New Protecting Groups for the Synthesis of Complex Peptides

• Autores: Albert Isidro Llobet
• Directores de la Tesis: Mercedes Álvarez Domingo (dir. tes.), Fernando Albericio Palomera (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2008
• Idioma: inglés
• Tribunal Calificador de la Tesis: Antoni Riera Escalé (presid.), Paul Lloyd-Williams (secret.), Juan José Vaquero López (voc.), Eduard Bardají Rodríguez (voc.), Andrés Parra Guerrero (voc.)
• Materias:
  • Química
    • Bioquímica
      • Péptidos
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • The increasing importance of peptides as drugs creates the necessity of new methodologies for the synthesis of complex peptides. This PhD thesis has been focused on the development of new protecting groups (including new linkers) for peptide synthesis. The work done has solved several problems in peptide synthesis making it more versatile. These are some of the results obtained:- The removal conditions of the pNZ group as α-amino and Orn and Lys side chain protector have been optimized. These optimized conditions make pNZ orthogonal to the most used protecting groups in the Fmoc/tBu solid phase peptide synthesis strategy (Fmoc, Boc and Alloc) and minimize its most important side reactions such as formation of diketopiperazines, aspartimides and removal of the α-Fmoc group. The use of the pNZ group allows also the synthesis of complex and biologically interesting peptides such as the antitumoral peptide Kahalalide F.- A new protecting agent, the Fmoc-2-mercaptobenzothiazole (Fmoc-MBT), has been developed. It prevents side reactions in the synthesis of Fmoc-amino acids.New protecting groups developed:- p-Nitromandelic linker (pNM): it is useful for the synthesis of peptides and depsipeptides using the Boc/Bn strategy.- Backbone protectors (3,4-ethylenedioxythenyl (EDOTn) and 1-methyl-3-indolylmethyl (MIM)): they improve some of the poperties of the present backbone protectors such as their difficult elimination and steric hindrance.- Phenyl-EDOTn derivatives as super acid labile carboxylic acid protecting groups.- 1,2-dimethylindole-3-sulfonyl (MIS) as a protector of the side chain of arginine: it is much more acid labile than the present protecting groups and it is compatible with tryptophan containing peptides.