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Chemically cross-linked hydrogels (chemical gels) offer a number of enhanced properties over their physical counterparts, particularly in biomedical applications such as drug delivery, tissue engineering, and cell encapsulation. Conventional chemical gels are generally too elastic to be introduced into the body without requiring surgical implantation, making them challenging to use in a clinical context. In response, this thesis is focused on developing injectable analogues of conventional hydrogel-based biomaterials as well as advanced, engineered injectable hydrogels, enabling the facile use of these hydrogels in biomedical applications. Cross-linking is achieved using hydrazone chemistry, in which one precursor is functionalized with aldehyde groups and the other is functionalized with hydrazide groups. Following coextrusion of the reactive precursors, a stable hydrogel network spontaneously forms within seconds. By employing this chemistry as a standard in all of this work, a number of injectable hydrogel systems with well-defined properties (including swelling, drug loading and release, optical properties, gel formation and degradation kinetics, response to the temperature of the surrounding environment, and tissue response) have been generated that can be tuned by rationally varying the charge content in the precursor polymers, the number of cross-linking functional groups used, the reactivity of the electrophilic cross-linking units, and the length and number of hydrophobic affinity domains present within the gels. This work therefore presents a series of independent methods for customizing hydrogels so that they may be adapted to a number of different biomedical applications. / Dissertation / Doctor of Philosophy (PhD)

<p> This thesis describes the development of the Wittig olefination reaction of stabilized, semistabilized allylic trialkylphosphorus ylides with various aldehydes to afford E olefins mainly (E>89%). Since the steric demand of trialkylphosphorus ylides was decreased, aldehydes achieved high E selectivity. On the other hand, predominant or exclusive formation of Z olefms was achieved by using allylic triphenylphosphorus ylides and aromatic aldehydes like benzylaldehyde, while the combination of allylic triphenylphosphorus ylides and such sterically hindered aldehydes as cyclohexanecarboxaldehyde led to E olefm formation upon ylide formation with LiHMDS. In the case of olefination reactions of aldehydes with dimethyl thiazole ylide, it was shown that among the aromatic aldehydes only 4-nitrobenzaldehyde reacted with this ylide and provided a pure E olefin product (41% yield). Dimethylmalonyltributylphosphorane (DMTP) reacted with aromatic aldehydes in toluene at 125 °C to give the corresponding alkenes. 4-Nitrobenzaldehyde· gave the alkene in a much higher yield (81%), followed by 4-chlorobenzaldehyde (31%). With benzaldehyde, the corresponding olefin was isolated in only 14% yield under these conditions. Clearly, this highly stabilized ylide only enters into reaction with electron deficient aldehydes. A possible approach to Z-a, P-unsaturated aldehydes was investigated through the olefination of an acetal-ylide followed by hydrolysis. However, E acetal olefins were in fact isolated from this 2'-(1,3-dioxolanyl)-triethylphosphorus ylide with aromatic aldehydes in good yields (62%-76%). This result is still mechanistically interesting in view of the chemoselective formation of such an ylide in the presence ofthree ethyl substituents on phosphorus. </p> <p> Class of flavonoids: Sakuranetin, Naringenin and (28)-7-methoxy-6hydroxyflavanone, have been isolated from the diseased bark of Prunus sp. The structures were elucidated based on the spectroscopic data. Locations of 4-keto, 5-0H and 7-methoxy were deduced from COSY and HMBC spectra. Such compounds are of interest for their potential antibiotic activity against vancomycin-resistant strains of microbes. </p> / Thesis / Master of Science (MSc)

No / Mechanochemistry provides a method to reduce or eliminate the use of solvents by carrying out reactions through the grinding of neat reagents. Until recently a significant drawback of this form of synthesis has been the limited ability to scale up. However, it has been shown that twin screw extrusion (TSE) may overcome this problem as demonstrated in the continuous synthesis of co-crystals, Metal Organic Frameworks (MOFs) and Deep Eutectic Solvents (DES), in multi kg h−1 quantities. TSE has provided a means to carry out mechanochemical synthesis in a continuous, large scale and efficient fashion, which is adaptable to a manufacturing process. Herein, we highlight the potential of this technique for organic synthesis by reporting four condensation reactions, the Knoevenagel condensation, imine formation, aldol reaction and the Michael addition, to produce analytically pure products, most of which did not require any post synthetic purification or isolation. Each reaction was carried out in the absence of solvents and the water byproduct was conveniently removed as water vapour during the extrusion process due to the elevated temperatures used. Furthermore, the Knoevenagel condensation has been studied in detail to gain insight into the mechanism by which these mechanochemical reactions proceed. The results point to effective wetting of one reactant by another as being critical for these reactions to occur under these reaction conditions. / EPSRC EP/L019655/1

Small molecule organic dyes with absorption and emission in the near infrared region (NIR) attracted much attention for various applications such as dye sensitized solar cells, fluorescent guided surgery, stimuli responsive bioimaging and photodynamic therapy. Dyes with high absorption and emission in the NIR region are beneficial for stimuli responsive bioimaging due to the deeper penetration of NIR light, less cell damage, high resolution, and low background autofluorescence from biomolecules. Of the many small molecule dyes, xanthene-based dyes exhibit outstanding photophysical properties and good stimuli response for use in bioimaging applications. However, absorption and emission of the xanthene dyes lie in the visible region, which limit their applications in cellular imaging. Many of the NIR dyes have very poor fluorescence; consequently, an alternative approach to fluorescent imaging is photoacoustic imaging that uses sound waves to generate pictures of deep tissues. In this dissertation, we discuss the utility of xanthene based NIR dyes as photoacoustic imaging contrast agents for multiplex imaging and deep tissue nitric oxide sensing in the drug-induced liver injury. Chapter I discuss the fundamentals of fluorescence and photoacoustic imaging, background of the xanthene dyes and other fluorescent dyes, and the design strategies to develop NIR xanthene-based dyes. Chapter II is based on our approach to the design and synthesis of NIR xanthene-based dyes by C-H bond functionalization, with the first example being Rhodindolizine, which absorb and emits in NIR II or short-wave infrared (SWIR) region. In chapter III, we describe the design and synthesis of thienylpiperidine xanthene-based NIR and shortwave-infrared (SWIR) dyes for the photoacoustic imaging. One dye in particular (XanthCR-880) boasts a strong PA signal at 880 nm with good biological compatibility and photostability, yields multiplexed imaging with an aza-BODIPY reference dye, and is detected at a depth of 4 cm. In chapter IV, we report a series of SWIR dyes based on a dibenzazepine donor conjugated to thiophene (SCR-1, SCR-4), thienothiophene (SCR-2, SCR-5), and bithiophene (SCR-3, SCR-6). We leverage the fact that SCR-1 undergoes a bathochromic shift when aggregated to develop a ratiometric nanoparticle for nitric oxide (NO) (rNP-NO). rNP-NO was used to successfully perform in vivo studies to visualize pathological levels of nitric oxide in a drug-induced liver injury model via deep tissue SWIR photoacoustic (PA) imaging. Chapter V describes another series of xanthene-based dyes with a thiophene ᴫ spacer and several different donors. UV-Vis absorption studies were performed after converting the dyes to the opened form with trifluoracetic acid. These novel XanthCR-TD dyes exhibit absorption maxima in NIR I region from 700 - 900 nm.

Yes / Marrying synthetic biology with synthetic chemistry provides a powerful approach toward natural product diversification, combining the best of both worlds: expediency and synthetic capability of biogenic pathways and chemical diversity enabled by organic synthesis. Biosynthetic pathway engineering can be employed to insert a chemically orthogonal tag into a complex natural scaffold affording the possibility of site-selective modification without employing protecting group strategies. Here we show that, by installing a sufficiently reactive handle (e.g., a C–Br bond) and developing compatible mild aqueous chemistries, synchronous biosynthesis of the tagged metabolite and its subsequent chemical modification in living culture can be achieved. This approach can potentially enable many new applications: for example, assay of directed evolution of enzymes catalyzing halo-metabolite biosynthesis in living cells or generating and following the fate of tagged metabolites and biomolecules in living systems. We report synthetic biological access to new-to-nature bromo-metabolites and the concomitant biorthogonal cross-coupling of halo-metabolites in living cultures. / European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013/ERC consolidator grant GCGXC grant agreement no 614779) and ERAIB (Grant no. 031A338A) and H2020-MSCA-IF-2014 Grant no. 659399

Chapter 1 is a brief literature review of the most recent progress in the area of C-H functionalization via palladium catalysis. This covers the functionalization of electron deficient arenes and heterocycles with alkenyl and alkyl halides both using inter- and intra-molecular reactions. The chapter also contains an overview of recent work from the Willis group. Chapter 2 presents the functionalization of electron deficient arenes and alkenyl bromides using palladium catalysis, as well as the use of statistical analysis software for optimizing the cross-coupling reaction. Chapter 3 describes the cross-coupling of substituted benzoxazoles, benzothiazole and benzimidazole with a range of alkenyl iodides using palladium catalysis. The reaction can tolerate both (E) and (Z) disubstituted alkenes and tri-substituted alkenyl iodides, with retention of the double bond geometry. Chapter 4 details the synthesis of sultams via an intramolecular C-H functionalization using palladium catalysis. The chapter covers the optimization of the starting material synthesis as well as the cross-coupling reaction. We can access the sulfonamides from cyclohexenone and were able to incorporate a large range of substitution patterns (Scheme 3). Finally, Chapter 5 contains all the experimental details, general considerations and compound data. All the NMR spectra of novel compounds can be found in the appendix.