Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides

[eng] In the present thesis we have investigated the development of new methodologies for the selective and straightforward chemical modification of Trp amino acid either alone or in peptides. In the first chapter, we have optimized a method for the chemoselective C-arylation of Trp amino acid in th...

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Autor: Mendive Tapia, Lorena
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2017
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/108587
Acceso en línea:https://hdl.handle.net/2445/108587
http://hdl.handle.net/10803/401593
Access Level:acceso abierto
Palabra clave:Pèptids
Triptòfan
Peptides
Tryptophan
id ES_cfbdb0d832862587b40bbdd4d5e6fbb0
oai_identifier_str oai:diposit.ub.edu:2445/108587
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
title Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
spellingShingle Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
Mendive Tapia, Lorena
Pèptids
Triptòfan
Peptides
Tryptophan
title_short Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
title_full Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
title_fullStr Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
title_full_unstemmed Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
title_sort Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
dc.creator.none.fl_str_mv Mendive Tapia, Lorena
author Mendive Tapia, Lorena
author_facet Mendive Tapia, Lorena
author_role author
dc.contributor.none.fl_str_mv Lavilla Grífols, Rodolfo
Albericio Palomera, Fernando
Universitat de Barcelona. Facultat de Química
dc.subject.none.fl_str_mv Pèptids
Triptòfan
Peptides
Tryptophan
topic Pèptids
Triptòfan
Peptides
Tryptophan
description [eng] In the present thesis we have investigated the development of new methodologies for the selective and straightforward chemical modification of Trp amino acid either alone or in peptides. In the first chapter, we have optimized a method for the chemoselective C-arylation of Trp amino acid in the C-2 position of the free indole ring, based on a C-H activation protocol catalyzed by palladium. To further demonstrate the versatility of the protocol, indoles from tryptamines, indole- carboxylic acids, Trp amino acid and Trp-containing peptides (e.g. Brevianamide F) were selectively arylated. In particular, the commercially available Fmoc-Trp-OH was arylated with a range of different aryl iodides with both electron-withdrawing and electron-donating substituents. It is noticeable that the location of the iodine atom can be programmed, giving rise to ortho, meta or para aryl derivatives. The direct incorporation of Fmoc-Trp(C2-Ar)-OH in solid-pahse peptide synthesis (SPPS), enables the straightforward preparation of Trp-arylated peptide sequences. As a proof of concept, we arylated an antimicrobial peptide derived from the fragment 107–115 of the C-terminus of the human lysozyme in order to enhance its biological activity. In the second chapter, we disclose the preparation of a fluorogenic BODIPY-Trp amino acid via the developed methodology for the straightforward synthesis of peptide-based imaging probes. Thus, this novel amino acid has been applied directly in SPPS to afford a BODIPY-antifungal PAF26 derivative for cell imaging fungal infections and a BODIPY-cyclic cLac mimic for cell imaging apoptosis. In the third chapter, we have applied the methodology disclosed in chapter 1 for the construction of biaryl peptidic topologies through Pd-catalyzed C-H activation reactions between Trp and I-Phe/I-Tyr residues. Thus, we have prepared stapled peptides, both in solution or in solid-phase, directly from linear precursors and we have determined the factors that control the cyclization/cyclodimerization outcome on these systems. Moreover, this C-H activation process enables the synthesis of macrocyclic conjugates and also bicyclic peptides generated from an internal stapling of a linear sequence and subsequent head-to-tail cyclization or from a double intramolecular C-H arylation within a linear peptide containing a commercially available diiodinated Tyr and two Trp units. These topologies could open the door to the access of simplified bismacrocyclic structural analogues of biologically relevant compounds in a straightforward manner from simple linear peptidic sequences prepared through SPPS out of commercially available amino acids. In the fourth chapter, we have developed a methodology based on cross-dehydrogenative processes for the selective formation of new C-C or C-N bonds in Trp-containing diketopiperazines with potential therapeutic interest. Specifically, we have got access to two different topologies depending on the oxidant source applied. [
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/108587
http://hdl.handle.net/10803/401593
url https://hdl.handle.net/2445/108587
http://hdl.handle.net/10803/401593
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv (c) Mendive, 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Mendive, 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv Tesis Doctorals - Facultat - Química
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptidesMendive Tapia, LorenaPèptidsTriptòfanPeptidesTryptophan[eng] In the present thesis we have investigated the development of new methodologies for the selective and straightforward chemical modification of Trp amino acid either alone or in peptides. In the first chapter, we have optimized a method for the chemoselective C-arylation of Trp amino acid in the C-2 position of the free indole ring, based on a C-H activation protocol catalyzed by palladium. To further demonstrate the versatility of the protocol, indoles from tryptamines, indole- carboxylic acids, Trp amino acid and Trp-containing peptides (e.g. Brevianamide F) were selectively arylated. In particular, the commercially available Fmoc-Trp-OH was arylated with a range of different aryl iodides with both electron-withdrawing and electron-donating substituents. It is noticeable that the location of the iodine atom can be programmed, giving rise to ortho, meta or para aryl derivatives. The direct incorporation of Fmoc-Trp(C2-Ar)-OH in solid-pahse peptide synthesis (SPPS), enables the straightforward preparation of Trp-arylated peptide sequences. As a proof of concept, we arylated an antimicrobial peptide derived from the fragment 107–115 of the C-terminus of the human lysozyme in order to enhance its biological activity. In the second chapter, we disclose the preparation of a fluorogenic BODIPY-Trp amino acid via the developed methodology for the straightforward synthesis of peptide-based imaging probes. Thus, this novel amino acid has been applied directly in SPPS to afford a BODIPY-antifungal PAF26 derivative for cell imaging fungal infections and a BODIPY-cyclic cLac mimic for cell imaging apoptosis. In the third chapter, we have applied the methodology disclosed in chapter 1 for the construction of biaryl peptidic topologies through Pd-catalyzed C-H activation reactions between Trp and I-Phe/I-Tyr residues. Thus, we have prepared stapled peptides, both in solution or in solid-phase, directly from linear precursors and we have determined the factors that control the cyclization/cyclodimerization outcome on these systems. Moreover, this C-H activation process enables the synthesis of macrocyclic conjugates and also bicyclic peptides generated from an internal stapling of a linear sequence and subsequent head-to-tail cyclization or from a double intramolecular C-H arylation within a linear peptide containing a commercially available diiodinated Tyr and two Trp units. These topologies could open the door to the access of simplified bismacrocyclic structural analogues of biologically relevant compounds in a straightforward manner from simple linear peptidic sequences prepared through SPPS out of commercially available amino acids. In the fourth chapter, we have developed a methodology based on cross-dehydrogenative processes for the selective formation of new C-C or C-N bonds in Trp-containing diketopiperazines with potential therapeutic interest. Specifically, we have got access to two different topologies depending on the oxidant source applied. [[spa] En esta tesis se ha investigado el desarrollo de nuevas metodologías para la modificación post- sintética del aminoácido Trp. En el primer capítulo, se ha optimizado un método de arilación en C-2 del grupo indol, basado en un proceso de activación C-H catalizado por paladio. En especial, se ha arilado de manera directa el aminoácido comercial Fmoc-Trp-OH con diferentes iodoarilos sustituidos, obteniendo así, nuevos derivados arilados que se pueden aplicar directamente en protocolos en fase sólida. En el segundo capítulo, se ha sintetizado un triptófano fluorogénico basado en el grupo BODIPY vía el proceso de activación C-H desarrollado en el capítulo 1. Así, este aminoácido se ha aplicado directamente en fase sólida para la síntesis de dos péptidos fluorogénicos con interés terapéutico: * Se ha sintetizado una serie de derivados fluorogénicos del péptido antifúngico PAF26 con la finalidad de visualizar infecciones fúngicas de diversos patógenos. * Se ha sintetizado el péptido cíclico fluorescente cLac-BODIPY para la detección de apoptosis, basado en la incorporación del grupo BODIPY a una secuencia peptídica simplificada de lactaderina. En el tercer capítulo, se ha aplicado este protocolo de activación C-H para el acceso a estructuras tipo grapa (staple), directamente a partir de secuencias lineales precursoras que contengan Trp y Phe/Tyr en un proceso de arilación C-H intramolecular. De este modo, se han sintetizado péptidos grapados de secuencias con interés biológico. Esta metodología también permite obtener un amplio rango de diferentes topologías. Así, se han obtenido conjugados macrocíclicos, macrocíclos diméricos, biciclopéptidos que incluyen una ciclación tipo grapa y otra ciclación N-terminal/C-terminal y otros biciclopéptidos formados por dos ciclaciones tipo grapa en una sola etapa sintética. En el cuarto capítulo, se ha desarrollado una metodología basada en reacciones de acoblamiento deshidrogenativo para la formación selectiva de enlaces C-C o C-N en dicetopiperacinas que contengan Trp. Concretamente, se ha accedido a dos tipos de topologías a partir de la correspondiente dicetopiperacina en un solo paso, de acuerdo a la naturaleza del oxidante utilizado.Universitat de BarcelonaLavilla Grífols, RodolfoAlbericio Palomera, FernandoUniversitat de Barcelona. Facultat de Química2017info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/108587http://hdl.handle.net/10803/401593Tesis Doctorals - Facultat - Químicareponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglés(c) Mendive, 2017info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1085872026-05-27T06:46:51Z
score 15,300724

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