No description available.

Poly(dimethylsiloxane) (PDMS) and similar polymers have proved to be of widespread interest for use in microfluidic and similar microanalytical devices. Surface modification of PDMS is required to extend the range of applications for devices made of this polymer, however. Here we report on the grafting of perfluorooctyltriethoxysilane via hydrolysis onto an oxidized PDMS substrate in order to form a fluorinated microchannel. Such a fluorinated device could be used for separating fluorous tagged proteins or peptides, similar to that which has been recently demonstrated in a capillary electrophoresis system, or in an open tubular capillary column. The modified polymer is characterized using chemical force titrations, contact angle measurements and X-ray photoelectron spectroscopy (XPS). We also report on a novel means of performing electroosmotic measurements on this material to determine the surface zeta potential. As might be expected, contact angle and chemical force titration measurements indicate the fluorinated surface to be highly hydrophobic. XPS indicates that fluorocarbon groups segregate to the surface of the polymer over a period of days following the initial surface modification, presumably driven by a lower surface free energy. One of the most interesting results is the zeta potential measurements, which show that significant surface charge can be maintained across a wide range of pH on this modified polymer, sufficient to promote electroosmotic flow in a microfluidic chip. Matrix-assisted time of flight mass spectrometry (MALDI-TOF MS) measurements show that a fluorous-tagged peptide will selectively adsorb on the fluorinated PDMS in aqueous solution, demonstrating that the fluorinated polymer could be used in devices designed forenrichment or enhanced detection of fluorous-labeled proteins and peptides. However, the non-specific adsorption of other proteins may interfere with the test results. The adsorption of four different proteins (cytochrome-C, carbonic anhydrase, insulin and ubiquitin) onto the unmodified, oxidized and fluorinated PDMS surfaces respectively was studied here with MALDI-TOF MS measurements. The results showed us that when rinsed in water/methanol solutions of high methanol concentration, cytochrome-C strongly adheres to the fluorinated surface. Carbonic anhydrase shows the opposite trend. Retention of ubiquitin on the surface shows relatively little sensitivity to either the nature of the substrate or the solution composition. Finally, the results using insulin demonstrated that this protein adheres relatively strongly to the oxidized PDMS surface as compared to the fluorinated or unmodified PDMS and showed a relative independence on the composition of the washing solution. The influence of the hydrophilicity of the protein, the surface and solvents, stability and size of proteins are discussed in the context of these observations. / Thesis (Master, Chemistry) -- Queen's University, 2008-05-12 16:49:23.672

No description available.

No description available.

Cyclooxygenase (COX) and lipoxygenase (LOX) catalyze the rate-determining step in the production of arachidonic acid- derived signaling molecules (eicosanoids) within the body. COX has been extensively investigated, which has enabled the design of non-steroidal inflammatory drugs (NSAIDs) such as aspirin, acetaminophen (ApAP) and ibuprofen. However, there are still fundamental questions surrounding the LOX family of enzymes, which has limited the development of isoform specific inhibitors. The structural basis and regio- and stereoselectivity of the LOX isoforms are not known. Herein, we describe two strategies to develop isoform-specific inhibitors of lipoxygenase. Efforts were focused on the synthesis of unnatural lipid derivatives, in which the methylene hydrogen atoms on the substrate were replaced with a moiety lacking a labile hydrogen atom, such as fluorine. This would allow the LOX enzyme to remain in an active form, while preventing enzyme turnover. This preliminary work will enable the assessment of their activity as inhibitors and attempts at their co-crystallization might provide the first insight into the binding mode of these fatty acid substrates. The preparation of a small library of acylated 2-aminopyrimidines and their efficacy as inhibitors of soybean lipoxygenase-1 was explored. Preliminary studies suggest the mode of action occurs through a bi-dentate coordination of the ferric iron atom. Modifications of the acylated 2-aminopyrimidines to make it more substrate-like and to increase its lipophilicity, yielded inhibitors with low micromolar IC50 values. With further optimization, acyl 2-aminopyrimidines could serve as a useful platform for the discovery of safe and efficient isoform specific inhibitors.

No description available.

The replacement of a hydrogen or hydroxy group with a fluorine atom is a popular strategy to alter the activity of biologically important molecules, as their similar sizes mean that such a replacement has little steric impact. The effect of fluorine substitution in a number of enzyme mediated processes has been investigated. 3-Fluorocyclohex-l-enylcarbonyl-CoA has been synthesised and the reaction with cyclohexenylcarbonyl-CoA reductase investigated. The fluorinated substrate has a comparable K(_m) value to that of the natural substrate but a V(_max) that is five times greater. A change in the rate-determining step of the reduction was also observed upon fluorine incorporation. The enzyme showed a small but significant stereochemical preference for the production of the axial isomer, consistent with an Anh-Eisenstein model for the transformation. The 6а and 6β isomers of benzyl fluoropenicillanate were synthesised and their methoxide-mediated hydrolyses were investigated. Competitive hydrolysis, using (^19)F NMR spectroscopy, demonstrated that the β isomer was hydrolysed preferentially. A frill kinetic analysis was undertaken, which furnished the rate and equilibrium constants. Monofluorinated enamines were treated in situ with a range a Michael acceptors to afford a variety of novel substituted a-fluoro ketones. 2-Fluorohexanal was synthesised from methyl hexanoate and was demonstrated to be a substrate for the enzyme transketolase with hydroxypyruvate. The enzyme reaction was monitored by (^19)F NMR spectroscopy. The enzyme showed a diastereoselectivity of 9:1 in the condensation of the aldehyde and hydroxypyruvate, and a self-condensation product was also produced. The enzymatic oxidation of the mono- and di-fluoromethylenephosphonate analogues of glycerol-3-phosphate was investigated at neutral pH using a co-factor recycling protocol. The reactions allowed for the first time the identification of the products of oxidation and demonstrated the lability of fluoride via non-enzymatic elimination and stoichiometric defluorination.

It is generally acknowledged that polyfluoroarenes are important fluorinated structural units for various organic molecules, such as pharmaceuticals, agrochemicals, and organic materials. Polyfluorinated aryl alkynes and alcohols are also powerful building blocks in chemical synthesis because of their versatility to be transformed into various useful molecules and also their ubiquity in natural product synthesis. Efficient methods for the synthesis of polyfluorinated aryl alkynes and alcohols are presented in Chapter 2 and Chapter 3. In addition, 3-amino-indoles have found a broad applications in medicinal chemistry as effective anticancer agents, compounds with analgesic properties and can function as potent inhibitors of tubulin polymerization, and agents for the prevention of type II diabetes. A simple method for the synthesis of 3-amino-indoles via the annulation reaction of polyfluorophenylboronates with DMF is reported in Chapter 4. Chapter 2 In Chapter 2, a mild process for the copper-catalyzed oxidative cross-coupling of electron-deficient polyfluorophenylboronate esters with terminal alkynes (Scheme S-1) is reported. This method displays good functional group tolerance and broad substrate scope, generating cross-coupled alkynyl(fluoro)arene products in moderate to excellent yields. This copper-catalyzed reaction was conducted on a gram scale to generate the corresponding product in good yield (72%). Scheme S-1. Copper-catalyzed oxidative cross-coupling of terminal alkynes with polyfluorophenylboronate esters. Based on previous reports and the aforementioned observations, a plausible catalytic cycle for this oxidative cross-coupling reaction is shown in Scheme S-2. The first step involves the addition of an alkynyl anion to Cu leading to the formation of alkynylcopper(II) species B. Subsequent transmetalation between ArFBpin and intermediate B occurs to form intermediate C. The desired product 3a is generated by eductive elimination. Finally, the oxidation of Cu(0) to Cu(II) with DDQ and Ag2O regenerates A to complete the catalytic cycle. Scheme S-2. Proposed mechanism of copper(II)-catalyzed oxidative cross-coupling between terminal alkynes and polyfluorophenylboronate esters. Chapter 3 In Chapter 3, A convenient and efficient protocol for the transition metal-free 1,2-addition of polyfluoroaryl boronate esters to aldehydes and ketones is reported, which provides secondary alcohols, tertiary alcohols, and ketones (Scheme S-3). The distinguishing features of this procedure include the employment of commercially available starting materials and the broad scope of the reaction with a wide variety of carbonyl compounds giving moderate to excellent yields. Scheme S-3. Base-promoted 1,2-addition of polyfluorophenylboronates to aldehydes and ketones. Control experiments were carried out to gain insight into the reaction mechanism. The reaction of 2a with pentafluorobenzene 5 under standard conditions was examined, yet 3a was not formed in any detectable amounts (Scheme S-4a), indicating that the C-Bpin moiety is essential and deprotonation of the fluoroarene or nucleophilic attack at the fluoroarene by the base is not a plausible pathway. Interestingly, for the standard reaction between 1a and 2a, the yield dropped dramatically if 18-crown-6 ether and K2CO3 were added (Scheme S-4b). This experimental result indicates that the presence of the potassium ion plays a crucial role for the outcome of the reaction. Furthermore, if the reaction of 1a and 2a was performed in the presence of only a catalytic amount of K2CO3 (20 mol%) (Scheme S-4c), reaction rates were reduced, and a week was required to produce 3a in good yield. This finding again indicates that the potassium ion (or the base) plays an important role in the reaction. Substituting ortho-fluorines by ortho-chlorines, using either C6Cl5Bpin 2,6-dichlorophenyl-1-Bpin as substrates, did not yield any product as shown by in situ GCMS studies. Scheme S-4. Control experiments. Based on DFT calculations, a mechanism for the 1,2-addition of polyfluorophenylboronates to aryl aldehydes in the presence of K2CO3 as base is proposed, as shown in Scheme S-5. K2CO3 interacts with the Lewis-acidic Bpin moiety of substrate 1 to generate base adduct A, which weakens the carbon-boron bond and ultimately cleaves the BC bond along with attachment of a potassium cation to the aryl group. The resulting ArF- anion adduct B undergoes nucleophilic attack at the aldehyde carbon atom of substrate 2 to generate methanolate C. The methanolate oxygen atom then attacks the electrophilic Bpin group to obtain compound D. Transfer of K2CO3 from intermediate D to the boron atom of the more Lewis-acidic polyfluorophenyl-Bpin 1 finally closes the cycle and regenerates complex A. Thus, the primary reaction product is the O-borylated addition product E, which was detected by HRMS and NMR spectroscopy for the perfluorinated derivative. Scheme S-5. Proposed mechanism of the 1,2-addition of polyfluorophenylboronates to aldehydes and ketones. Chapter 4 Chapter 4 presents a novel protocol for the transition metal-free addition and annulation of polyfluoroarylboronate esters to DMF, which provides 3-aminoindoles and tertiary amines in moderate to excellent yields (Scheme S-6). Scheme S-6. Annulation and addition reactions of polyfluorophenylboronates with DMF. While exploring the application of this strategy in synthesis, perfluorophenylBpin reacted smoothly with ethynylarenes and DMF to afford propargylamines with moderate to excellent yields (Scheme S-7). Scheme S-7. Three-component cross-coupling reaction for the synthesis of propargylamines. / Polyfluorarene sind wichtige fluorierte Schlüsselstruktureinheiten für verschiedene organische Moleküle, wie z. B. Pharmazeutika, Agrochemikalien und organische Materialien. Auch polyfluorierte Arylalkine und -alkohole sind aufgrund ihrer vielseitigen Möglichkeiten, in verschiedene nützliche Moleküle umgewandelt zu werden als auch wegen ihrer Allgegenwart in der Naturstoffsynthese, leistungsfähige Bausteine. Effiziente Methoden zur Synthese polyfluorierter Arylalkine und -alkohole werden in Kapitel 2 und Kapitel 3 vorgestellt. Darüber hinaus haben 3-Amino-Indole eine breite Anwendung in der medizinischen Chemie als wirksame Antikrebsmittel, Verbindungen mit analgetischen Eigenschaften und als potente Inhibitoren der Tubulinpolymerisation sowie als Mittel zur Prävention von Typ-II-Diabetes gefunden. Eine einfache Methode zur Synthese von 3-Amino-Indolen über die Annulierungssreaktion von Polyfluorphenylboronaten mit DMF wird in Kapitel 4 berichtet. Kapitel 2 In Kapitel 2 wird über ein mildes Verfahren zur kupferkatalysierten oxidativen Kreuzkupplung von elektronenarmen Polyfluorphenylboronatestern mit terminalen Alkinen (Schema S-1) berichtet. Diese Methode zeichnet sich durch eine gute Toleranz gegenüber funktionellen Gruppen und eine große Bandbreite an Substraten aus und erzeugt kreuzgekoppelte Alkinyl(fluor)aren-Produkte in moderaten bis exzellenten Ausbeuten. Diese kupferkatalysierte Reaktion wurde im Gramm-Maßstab durchgeführt, und erzeugt das entsprechende Produkt in guter Ausbeute (72 %). Schema S-1. Kupfer-katalysierte oxidative Kreuzkupplung terminaler Alkine mit Polyfluorphenylboronatestern. Basierend auf früheren Arbeiten und den oben erwähnten Beobachtungen ist ein plausibler katalytischer Zyklus für diese oxidative Kreuzkupplungsreaktion in Schema S-2 dargestellt. Der erste Schritt beinhaltet die Addition eines Alkinylanions, was zur Bildung des Alkinylkupfer(II)-Komplexes B führen sollte. Anschließend erfolgt eine Transmetallierung zwischen ArFBpin und dem Zwischenprodukt B zur Bildung des Zwischenproduktes C. Das gewünschte Produkt 3a wirde dann daraus durch reduktive Eliminierung erzeugt. Durch eine Oxidation des dabei entstehenden Cu(0)-Komplexes mit DDQ und Ag2O wird Komplex A regeneriert und der katalytische Zyklus schließt sich. Schema S-2. Vorgeschlagener Mechanismus der Kupfer(II)-katalysierten oxidativen Kreuzkupplung terminaler Alkine und Polyfluorphenylboronatestern. Kapitel 3 In Kapitel 3 wird ein praktisches und effizientes Protokoll für die übergangsmetallfreie 1,2-Addition von Polyfluorarylboronatestern an Aldehyde und Ketone vorgestellt, welches sekundäre Alkohole, tertiäre Alkohole und Ketone liefert (Schema S-3). Die besonderen Merkmale dieses Verfahrens sind die Verwendung kommerziell erhältlicher Ausgangsmaterialien und die große Bandbreite der Reaktion mit einer Vielzahl von Carbonylverbindungen, die mäßige bis exzellente Ausbeuten erbringen. Schema S-3. Basen-unterstützte 1,2-Addition von Polyfluorphenylboronaten an Aldehyde und Ketone. Um einen Einblick in den Reaktionsmechanismus zu erhalten, wurden Kontrollexperimente durchgeführt. Die Reaktion von 2a mit Pentafluorbenzol 5 unter Standardbedingungen wurde untersucht, jedoch wurde 3a nicht in nachweisbaren Mengen gebildet (Schema S-4a). Dies deudet darauf hin, dass der C-Bpin Anteil essenziell ist und eine Deprotonierung des Fluorarens oder ein nukleophiler Angriff am Fluoraren durch die Base kein plausibler Weg ist. Interessanterweise sank bei der Standardreaktion zwischen 1a und 2a die Ausbeute dramatisch, wenn 18-Kronen-6-Ether und K2CO3 zugesetzt wurden (Schema S-4b). Dieses experimentelle Ergebnis belegt, dass die Anwesenheit des Kalium-Ions eine entscheidende Rolle für den Ausgang der Reaktion spielt. Wenn die Reaktion von 1a und 2a in Gegenwart von nur einer katalytischen Menge K2CO3 (20 mol%) durchgeführt wurde (Schema S-4c), waren die Reaktionsgeschwindigkeiten geringer und es war eine Woche erforderlich, um 3a in guter Ausbeute zu erlangen. Dieser Befund weist erneut darauf hin, dass das Kalium-Ion (oder die Base) eine wichtige Rolle bei der Reaktion spielt. Die Substitution von ortho-Fluorsubstituenten durch ortho-Chlorsubstituenten, wobei entweder C6Cl5Bpin oder 2,6-Dichlorphenyl-Bpin als Substrate verwendet wurden, lieferte kein Produkt, wie in situ GCMS-Studien zeigten. Schema S-4. Kontrollexperimente. Ein Vorschlag zum Mechanismus der 1,2-Addition von Polyfluorphenylboronaten an Arylaldehyde in Gegenwart von K2CO3 als Base wird in Schema S-5 vorgeschlagen. Dabei wechselwirkt die Base K2CO3 mit der Lewis-sauren Bpin-Einheit des Substrats 1 unter Ausbildung des Basenadduktes A, in welchem die Kohlenstoff-Bor-Bindung geschwächt ist und schließlich die B-C Bindung gespalteen wird, wobei sich ein Kaliumkation an die Arylgruppe anlagert. Das resultierende ArF- Anion im Addukt B greift nukleophil am Aldehyd-Kohlenstoffatom von Substrat 2 an, um Methanolat C zu erzeugen. Das Methanolat-Sauerstoffatom reagiert dann mit der elektrophilen Bpin-Gruppe, um Verbindung D zu erhalten. Die Übertragung von K2CO3 vom Zwischenprodukt D auf das Boratom des Lewis-acideren Polyfluorphenyl-Bpin 1 schließt schließlich den Zyklus und regeneriert den Komplex A. Das primäre Reaktionsprodukt ist also das O-borylierte Additionsprodukt E, das mittels HRMS und NMR-Spektroskopie für das perfluorierte Derivat nachgewiesen wurde. Schema S-5. Vorgeschlagener Mechanismus der 1,2-Addition von Polyfluorphenylboronaten an Aldehyden und Ketonen. Kapitel 4 In Kapitel 4 wird ein neuartiges Protokoll für die übergangsmetallfreie Addition und Annulierungsreaktion von Polyfluorarylboronatestern an DMF vorgestellt, das 3-Aminoindole und tertiäre Amine in mäßigen bis ausgezeichneten Ausbeuten liefert(Schema S-6). Schema S-6. Annulierungs- und Additionsreaktion von Polyfluorphenylboronaten mit DMF. Bei der Erkundung der Anwendung dieser Strategie in der Synthese konnten Propargylamine mit mäßigen bis ausgezeichneten Ausbeuten hergestellt werden (Schema S-7). Schema S-7. Kreuzkupplungsreaktion für die Synthese von Propargylaminen.

No description available.

Contact antimicrobials for use in the medical device industry are being studied extensively to minimize the risk of hospital acquired infections, which are among the top ten leading causes of death in the US. Surfaces modified with quaternary ammonium containing side chains have been known to demonstrate excellent antimicrobial properties. Prior work has indicated that polyurethane surfaces with copolyoxetane soft blocks consisting of fluorinated and quaternary ammonium side chains can act as good antimicrobials. However, stabilizing the positive charge on the surface has been a challenge. The dissertation is aimed at creating a surface modifier that would confer a stable contact kill antimicrobial surface at very low modifier content, that is, less than 2 wt%. To achieve this objective, the study explored the introduction of a different fluorous group in the soft block to enhance stability. In particular, prior studies by other groups and early work by Kurt have shown that replacement of one of the terminal “chaperone” C-F bonds by C-H decreased surface tension. This led to the hypothesis that a –CF2H terminated “chaperone” group would be “amphiphilic” resulting in surface stability under both dry and wet conditions. Keeping this hypothesis in mind, a –CF2-CF2H (4F) terminal “chaperone” group was created in a modifier having two different 4F to quaternerary C12 ratios. It was found that polyurethanes prepared with a 66:34 ratio of 4F:C12 as the diol, performed as a very good surface modifier with high zeta potentials over a long period of time compared to the –CF3 based modifier. Antimicrobial tests performed within one week and four weeks after coating preparation have provided promising results that demonstrate improved biocidal stability. Guided by improved antimicrobial properties obtained with surface modifier polyurethanes made from P[(4F)(C12)-66:34-Mn], a new concept was explored by end-capping the same diol with isocyanatopropyltriethoxysilane and blending the end-capped diol with base polyurethane along with a 10 wt % cross linker. These modifiers show excellent antimicrobial properties (100% kill of bacteria) over one month with no observable changes in the zeta potential or surface morphologies. XPS analysis confirms the presence of quaternary ammonium on the surface. Preliminary kinetic studies show excellent antimicrobial properties for a 2 wt% modifier and 100% kill within 1 hr.