Miméticos del antígeno tn conformacionalmente restringidossíntesis, análisis estructural y propiedades biológicas stars

  1. Claudio D. Navo
Supervised by:
  1. Jesús Manuel Peregrina García Director
  2. Gonzalo Jiménez Oses Director

Defence university: Universidad de La Rioja

Year of defence: 2018

  1. José Manuel García Fernández Chair
  2. Carmen Ortiz Mellet Secretary
  3. Stefania Da Luca Committee member
Doctoral thesis with
  1. Mención internacional
  1. Chemistry
Doctoral Programme:
  1. Programa de Doctorado en Química por la Universidad de La Rioja

Type: Thesis


In this Doctoral Thesis, novel unnatural and conformationally restricted glyco-amino-acids are presented. The restrictions aim to fix a bioactive three-dimensional structure in order to increase the interactions with target biomolecules, such as enzymes, lectins or antibodies, given the energetic penalty associated to conformational changes from the free-state to the bound-state. In this way, higher inhibition ratios, stronger recognition, or even higher immune responses are expected. The synthesis of a new family of conformationally-locked C-glyco-amino-acids is exposed throughout chapter 2. These compounds were ob-tained through a double diastereoselective Michael addition between a chiral bicyclic serine equivalent and a nitrogalactal derivative. These unnatural glycosides adopt quite rigid structures and show affinities for lectins similar to those found for natural compounds, like the Tn antigen. This antigen is one of the most specific human tumor-associated structures, which has been related to carcinoma aggressiveness and is considered an important cancer biomarker. Following the same methodology, a set of potential glycosidase inhibitors is presented in chapter 3. Glycosidases hydrolyze glycosidic bonds and are involved in several biological processes, being the desing of more potent and selective glycosidase inhibitors therefore essential. In vitro screening of such compounds showed highly selective inhibition of bovine liver beta-galactosidase and specific inhibition of human beta-glucocerebrosidase among lysosomal glycosidases for derivatives bearing long alkyl chains. The best lead was found to behave as pharmacological chaperone in Gaucher fibroblast with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound Ambroxol®. The synthesis of serine and threonine glycomimetics alpha-O-linked to sp2-iminosugars is addressed in chapter 4. The key step in our synthesis is the completely diastereoselective alpha-O-glycosylation, which is mainly due to strong anomeric effects and reduced torsional strains imposed by the bicyclic system. These amino acids were incorporated into mucin-type peptides, particularly MUC1, which is overexpressed and aberrantly glycosylated in cancer cells, and their ability to be recognized by anti-MUC1 antibodies was then evaluated. Owing to the high affinity showed by one of the candidates, being even higher to that found for the natural Tn antigen, a complete conformational study was performed, combining crystallographic techniques and computational modelling, with the aim of designing and synthesizing a carbohydrate-based cancer vaccine, which is currently being evaluated. Finally, the most relevant results obtained during two international short-term research stays are briefly discussed in chapter 5. At M. Brimble research group (University of Auckland, New Zealand), the bacteriocin glycocin F was fully synthesized, as well as an analog incorporating an unnatural amino acid. On the other hand, at W. van der Donk’s lab (University of Illinois, US), the formation of lisinoalanine in the lantipeptide duramycin catalyzed by the enzyme DurN was studied from a computation-al point of view.