BODIPY dye series, carrying a cation-sensitive phenylazacrown ether group conjugated to the core, and investigated the ion sensing properties of these compounds. Both aza-crown derivatives displayed selectivity towards Ca(II).

Nature has inspired chemists to develop complex assemblies that perform functions in biologically relevant solutions. Yet this is not a trivial task. Not only does water act as a competitive medium but the salts that are inevitably present hamper supramolecular hosts from properly binding and carrying out their programmed function. This work was inspired by a serendipitous discovery of water-soluble functionalized calix[4]arenes that self-assemble into homodimers in salty water, mock serum and real urine. This thesis aims to explore this homodimerizing motif to learn more about self-assembly in salty water and to develop useful supramolecular tools. First the structural limits of the calixarene motif was explored by the transformation into a clip-like host that assembled similarly in water. NMR titrations revealed that the homodimers responded to hydrophobic cationic guests by dissociating to form new host-guest complexes. The resilience of the self-assembling motif was then tested against extreme co-solute conditions. In this part of the study, reversible covalent bonds were introduced within the dimer scaffold to afford a dynamic library of exchangeable hosts. Quantitative NMR was used to monitor each host in response to molar concentrations of urea and salt. This work also reports on a new class of salt-tolerant supramolecular chemosensors, called DimerDyes. These sensors form quenched homodimers in water but dissociate in the presence of hydrophobic cations to form new emissive complexes. Its mode of action was characterized by DOSY, 1H NMR and fluorescence spectroscopy. DimerDyes successfully monitored enzymatic reaction in real-time despite the presence of competitive salts and co-factors. The DimerDye concept was quickly expanded by the parallel synthesis of crude DimerDyes and efficient testing for illicit drugs without the need for purification. “Hit” dimers were then purified, characterized and were able to detect multiple different drug classes in real saliva. / Graduate / 2020-09-19

Carbohydrates are known to play important roles in a large number of physiological and pathological processes. Conceivably, “binders” of carbohydrates of biological importance could be used as diagnostic and therapeutic agents. Currently, lectins are the major available tools in research for carbohydrate recognition. However, the available lectins often have cross-reactivity issues, along with the high costs and stability issues. Therefore, there is a critical need to develop alternatives (lectin mimics). In this regard, there have been very active efforts in developing different “binders”, such as small molecule lectinmimics and aptamers. Among all the small molecule lectinbmimics developments, boronic acid stands out as the most important building blocks of the sensors design for carbohydrates biomarkers due to its intrinsic binding affinities with diols. To address a fundamental question that whether boronic acid also binds to six-membered ring sugars, with very limited precedents, we provided a concrete experimental evidence of the binding. Specifically, a series of isoquinolinylboronic acids were found to have remarkably high binding affinities with fluorescence change upon binding to representative sugars. Most importantly, these isoquinolinylboronic aicds showed weak but very encouraging bindings with six-membered sugar model. All these promising results paves the way of using boronic acids, especially isoquinolinylboronic acid as building blocks for chemosensors design for biological carbohydrates biomarkers, which universally contain six-membered ring and liner diols. Aptamer provides another alternative way for sensors development for carbohydrates biomarkers as lectin mimics. Compared to lectins, they are normally cheaper and more stable. However, there is much less options. Another challenging area for aptamer-based lectin mimics development is the difficulty to differentiate changes in glycosylation patterns of a glycoprotein, which affect the function of a glycoprotein and thus recognized as biomarkers. To address this major challenge, our group first demonstrated that the incorporation of a boronic acid into DNA would allow for the aptamer selection process to gravitate towards the glycosylation site. To examine the generality of boronic acid incorporation, increase the structural diversity, and broaden the application of boronic acid-modified DNA, a series of B-TTP analogues with simplified structures were designed, synthesized, and successfully incorporated into DNA. A simple route was also developed using 1,7-octadiyne as a linker for both Sonogashira coupling with thymidine and CuAAC tethering of a boronic acid moiety. This paves the way for the preparation of a large number of B-TTPs with different structural features for aptamer selection or array analysis. Finally, bacterial quorum sensing has received much attention in recent years because of its relevance to pathological events such as biofilm formation. As one of the very first groups that developed a series of antagonists for AI-2 mediated quorum sensing, we herein designed and synthesized a series of analogues based on the structures of two lead inhibitors identified through virtual screening. Besides, we also examined their inhibitory activities, twelve of which showed equal or better inhibitory activities compared with the lead inhibitors. The best compound showed an IC50 of about 6 mM in a whole cell assay using Vibrio harveyi as the model organism. This encouraging results and SAR discuss also paves the way for the finding of more potent compound through further structure optimization.

Boronic acids play an important role in the design and synthesis of chemosensors for carbohydrates due to their ability to reversibly bind with diol-containing compounds. Along this line, the availability of boronic acids that change fluorescence upon sugar binding is critical to a successful sensor design effort. Here, two boronic acids that show strong fluorescent intensity changes upon sugar binding are reported: isoquinoline-7-boronic acid (7-IQBA) and phenoxathiin-4-boronic acid (4-POBA).

Supramolecular chemistry is an emerging field of chemistry which has attracted much attention in recent years as a result of its broad applicability in many areas. Thus, the design of functional supramolecular systems is strongly in demand in this field. For this purpose, we have developed near-IR emitting ratiometric fluorescent chemosensors for transition metal ions. Judicious placement of dithiodioxaazamacrocycles on the BODIPY chromophore generates this chemosensor which is selective for Hg(II) ions and both absorption and emission spectra display large changes that would allow ratiometric sensing.

Rational design of fluorescent chemosensors is an active area of supramolecular chemistry, photochemistry and photophysics. Ratiometric chemosensors are even more important, as they have an internal system for selfcalibration. In order to develop a new methodology for a ratiometric chemosensor design, we proposed coupling of energy transfer phenomenon to ion sensing. In this study, we targeted energy transfer cassette type chemosensors, where the efficiency of transfer is modulated on the donor side, by metal ion binding which changes the spectral overlap. This work involves the synthesis of a number of EET systems with varying degrees of EET efficiency. The results suggest that this strategy for ratiometric ion sensing is a promising one, enabling a modular approach in chemosensor design.

Near-IR dyes that absorb and emit in the red visible or near-IR region have attracted great interest in the fields of medicinal chemistry and biochemistry for the last few decades. This interest is due to the multiple notes of metal ions in biological and enviromental processes. Therefore the development of cation selective and sensitive sensors have been a hot subject for many researchers. Consequently, fluorescence based sensors are the most efficient and favorable ones among its counterparts in the field of sensor research. In this study, we have targeted to synthesize BODIPY based near-IR dyes as a selective fluorophore for Zn (II) and Hg (II) cations. We have also demonstrated that the versatile BODIPY fluorophore can be functionalized for long wavelength emission on the 3 and 5 position of the BODIPY core with multiple and distinct functional groups in a stepwise manner. Thus we are able to link two BODIPY cores with a different absorption wavelengths to each other first time with click chemistry strategy to generate a chemosensor for Hg (II) cation.

This thesis covers the combination of two seperate work accomplished during the throughout the study. In the first part of the study, xanthene based artificial enzymes were synthesized, and kinetic hydrolysis studies done. Artificial enzyme design is an active field of supramolecular chemistry and metalloenzymes are attractive targets in such studies. Enzymatic catalysis is essentially a &lsquo / multifuctional&rsquo / catalysis. As part of our work, we designed and synthesized three novel xanthene derivatives. All three model contain Zn(II) in their active sites. Using the model substrate p-nitrophenyl acetate, we showed that the bifunctional model is at least an order of magnitude more active in catalyzing the hydrolysis of the substrate. Compared to the uncatalyzed hydrolysis reaction of the p-nitrophenyl ester at pH 7.0, the bifunctional model complex showed a 5714-fold rate acceleration. The second part of the thesis involves the design of a dimeric calixpyrrole as a chromogenic chemosensor. Anions are involved in a large number of biological processes and there is an interest in developing molecular sensors for these charged species. The calixpyrroles are a class of old but new heterocalixarene analogues that show considerable promise in the area of anion sensing. In this work, we have designed, synthesized and characterized a calixpyrrole-dimer anion sensor for its anion binding strength. The dimer forms stable complexes with p-nitrophenolate ion. This formed complex is used as a colorimetric sensor by displacing the chromogenic anion with the addition of various anions. like fluoride and acetate. The receptor shows strong affinity and high selectivity for fluoride anion, and also show reasonable affinity toward acetate. Thus, effective optical sensing of biochemically relevant these anions is accomplished using the calixpyrrole dimer.

The aim of the diploma thesis was to prepare and characterize fluorescence sensor systems based on fluorophores and supramolecular components - cyclodextrins - attached to solid supports. In this work, functionalized 75 µm glass beads and two types of Nafion membranes were used as negatively charged solid surfaces. Derivatives of naphthalimide with a positively charged part allowing the attachment to surfaces were synthesized. The positively charged naphthalimide derivative was then attached on negatively charged surfaces via electrostatic interactions and the binding to the solid supports was examined using UV-VIS spectroscopy. Alternatively, the positively charged β-cyclodextrin derivative was also attached to the surface in an equimolar ratio with PNI-HEMPDA. The focus of the work were measurements of fluorescence sensor responses in the gas and liquid phase to linear alcohols - methanol to n-hexanol - for all sensor systems. For the studied sensor systems, the selected sensor parameters were determined - sensitivity, the limit of detection, linear dynamic range and a sensor response time constant. A practical application of the novel sensor system for the detection of ethanol in gasoline was examined. Fluorescence sensor response measurements of the prepared systems based on naphthalimide and...

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18299号 / 工博第3891号 / 新制||工||1597(附属図書館) / 31157 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 濵地 格, 教授 梅田 眞郷, 教授 森 泰生 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM