Carregant...
Tipus de document
TesiVersió
Versió publicadaData de publicació
Tots els drets reservats
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/108587
Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides
Títol de la revista
Autors
Director/Tutor
ISSN de la revista
Títol del volum
Recurs relacionat
Resum
[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. [
Matèries (anglès)
Citació
Col·leccions
Citació
MENDIVE TAPIA, Lorena. Indole arylation in tryptophan residues: development of new chemical methodologies, synthetic studies and biological evaluation of modified peptides. [consulta: 13 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/108587]