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Nuevos Avances En La RMN Anisotrópica Y Detección De Productos Naturales Marinos Bioactivos

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Nuevos Avances En La RMN Anisotrópica Y Detección De Productos Naturales Marinos Bioactivos DEPARTAMENTO DE QUÍMICA FUNDAMENTAL Programa regulado por el RD 1393/2007: Química Ambiental y Fundamental New Advances on Anisotropic NMR and Detection of Bioactive Marine Natural Products Nuevos Avances en la RMN Anisotrópica y Detección de Productos Naturales Marinos Bioactivos Memoria presentada por Juan Carlos C. Fuente Monteverde Directores: Dr. Jaime Rodríguez González Dr. Carlos Jiménez González A Coruña 2018 i ii Acta de Tesis El tribunal, nombrado por el Excmo. Sr. Rector de la Universidade da Coruña para calificar la tesis doctoral titulada “Nuevos Avances en la RMN Anisotrópica y Detección de Productos Naturales Marinos Bioactivos/New Advances on Anisotropic NMR and Detection of Bioactive Marine Natural Products” dirigida por los Drs. Jaime Rodríguez González y Carlos Jiménez González, presentada por Don Juan Carlos de la Cruz Fuentes Monteverde y constituido en el día de la fecha por los miembros que subscriben la presente Acta, una vez efectuada la defensa por el doctorando y contestadas las objeciones y/o sugerencias que se le han formulado, ha otorgado por …………………………la calificación de: En A Coruña, a……………… de ……………………………… de 2019 PRESIDENTE SECRETARIO VOCAL Prof. Dr. Michael Reggelin Pr. Dr. Marcos D. García Romero Pr. Dr. Victor Sanchez Pedregal Organic Chemistry Pr. Titular Química Orgánica Pr. Titular de Química Orgánica Technische Universität Darmstadt Firmado Firmado Firmado iii iv Don Juan Carlos de la Cruz Fuentes Monteverde: Presenta la memoria adjunta, titulada “Nuevos Avances en la RMN Anisotrópica y Detección de Productos Naturales Marinos Bioactivos/New Advances on Anisotropic NMR and Detection of Bioactive Marine Natural Products” para optar al grado de Doctor en Química que ha sido realizado bajo la dirección de los Doctores Jaime Rodríguez González y Carlos Jiménez González en los laboratorios del Centro de Investigaciones Científicas Avanzadas (CICA) de la Universidade da Coruña. A Coruña, a 7 de diciembre de 2018. Fdo. Juan Carlos de la Cruz Fuentes Monteverde Fdo. Jaime Rodríguez González Fdo. Carlos Jiménez González v vi D. Jaime Rodríguez González y D. Carlos Jiménez González, Catedráticos de Universidad, pertenecientes al Departamento de Química (Área de Química Orgánica) de la Facultad de Ciencias de la Universidade da Coruña, Certifican: Que la memoria adjunta, titulada “Nuevos Avances en la RMN Anisotrópica y Detección de Productos Naturales Marinos Bioactivos/New Advances on Anisotropic NMR and Detection of Bioactive Marine Natural Products”. ha sido realizada bajo su dirección por el licenciado en Química Don Juan Carlos de la Cruz Fuentes Monteverde, en el Área de Química Orgánica dependiente del Departamento de Química. Considerando que constituye trabajo de Tesis, autorizan su presentación en la Universidade da Coruña para optar al grado de Doctor en Química. Y para que así conste, expiden el presente certificado en A Coruña, a 7 de diciembre de 2018. Fdo. Jaime Rodríguez González Fdo. Carlos Jiménez González vii viii New Advances on Anisotropic NMR and Detection of Bioactive Marine Natural Products ix x ABREVIATURAS λ Longitud de onda [α]D Rotación óptica específica A549 Línea celular de carcinoma humano APCI Ionización química a presión atmosférica APT Attached Proton Test Experimento de multiplicidad de 13C CC Cromatografía en columna CCF Cromatografía en capa fina COSY Experimento de RMN bidimensional de correlación homonuclear protón-protón δ(ppm) Desplazamiento químico en partes por millón d Doblete da Doblete ancho dd Doble doblete ddd Doble doble doblete DEPT Distorsionless Enhacement by Polarization transfer. Amplificación sin distorsión por transferencia de polarización DFT Density Functional Theory.Teoría de Funcionales de Densidad EMEA Agencia Europea Medicamentos ESI Ionización por electrospray FAB Ionización por bombardeo con átomos acelerados FD Fracción de Diclorometano FH Fracción de hexano FM Fracción de acuosa-metanólica FT-IR Espectrometria de infrarrojo con transformada de Fourier FT-MS Espectrómetro de masas con transformada de Fourier g Gramo HSQC-HECADE (Heteronuclear Couplings from ASSCI-Domain Experiments with E.COSYtype crosspeaks) Experimento de correlación heteronuclear de medida de constante de acoplamiento mediante HSQC-TOCSY HL-60 Línea celular de leucemia promielocítica humana HMBC (Heteronuclear Multiple-Bond Correlation).Experimento de correlación heteronuclear a larga distancia HMQC (Heteronuclear Multiple-Quantum Correlation).Experimento de correlación heteronuclear directo mediante cuanto múltiple HPLC Cromatografía líquida de alta eficacia HRMS Espectrometría de masas de alta resolución HREIMS Espectrometría de masas de alta resolución, técnica de impacto electrónico Hz Hercios IC50 Concentración que inhibe el 50% del crecimiento celular IR Infrarrojo J Constante de acoplamiento m Multiplete xi MS Espectro de masas m/z Relación masa carga mg Milígramo min Minuto mL Mililitro NOESY Nuclear Overhauser Enhancement Spectroscopy. Experimento bidimensional homonuclear de correlación nOe Ref. Referencia PM Peso molecular RMN Resonancia Magnética Nuclear RMN 13C Resonancia Magnética Nuclear de carbono-13 RMN 1H Resonancia Magnética Nuclear de protón RP-HPLC Cromatografía Líquida de Alta Eficacia en Fase Invertida s Singulete sa Singulete ancho t Triplete ta Triplete ancho tR Tiempo de retención UV Ultravioleta WB Fracción de n-BuOH WW Fracción acuosa xii Resumen A continuación, se presenta un breve resumen de cada capítulo: Capítulo 1: El uso de RMN anisotrópica en el análisis estructural de moléculas pequeñas quirales se ha expandido en los años recientes. En la actualidad, las Constantes Dipolares Residuales (CDR) pueden ser aplicadas como una herramienta estándar en el mejoramiento eficiente de la determinación de la configuración relativa de compuestos de pequeño tamaño mediante RMN estándar. En la presente tesis doctoral hemos desarrollado otra metodología de RMN anisotrópica basada en medidas de anisotropía de desplazamiento químico residual de protones (1H RCSA) que ha sido aplicada, primero a moléculas modelo, estricnina, estrona, retrorsina y a-santonina, y posteriormente a nuevos productos naturales: a un meroditerpeno aislado del alga parda Sargassum muticum, a las tricloromammindas A y B aisladas del hongo no comestible Tricholoma equestre y, finalmente a un briarano de origen marino aislado de la gorgonia Briareum asbestinum recolectada de la penísula de Yucatán. Toda esta nueva metodología se ha podido realizar a través de la mejora de nuevos dispositivos de compresión y extensión de geles aplicados a tubos de RMN de menos de 5 mm. Este desarrollo de este tipo de dispositivos es una herramienta adicional que puede ser utilizada en el futuro por espectroscopistas en el campo de RMN anisotrópica. Por último, también hemos introducido un nuevo gel deuterado (PMMA-d8) derivado de polimetilmetacrilato deuterado como medio alineante. xiii Capítulo 2: La detección y cuantificación de productos naturales presentes en trazas en mezclas complejas es aún un campo de investigación activo para los químicos. Desde la introducción en el mercado del detector de masas Orbitrap® se iniciado una revolución en las técnicas analíticas de detección. En la presente Tesis Doctoral hemos aprovechado esta tecnología para la detección y, en algunos casos, el aislamiento y la cuantificación de algunos productos naturales de origen marino de interés biológico. Las distintas aproximaciones en las técnicas de LC/HRMS empleadas fueron aplicadas a: La detection y el aislamiento de la producción de sideróforos en varias bacteria marinas patógenas: tipo vancrobactina en tres especies de Vibrio, tipo piscibactina en una cepa mutante de Vibrio alginolyticus, el sideróforo producido por las bacterias Edwardsiella tarda y Photobacterium damselae subsp. damselae. Detección y cuantification de AHLs en tres especies patógenas de Vibrio. Detección de (TTX) en el pez Diodon hystrix recolectado en El Salvador. vancrobactina divancrobactina piscibactina vibrioferrina TTX xiv Resumo A continuación amósase un resumo de cada capítulo. Capítulo 1 O uso da RMN anisotrópica na análise estrutural de moléculas pequenas quiraies, expandiuse nos anos recentes. Na actualidade, as Constantes Dipolares Residuais (CDR) poden ser aplicadas como unha ferramenta estándar na millora eficiente da determinación da configuración relativa de compostos de pequeno tamano mediante RMN estándar. Na presente Tese Doutoral desenvolvemos outra metodoloxía de RMN anisotrópica baseada en medidas de anisotropía de desprazamento químico residual de protones (1H RCSA) que foi aplicada, primeiro a moléculas modelo, estricnina, estrona, retrorsina e -santonina, e posteriormente a novos produtos naturais: a un meroditerpeno illado do alga parda Sargassum muticum, ás tricloromammindas A e B illadas do fungo non comestible Tricholoma equestre e, finalmente a un briarano de orixe mariña illada da gorgonia Briareum asbestinum colleitada da penísula de Iucatán: Toda esta nova metodoloxía púidose realizar a través da mellora de novos dispositivos de compresión e extensión de xeles aplicados a tubos de RMN de menos de 5 mm. Este desenvolvemento deste tipo de dispositivos é unha ferramenta adicional que pode ser utilizada no futuro por espectroscopistas no campo de RMN anisotrópica. Por último, tamén introducimos un novo xel deuterado (PMMA-d8) derivado de polimetilmetacrilato deuterado como medio alineante. xv Capítulo 2 A detección e cuantificación de produtos naturais presentes en trazas en mesturas complexas é aínda
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