Métabolites pyrrole-2-aminoimidazoles marins bioactifs (réactivité et synthèse biomimétique)

Le travail qui est décrit dans ce mémoire est articulé autour de la réactivité des alcaloïdes pyrrole-2-aminoimidazoles extraits d'éponges marines. Cette étude est notamment basée sur une hypothèse biogénétique qui permet d'expliquer la formation de la plupart de ces composés à partir de précurseurs simples tels que l'oroidine et le dispacamide A. Il existe au sein de cette famille des métabolites linéaires et polycycliques. L'acide 2-pyrrole carboxylique plus ou moins bromé et le 2-aminoimidazole constituent les éléments réactifs les plus importants dans cette série. Le manuscrit est composé de trois études indispensables à la synthèse biomimétique de cette famille d'alcaloïdes: L'étude des réactions de cyclisation N1-C et C3-C intramoléculaires sur le pyrrole permet d'envisager une voie de synthèse vers de nombreux composés polycycliques. L'étude de l'oxydation et de l'ouverture de dimères pyrrole-proline ou proline-proline donne accès à des composés linéaires; elle nous a notamment permis la synthèse biomimétique du dispacamide A et de ses dérivés. L'analyse biomécanistique et la voie de synthèse de l'oroidine, de l'hyménidine et de la clathrodine en utilisant les N-acyl-1,2-dihydropyridines. L'ensemble de cette étude a permis de comprendre de nombreux mécanismes impliqués dans la réactivité des pyrrole-2-aminoimidazoles et de mettre en place une stratégie de synthèse biomimétique qui semble cohérente.The work described in this manuscript is centered on the reactivity of pyrrole-2-aminoimidazole alcaloids isolated from marine sponges. This study is based on a biogenetic hypothesis which could explain the chemical pathways formation of most of this compounds, starting from very simple precursors like oroidine and dispacamide A. This family of compounds comprise linear and polycyclic structural groups. 2-Pyrrolecarboxylic acid, more or less brominated, and 2-aminoimidazole parts are the most important building blocks. The manuscript is divided into three studies: the study of N1-C and C3-C intramolecular cyclisations on pyrrole-aminoacids derivates allowed us to postulate a new synthetic scheme towards many polycyclic compounds belonging to this family. The study of dimeric pyrrole-proline or proline-proline systems and their biomimetic spontaneous transformations to dispacamide A and derivates. Biomechanistic analysis and the access to oroidine, hymenidine and clathrodine, using N-acyl-1,2-dihydropyridines. This general study allowed us to understand numbers of chemical mecanisms involved in the reactivity of pyrrole-2-aminoimidazole alcaloids.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Oligomeric PEG-Phospholipids for Solubilization and Stabilization of Fluorescent Nanocrystals in Water

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In Situ Electron-Beam Polymerization Stabilized Quantum Dot Micelles

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A New in Silico antibody similarity measure both identifies large sets of epitope binders with distinct CDRs and accurately predicts off-target reactivity

International audienceDeveloping a therapeutic antibody is a long, tedious, and expensive process. Many obstacles need to be overcome, such as biophysical properties (issues of solubility, stability, weak production yields, etc.), as well as cross-reactivity and subsequent toxicity, which are major issues. No in silico method exists today to solve such issues. We hypothesized that if we were able to properly measure the similarity between the CDRs of antibodies (Ab) by considering not only their evolutionary proximity (sequence identity) but also their structural features, we would be able to identify families of Ab recognizing similar epitopes. As a consequence, Ab within the family would share the property to recognize their targets, which would allow (i) to identify off-targets and forecast the cross-reactions, and (ii) to identify new Ab specific for a given target. Testing our method on 238D2, an antagonistic anti-CXCR4 nanobody, we were able to find new nanobodies against CXCR4 and to identify influenza hemagglutinin as an off-target of 238D2