Novel One-Pot Syntheses of Uracils and Arylidenehydantoins, and Analysis of Xylitol in Chewing Gum by Gc-Ms

The first section of this dissertation (Chapter I-III) describes the development of new methodologies to prepare uracil and arylidenehydantoin derivatives. A regioselective synthesis of 6-alkyl- and 6-aryluracils was developed by the dimerization of 3-alkyl- and 3-aryl-2-propynamides promoted by either Cs2CO3 or K3PO4. A range of 3-aryl-2- propynamides, with both electron-deficient and electron-rich 3-aryl substituents, were successfully reacted in high yields. A synthetic route to prepare arylidenehydantoins was developed using the Pd-catalyzed dimerization of 3-aryl-2-propynamides. Both electron rich and electron deficient 3-aryl-2-propynamides were dimerized successfully to produce the desired arylidenehydantoins in moderate to excellent yields. The second section of this dissertation (Chapter IV and V) describes the development of a reliable low-cost method to determine amounts of xylitol in sugar free gum samples to predict dangerous exposure levels for dogs. Xylitol is generally considered safe for human consumption and is frequently used in sugar free gum, however, it is extremely toxic to dogs. It is unknown if partially consumed chewing gum is also dangerous. A method to determine xylitol content of these sugar free gum samples employing GC-MS with direct aqueous injection (DAI) is presented. This method was successfully applied to over 120 samples including, fresh gum, 5 min, 15 min, and 30 min chewed gum samples. Further extension of this work resulted in the development of an undergraduate laboratory experiment for upper-level undergraduate chemistry students which teaches calibration methods, xylitol extraction, sample preparation for GC-MS analysis, and data analysis

Synthesis of modified D-allohexofuranosyl-uracil nucleoside analogs

Abstract The study of nucleosides, nucleotides, and their polymers is essential due to their critical roles in cellular processes such as DNA replication, RNA transcription, protein synthesis, signaling, and energy transfer. These molecules serve as the building blocks of life, making them fundamental to genetics, molecular biology, pharmacology, and other relevant scientific fields. Beyond their natural functions, chemically modified nucleosides, nucleotides, and their oligomers have emerged as powerful tools in medicine, biotechnology, and research. These advancements include the development of antiviral and anticancer therapies using modified nucleoside analogs, as well as therapies employing oligonucleotide-based treatments targeting pre-mRNA and mRNA. Furthermore, these modifications have enhanced diagnostic technologies and research tools. The ability to modify and efficiently synthesize these modified analogs and their oligomers opens new possibilities for therapeutic applications, offering improved stability, specificity, and efficacy. This work builds on an extensive body of literature exploring the roles of nucleotides, nucleosides, and their modified analogs. Initially, the review covers the physiological significance of natural nucleos(t)ides, emphasizing their central role in genetic information transfer and cellular metabolism. Then focus shifts toward chemically modified nucleos(t)ides, which have become increasingly important in antiviral, anticancer, gene therapies, and biotechnological tools. Various synthetic strategies for altering sugar, nucleobase, and phosphate moieties are critically reviewed, with a particular emphasis on methods that enable precise structural alterations. Special attention is also given to the utility of D-allofuranose, an atypical sugar that served as a scaffold for modified nucleoside analogs developed in the practical part of this work. These insights underscore the potential of developing novel therapeutic agents with enhanced properties and directly inform the synthetic approaches. This review guided the selection of synthetic routes, protecting group strategies, and targeted modifications that were further practically explored in this study. The experimental part of this research focused on synthesizing D-allofuranosyl-uracil analogs, with a special focus on modifying the 6’-hydroxyl group. The study explored the effectiveness of two different synthetic routes for the initial sugar configuration preparation, the separation of the α/β-anomer forms of the resulting uracil nucleosides, and the introduction of an azide group at the 6’OH-position. Despite encountering challenges, such as the unsuccessful addition of a triphosphate group, the research demonstrated the feasibility of synthesizing a modified nucleoside key intermediate. Further work is needed to optimize the phosphorylation process and fully evaluate the biological properties of consequently derived nucleotides’ antiviral properties

Synthesis, analysis and biological evaluation of heterocyclic drugs

Chapter 1: Chapter One provides an overview on the Bohlmann-Rahtz pyridine synthesis. New procedures, implementing metal based Lewis acids, Brønsted acids and metal-free Lewis acid catalysts have been used in this process. Also, new one-pot two- and three-component methodologies have been developed for the synthesis of various natural products containing the pyridine motif and these have been compared and contrasted. This chapter also discusses signalling pathways in Werner syndrome cells. The inhibitor SB203580 has been shown to prevent the phosphorylation of the p38α kinase in a ATP competitive manner and this implicates this mechanism in accelerated ageing and gives potential to the prospect of targeting this pathway in a drug discovery programme, if better mechanistic understanding can be garnered. Chapter 2: Chapter Two discusses the Bohlman–Rahtz synthesis of various substituted pyridines. The process has been modified to be simple, involves mild conditions and provides the heterocyclic targets in high yield. We have shown that substituted pyridines could be synthesised efficiently under microwave conditions using a relatively short reaction time. The process was also successful for the production of a range of fused heterocycles containing the pyridine moiety in high yield, including pyrido[2,3-d]pyrimidin-4(3H)-ones and pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones. Chapter 3: Chapter Three describes the efficient synthesis of the p38 MAPK inhibitor UR-13756 using a Hantzsch-type three component cyclocondensation. Microwave irradiation of a mixture of 3-amino-1-methylpyrazole hydrochloride, 1-(4-fluorophenyl)-2-(pyridine-4-yl)ethanone and 4-fluorobenzaldhyde for 4 hours in ethanol under acidic catalytic conditions provided UR-13756 in high yield (71%) after purification by column chromatography. Chapter 4: Chapter Four shows the synthesis of 4-(3-amino-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzamide in three steps by the use of rigorous experimental procedures under microwave conditions. This technique led to faster heating rates and allowed the rapid optimization of yields. These advantages were observed in all steps and allow formation of products in high yields. Biological study of the inhibitor 4-(3-amino-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)benzamide showed, by ELISA analysis, that p38 signalling was inhibited in control dermal cells. Some progress was made towards the synthesis of 3-amino-4-[1-(3-1H-pyrazol-4-yl)]benzamide. Chapter 5: Chapter Five investigates the synthesis of the chemotherapeutic agent RO3201195, a highly selective inhibitor of p38α, in seven steps under microwave conditions. The procedure provides a relatively high overall yield of the desired product and all other intermediates involved in individual steps compared with conventional heating methods. Chapter 6: Chapter Six provides the experimental procedures and various spectroscopic data for the synthesized compounds

Application of Enzymes in Regioselective and Stereoselective Organic Reactions

Nowadays, biocatalysts have received much more attention in chemistry regarding their potential to enable high efficiency, high yield, and eco-friendly processes for a myriad of applications. Nature’s vast repository of catalysts has inspired synthetic chemists. Furthermore, the revolutionary technologies in bioengineering have provided the fast discovery and evolution of enzymes that empower chemical synthesis. This article attempts to deliver a comprehensive overview of the last two decades of investigation into enzymatic reactions and highlights the effective performance progress of bio-enzymes exploited in organic synthesis. Based on the types of enzymatic reactions and enzyme commission (E.C.) numbers, the enzymes discussed in the article are classified into oxidoreductases, transferases, hydrolases, and lyases. These applications should provide us with some insight into enzyme design strategies and molecular mechanisms

Design and Synthesis of New A2B Adenosine Receptor Antagonists

Starting from chemical structure of N-benzo-[1,3]dioxol-5-yl-2-[5-(2,6dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol3-yloxy]-acetamide, MRE2029F20* various structural modifications were realized to afford a new series of A2B antagonists. The bioisosteric replacement of the anilide moiety with benzimidazole or quinazoline rings, the effect of the substitution of pyrazole with isoxazole moiety were investigated. Amide bond has been also replaced with the 5phenyl-1,2,4-oxadiazole nucleus on the basis of other adenosine pharmacophores reported previously. In this context the effect of the nitrogen at the 9-position has been also studied preparing four 9-deaza direct analogs of 8pyrazol-xanthine compounds to compare affinity and selectivity at A2B adenosine receptor. The most significant result was obtained by bioisosteric replacement of the anilide moiety with benzimidazole, achieving antagonists with high affinity and selectivity toward the A2BAR. In particular compound 8-[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (hA1 Ki = 2530 nM, hA2A Ki > 1000 nM, hA2B Ki = 9.4 nM, hA3 Ki > 1000 nM) and compound 8-[5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7 dihydro-purine-2,6-dione (hA1 Ki = 4462 nM, hA2A Ki > 1000 nM, hA2B Ki = 25 nM, hA3 Ki > 1000 nM), showed the best biological data. These new selective and potent A2B antagonists will aid in the elucidation of the physiological role of this receptor and possibily lead to therapeutilally useful agents for treating asthma, diabetes and other diseases

Acyl-Imidazoles A Privileged Ester Surrogate for Enantioselective Synthesis

International audienceSince the first report by Evans in asymmetric Friedel‐Crafts reactions, the use of acyl‐imidazoles has blossomed as powerful ester/amide surrogates. The imidazole scaffold indeed displays stability and special activation features allowing both better reactivity and selectivity in traditional ester/amide functionalizations: α‐(enolate chemistry), β‐(conjugate additions), α,β‐(cycloadditions) or γ/δ‐(vinylogous). An overview of the contemporary and growing interest in acyl‐imidazoles in metal‐ and organo‐catalyzed transformations (bio‐hybrid catalytic systems will be fully described in a back‐to‐back Minireview) will be highlighted. Moreover, post‐functionalization expediencies are also going to be discussed in this Minireview

Self-assembly and supramolecular cross-linking of amphiphilic block copolymers based on 2,6-diaminopyridine for application in nanomedicine

Durante las últimas décadas, el autoensamblado de los copolímeros bloque anfífilos en disolución ha atraído la atención considerablemente, ya que da lugar a estructuras con dimensiones nanométricas y un amplio rango de morfologías entre las que se incluyen micelas esféricas, y/o cilíndricas, vesículas y otras estructuras más complejas o de alto orden. Estos agregados poliméricos presentan aplicaciones en numerosos campos, desde la nanomedicina, con la encapsulación, transporte y liberación de moléculas de interés, a aplicaciones más industriales como polielectrólitos o nanorreactores, pasando por la preparación de materiales híbridos, o la cosmética. Por ejemplo, Synperonic¿ y Kolliphor¿ son copolímeros bloque anfífilos que se utilizan como surfactantes y emulsionantes en cosméticos y en productos farmacéuticos. El grupo de Cristales Líquidos y Polímeros ha trabajado en los últimos años en la síntesis de copolímeros bloque anfífilos, con diversas estructuras y/o arquitecturas, en los cuales se han incorporado de forma covalente unidades con respuesta a la luz (derivados de azobenceno o cumarina), con el objetivo de preparar dispersiones acuosas de nanotransportadores con respuesta a estímulos para la liberación controlada de fármacos. También se ha explorado la incorporación de derivados de la unidad de 2,6-diaminopiridina (DAP) a copolímeros bloque anfífilos. Dichas unidades son un análogo de la adenina capaz de interaccionar con unidades de timina mediante reconocimiento molecular a través de tres enlaces de hidrógeno. Por tanto, derivados de timina se pueden unir a copolímeros bloque para introducir una funcionalidad, como se ha probado con derivados de azobenceno, y así inducir fotorrespuesta en los resultantes agregados poliméricos. Dicha funcionalización supramolecular constituye una aproximación más versátil que la química covalente.Teniendo en cuenta estos antecedentes, el objetivo general planteado para esta tesis doctoral ha sido la síntesis de distintos copolímeros bloque anfífilos incorporando unidades de DAP, explorando nuevas arquitecturas, y el estudio de su autoensamblado en agua mediante distintas metodologías. En los trabajos desarrollados en nuestro grupo, los autoensamblados poliméricos se han preparado tradicionalmente mediante el método de co-solvente, el cual resulta lento, especialmente cuando se necesita preparar cantidades significativas de material. Una alternativa a este método es la microfluídica, que permite la obtención de nanopartículas poliméricas de una forma fácil, rápida y reproducible, ya que se consiguen procesos de mezcla y calentamiento controlados y homogéneos debido a las pequeñas dimensiones de los microrreactores. Además, el autoensamblado inducido por polimerización (PISA) ha emergido en los últimos años como una metodología atractiva, puesto que la preparación de autoensamblados tiene lugar al mismo tiempo que la polimerización del copolímero bloque, en una sola etapa. PISA permite obtener dispersiones poliméricas altamente concentradas con morfologías complejas y de alto orden. También se ha llevado a cabo la reticulación supramolecular de los autoensamblados poliméricos mediante enlace de hidrógeno entre las unidades de DAP y timina, utilizando para ello diversas estrategias. Asimismo, se ha planteado el estudio de la viabilidad celular de estas dispersiones de autoensamblados, así como la evaluación para su potencial aplicación como transportadores de transductores térmicos, transporte y liberación de fármacos o en catálisis.Con estos objetivos, el trabajo recogido en esta tesis doctoral se ha organizado en diferentes capítulos cuyo contenido se describe a continuación:- Síntesis de una serie de copolímeros bloque anfífilos dendrítico-lineales con un bloque lineal hidrófilo de polietilenglicol (PEG) y un bloque hidrófobo compuesto por un dendrón derivado del ácido 2,2-bis(hidroximetil)propionico (de generación 1, 2, 3 o 4) funcionalizado con unidades DAP en la periferia. Estudio de su autoensamblado en agua mediante el método de co-solvente y mediante microfluídica, y estudio de la reticulación supramolecular de los autoensamblados resultantes utilizando reticulantes basados en timina con distintos puntos de entrecruzamiento (Capítulo 2).- Síntesis de un copolímero bloque anfífilo lineal-lineal formado por un bloque hidrófilo de PEG y un bloque hidrófobo compuesto por un polimetacrilato con unidades laterales DAP, y estudio de su autoensamblado por co-solvente y por microfluídica. Encapsulación de naproxeno mediante microfluídica en las nanopartículas poliméricas y estudio de su liberación en función de la temperatura. Preparación de nanopartículas híbridas poliméricas y de paladio con dicho copolímero bloque por microfluídica y evaluación de su aplicación en terapia fototérmica y de su actividad catalítica (Capítulo 3).- Estudio de la reticulación supramolecular mediante enlace de hidrógeno a través de dos estrategias diferentes. Reticulación usando reticulantes moleculares basados en timina con distintos puntos de entrecruzamiento. Reticulación mediante autoreconocimiento de unidades laterales DAP-timina presentes en uno de los segmentos del copolímero bloque (Capítulo 4).- Preparación de dispersiones acuosas de autoensamblados poliméricos altamente concentradas, que contiene unidades de DAP, utilizando la metodología PISA, así como estudio de la reticulación supramolecular por enlace de hidrógeno de los autoensamblados formados, utilizando un agente reticulante basado en timina (Capítulo 5).<br /

Design and Synthesis of New A2B Adenosine Receptor Antagonists

Starting from chemical structure of N-benzo-[1,3]dioxol-5-yl-2-[5-(2,6dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol3-yloxy]-acetamide, MRE2029F20* various structural modifications were realized to afford a new series of A2B antagonists. The bioisosteric replacement of the anilide moiety with benzimidazole or quinazoline rings, the effect of the substitution of pyrazole with isoxazole moiety were investigated. Amide bond has been also replaced with the 5phenyl-1,2,4-oxadiazole nucleus on the basis of other adenosine pharmacophores reported previously. In this context the effect of the nitrogen at the 9-position has been also studied preparing four 9-deaza direct analogs of 8pyrazol-xanthine compounds to compare affinity and selectivity at A2B adenosine receptor. The most significant result was obtained by bioisosteric replacement of the anilide moiety with benzimidazole, achieving antagonists with high affinity and selectivity toward the A2BAR. In particular compound 8-[5-(4-Chloro-6-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (hA1 Ki = 2530 nM, hA2A Ki > 1000 nM, hA2B Ki = 9.4 nM, hA3 Ki > 1000 nM) and compound 8-[5-(4,6-Bis-trifluoromethyl-1H-benzoimidazol-2-ylmethoxy)-2methyl-2H-pyrazol-3-yl]-1,3-dipropyl-3,7 dihydro-purine-2,6-dione (hA1 Ki = 4462 nM, hA2A Ki > 1000 nM, hA2B Ki = 25 nM, hA3 Ki > 1000 nM), showed the best biological data. These new selective and potent A2B antagonists will aid in the elucidation of the physiological role of this receptor and possibily lead to therapeutilally useful agents for treating asthma, diabetes and other diseases

Alkoxyalkylation of Electron-Rich Aromatic Compounds

Alkoxyalkylation and hydroxyalkylation methods utilizing oxo-compound derivatives such as aldehydes, acetals or acetylenes and various alcohols or water are widely used tools in preparative organic chemistry to synthesize bioactive compounds, biosensors, supramolecular compounds and petrochemicals. The syntheses of such molecules of broad relevance are facilitated by acid, base or heterogenous catalysis. However, degradation of the N-analogous Mannich bases are reported to yield alkoxyalkyl derivatives via the retro-Mannich reaction. The mutual derivative of all mentioned species are quinone methides, which are reported to form under both alkoxy- and aminoalkylative conditions and via the degradation of the Mannich-products. The aim of this review is to summarize the alkoxyalkylation (most commonly alkoxymethylation) of electron-rich arenes sorted by the methods of alkoxyalkylation (direct or via retro-Mannich reaction) and the substrate arenes, such as phenolic and derived carbocycles, heterocycles and the widely examined indole derivatives