Photocontrol of Antibacterial Activity
This doctoral thesis describes the design, synthesis, and evaluation of compounds whose antibacterial activity can be controlled using light. In the first chapter, a brief historical perspective in photochemistry and the use of light in medical therapy is introduced. From the evolution of these two...
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Universidad de La Rioja (España)
2020
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This doctoral thesis describes the design, synthesis, and evaluation of compounds whose antibacterial activity can be controlled using light. In the first chapter, a brief historical perspective in photochemistry and the use of light in medical therapy is introduced. From the evolution of these two areas have emerged different alternatives that rely on light stimuli to treat diverse diseases.
The second chapter focuses on some of these alternatives: the photopharmacological approach and the use of photoreleasable protective groups to cage drugs. Photopharmacology is based on bioactive molecules that incorporate in their structure a molecular switch. The photoactive moiety can undergo an isomerization process that induces changes in the molecule properties like dipole moment, geometry, or electronics. These changes can result in isomers with different biological activity. Thus, a reversible system can be created where one isomer presents activity against the desired target while the other does not. On the contrary, the use of a photoreleasable protective group to cage a drug creates an irreversible system. The protective group is linked in a position that renders the drug inactive, upon light irradiation, the drug is released recovering its activity. These two options can help to solve some of the problems that classic pharmacological agents present. More specifically, the work here described is aimed at antibiotic drugs.
The objectives of this thesis are listed in the third chapter.
The fourth chapter focuses on the photopharmacological approach. Several molecules were designed with their structure based on quinolone antibiotics and a molecular switch linked in different positions. The molecular switches employed were based on the hydantoin structure and the pyrrole of the phytochrome chromophore. After their synthesis, their photochemical properties were evaluated. All of them were able to carry out the isomerization process with UV or visible light, and different photostationary states were found. Furthermore, the characteristics of one of the derivatives were studied more in-depth to test its efficiency and stability as a molecular switch. Finally, a study to evaluate possible changes in the activity of the initial isomers and the photostationary states obtained was carried out. The biological study showed that two compounds changed their activity after irradiation.
The fifth chapter describes the caging process of ciprofloxacin, a quinolone antibiotic, using oxime esters. Different oxime parts were synthesized to try to achieve a bathochromic shift in their absorption. The coupling reaction between the oxime and the antibiotic was designed to form an oxime ester at position 3 of ciprofloxacin.
This position is of great importance for the antibacterial activity of the drug. The study of the photochemical properties showed strong absorption in the UV region for all derivatives. The release reaction was successfully induced in all cases with good yields. Moreover, absorption in the visible region was achieved when tetrafluoroboric acid was added to the samples in halogenated solvents. A new band in the blue region of the spectrum appeared, making possible their irradiation with visible light. Finally, to improve the solubility in water of these compounds, one of the oxime esters was trapped in a polymeric micelle, which highly enhanced this property.
Lastly, the sixth chapter also focuses on the caging technique and tries to solve some of the drawbacks that oxime esters present. In this chapter, a new photoreleasable group was employed, known as BODIPY. Several BODIPY structures were synthesized to achieve absorption inside the therapeutic window and make the molecules totally or partially soluble in water. This group was coupled at position 3 of two quinolones antibiotics: nalidixic acid and ciprofloxacin. All photoreleasable quinolones displayed absorption in the visible region varying from the green to the NIR region. Irradiation of the samples with visible light allowed the complete release of the antibiotic part in all cases. Furthermore, their stability and efficiency were evaluated. Finally, a biological study was performed to evaluate possible differences in the activity of the caged and uncaged compound. Results showed a strong deactivation of the antibacterial properties when the BODIPY group was linked to the antibiotic. Upon light irradiation, the activity of the drugs was recovered. |
| author2 |
Sampedro Ruiz, Diego (Universidad de La Rioja) |
| author_facet |
Sampedro Ruiz, Diego (Universidad de La Rioja) Contreras García, Elena |
| format |
text (thesis) |
| author |
Contreras García, Elena |
| spellingShingle |
Contreras García, Elena Photocontrol of Antibacterial Activity |
| author_sort |
Contreras García, Elena |
| title |
Photocontrol of Antibacterial Activity |
| title_short |
Photocontrol of Antibacterial Activity |
| title_full |
Photocontrol of Antibacterial Activity |
| title_fullStr |
Photocontrol of Antibacterial Activity |
| title_full_unstemmed |
Photocontrol of Antibacterial Activity |
| title_sort |
photocontrol of antibacterial activity |
| publisher |
Universidad de La Rioja (España) |
| publishDate |
2020 |
| url |
https://dialnet.unirioja.es/servlet/oaites?codigo=285337 |
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AT contrerasgarciaelena photocontrolofantibacterialactivity |
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1718346691845816320 |
| spelling |
oai-TES00000229742021-02-10Photocontrol of Antibacterial ActivityContreras García, ElenaThis doctoral thesis describes the design, synthesis, and evaluation of compounds whose antibacterial activity can be controlled using light. In the first chapter, a brief historical perspective in photochemistry and the use of light in medical therapy is introduced. From the evolution of these two areas have emerged different alternatives that rely on light stimuli to treat diverse diseases. The second chapter focuses on some of these alternatives: the photopharmacological approach and the use of photoreleasable protective groups to cage drugs. Photopharmacology is based on bioactive molecules that incorporate in their structure a molecular switch. The photoactive moiety can undergo an isomerization process that induces changes in the molecule properties like dipole moment, geometry, or electronics. These changes can result in isomers with different biological activity. Thus, a reversible system can be created where one isomer presents activity against the desired target while the other does not. On the contrary, the use of a photoreleasable protective group to cage a drug creates an irreversible system. The protective group is linked in a position that renders the drug inactive, upon light irradiation, the drug is released recovering its activity. These two options can help to solve some of the problems that classic pharmacological agents present. More specifically, the work here described is aimed at antibiotic drugs. The objectives of this thesis are listed in the third chapter. The fourth chapter focuses on the photopharmacological approach. Several molecules were designed with their structure based on quinolone antibiotics and a molecular switch linked in different positions. The molecular switches employed were based on the hydantoin structure and the pyrrole of the phytochrome chromophore. After their synthesis, their photochemical properties were evaluated. All of them were able to carry out the isomerization process with UV or visible light, and different photostationary states were found. Furthermore, the characteristics of one of the derivatives were studied more in-depth to test its efficiency and stability as a molecular switch. Finally, a study to evaluate possible changes in the activity of the initial isomers and the photostationary states obtained was carried out. The biological study showed that two compounds changed their activity after irradiation. The fifth chapter describes the caging process of ciprofloxacin, a quinolone antibiotic, using oxime esters. Different oxime parts were synthesized to try to achieve a bathochromic shift in their absorption. The coupling reaction between the oxime and the antibiotic was designed to form an oxime ester at position 3 of ciprofloxacin. This position is of great importance for the antibacterial activity of the drug. The study of the photochemical properties showed strong absorption in the UV region for all derivatives. The release reaction was successfully induced in all cases with good yields. Moreover, absorption in the visible region was achieved when tetrafluoroboric acid was added to the samples in halogenated solvents. A new band in the blue region of the spectrum appeared, making possible their irradiation with visible light. Finally, to improve the solubility in water of these compounds, one of the oxime esters was trapped in a polymeric micelle, which highly enhanced this property. Lastly, the sixth chapter also focuses on the caging technique and tries to solve some of the drawbacks that oxime esters present. In this chapter, a new photoreleasable group was employed, known as BODIPY. Several BODIPY structures were synthesized to achieve absorption inside the therapeutic window and make the molecules totally or partially soluble in water. This group was coupled at position 3 of two quinolones antibiotics: nalidixic acid and ciprofloxacin. All photoreleasable quinolones displayed absorption in the visible region varying from the green to the NIR region. Irradiation of the samples with visible light allowed the complete release of the antibiotic part in all cases. Furthermore, their stability and efficiency were evaluated. Finally, a biological study was performed to evaluate possible differences in the activity of the caged and uncaged compound. Results showed a strong deactivation of the antibacterial properties when the BODIPY group was linked to the antibiotic. Upon light irradiation, the activity of the drugs was recovered.Esta tesis doctoral describe el diseño, síntesis y evaluación de compuestos cuya actividad antibacteriana puede ser controlada mediante el estímulo de la luz. En el primer capítulo, se introduce brevemente una perspectiva histórica de la fotoquímica, así como del uso de la luz en la terapia médica. De la evolución de estas áreas han surgido diferentes alternativas que se basan en el estímulo de la luz para tratar diversas enfermedades. El segundo capítulo se centra en algunas de estas alternativas: el enfoque fotofarmacológico y el uso de grupos protectores fotoliberables para enjaular medicamentos. La fotofarmacología está basada en moléculas con actividad biológica que incorporan en su estructura un interruptor molecular. La parte fotoactiva puede experimentar un proceso de isomerización que induce un cambio en ciertas propiedades de la molécula como el momento dipolar, la geometría o la electrónica. Estos cambios pueden dar como resultado isómeros con diferentes actividades biológicas. Por tanto, se puede crear un sistema reversible donde un isómero presenta actividad contra el objetivo deseado mientras que el otro no. Por el contrario, el uso de un grupo protector fotoliberable para enjaular un medicamento da lugar a un sistema irreversible. El grupo fotoprotector se enlaza en una posición que hace que el medicamento se inactive. Cuando este es irradiado con luz, el medicamento se libera y recupera su actividad. Estas dos opciones pueden ayudar a resolver algunos de los problemas que presentan los agentes farmacológicos clásicos. Más específicamente, el trabajo aquí descrito está dirigido hacia medicamentos antibacterianos. Los objetivos de esta tesis aparecen descritos en el tercer capítulo. El cuarto capítulo se centra en el enfoque fotofarmacológico. Se diseñaron varias moléculas con su estructura basada en quinolonas unidas a un interruptor molecular en diferentes posiciones. Los interruptores moleculares empleados se basaron en la estructura de la hidantoína y en el pirrol del cromóforo del fitocromo. Tras su síntesis, se evaluaron sus propiedades fotoquímicas. Todos ellos llevaron a cabo el proceso de isomerización con luz UV o visible, encontrándose distintos estados fotoestacionarios para cada uno de ellos. Además, se estudiaron más a fondo las características de uno de los derivados para comprobar su eficiencia y estabilidad como interruptor molecular. Finalmente, se llevó a cabo un estudio para evaluar posibles cambios en la actividad de los isómeros iniciales y los estados fotoestacionarios obtenidos. El estudio biológico mostró que dos de los compuestos cambiaron su actividad después de ser irradiados. Los mejores resultados mostraron un cambio de 4 órdenes. El quinto capítulo describe el proceso de fotoliberación del ciprofloxacino, un antibiótico perteneciente a las quinolonas, usando ésteres de oxima. Se sintetizaron diferentes oximas para intentar conseguir un desplazamiento batocrómico en su absorción. La reacción de acoplamiento entre la oxima y el antibiótico se diseñó para que el éster de oxima se formase en la posición 3 del ciprofloxacino. Esta posición es de vital importancia para la actividad antibacteriana del medicamento. El estudio de las propiedades fotoquímicas mostró una fuerte absorción de todos los derivados en la zona UV del espectro. El proceso de liberación se llevó a cabo satisfactoriamente en todos los casos con buenos rendimientos. Además, se logró la absorción en la región visible del espectro cuando se añadió ácido tetrafluorobórico a las muestras en disolventes halogenados. Se descubrió una nueva banda en la región azul del espectro, lo que hizo posible la irradiación con luz visible. Por último, para mejorar la solubilidad en agua de estos compuestos, uno de los ésteres de oxima fue atrapado en una micela polimérica, lo que mejoro notoriamente esta propiedad. Finalmente, el sexto capítulo también está centrado en la estrategia de fotoliberación y trata de resolver algunos de los inconvenientes que presentan los esteres de oxima. En este capítulo, se utilizó un nuevo grupo fotoliberable conocido como BODIPY. Se sintetizaron varios BODIPYs con el fin de lograr la absorción dentro de la ventana terapéutica y hacer las moléculas total o parcialmente solubles en agua. Este grupo se acopló en la posición 3 de dos quinolonas: ácido nalidíxico y ciprofloxacino. Todas las quinolonas fotoliberables mostraron absorción en la zona visible del espectro, variando desde la región verde hasta el infrarrojo cercano. La irradiación de las muestras se llevó a cabo con luz visible y permitió la completa liberación del antibiótico en todos los casos. Además, también se evaluó su estabilidad y eficiencia. Por último, se realizó un estudio biológico para evaluar posibles diferencias en la actividad de los compuestos enjaulados y liberados. Los resultados obtenidos mostraron una fuerte desactivación de las propiedades antibacterianas cuando el grupo BODIPY estaba unido al antibiótico. Tras la irradiación con luz, la actividad del medicamento se recuperó. Los mejores resultados mostraron una diferencia de diez ordenes de cambio en la actividad.Universidad de La Rioja (España)Sampedro Ruiz, Diego (Universidad de La Rioja)2020text (thesis)application/pdfhttps://dialnet.unirioja.es/servlet/oaites?codigo=285337engLICENCIA DE USO: Los documentos a texto completo incluidos en Dialnet son de acceso libre y propiedad de sus autores y/o editores. Por tanto, cualquier acto de reproducción, distribución, comunicación pública y/o transformación total o parcial requiere el consentimiento expreso y escrito de aquéllos. Cualquier enlace al texto completo de estos documentos deberá hacerse a través de la URL oficial de éstos en Dialnet. 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