21 research outputs found
One-pot photochemical ring-opening/cleavage approach for the synthesis and decoding of cyclic peptide libraries
A novel dual ring-opening/cleavage strategy to
determine the sequence of cyclic peptides from one bead, one
compound libraries is described. The approach uses a
photolabile residue within the macrocycle and as a linker to
allow a simultaneous ring opening and cleavage from the beads
upon UV irradiation and provide linearized molecules. Cyclic
peptides of five to nine residues were synthesized and the
generated linear peptides successfully sequenced by tandem
mass spectrometry
Mesoionic compounds : new tools for drug delivery
TrĂšs rĂ©cemment, notre Ă©quipe a mis en Ă©vidence une rĂ©action dite de ligation et coupure entre une famille de composĂ©s mĂ©soioniques, les sydnone-imines, et les cyclooctynes. Cette rĂ©action bioorthogonale agit selon un processus en deux Ă©tapes, une cycloaddition [3+2] suivie dâune rĂ©tro Diels-Alder, qui gĂ©nĂšre deux nouveaux composĂ©s : un produit de ligation et un produit de coupure. Lâobjectif de cette thĂšse consiste Ă amĂ©liorer la cinĂ©tique de rĂ©action entre ces deux partenaires afin de pouvoir lâutiliser en tant quâoutil pour la libĂ©ration contrĂŽlĂ©e de principes actifs in vivo.Trois stratĂ©gies ont Ă©tĂ© dĂ©veloppĂ©es lors de cette thĂšse afin dâoptimiser ce systĂšme rĂ©actionnel : lâĂ©tude dâune relation structure/rĂ©activitĂ© du partenaire sydnone-imine vis-Ă -vis de la rĂ©action bioorthogonale; lâutilisation de micelles constituĂ©es dâamphiphiles possĂ©dant un motif sydnone-imine en tant que lien clivable entre la partie hydrophobe et la partie hydrophile de la molĂ©cule; et enfin, lâĂ©tude de lâutilisation de la reconnaissance molĂ©culaire entre deux brins dâacides nuclĂ©iques peptidiques (ANP) complĂ©mentaires.Recently, our laboratory has discovered a click and release reaction involving iminosydnones, a family of mesoionic compounds, and cyclooctynes. This bioorthogonal reaction occurs via a two step process: a [3+2] cycloaddition followed by a retro Diels-Alder, to give two new compounds: a click product and a release product.The main goal of this work is to improve the kinetic of the reaction between these two partners in order to use it as a powerful tool for in vivo drug delivery. Three strategies were developed during this thesis to optimize this reaction system: the study of a structure/reactivity relationship of the iminosydnone partner regarding the bioorthogonal reaction; the development of micelles built by amphiphiles containing an iminosydnone moiety as a cleavable linker, strategically located between the hydrophobic and the hydrophilic part of the compound and finally, the use of molecular recognition between two peptide nucleic acids (PNA) complementary strands
Fluorogenic iminosydnones: bioorthogonal tools for double turn-on click-and-release reactions
International audienceIn this article, we report the synthesis and use of iminosydnone-based profluorophores as bioorthogonal cleavable linkers for imaging applications. These linkers react with cycloalkynes via subsequent [3+2] cycloaddition and retro Diels-Alder reactions, allowing simultaneous release of two dyes in biological media
Versatile Access to N-Functionalized Iminosydnones by Carbonylimidazolium Activation
International audienceA new methodology for N-exocyclic functionalization of iminosydnones was developed involving the addition of a large variety of nucleophiles on carbonyl-imidazolium activated iminosydnones. This practical and highly versatile method pro-vided access to new classes of iminosydnones and opened a straight-forward synthetic route to prepare iminosydnone-based prodrugs
A practical synthesis of valuable strained 8-membered ring derivatives for click chemistry
International audienceA convenient and cost-effective synthetic access to cyclooctyne and trans-cyclooctene derivatives is described. A cyclopropanation step using copper powder in lieu of Rhâ(OAc)â as catalyst and a symmetric diazomalonate enabled to drastically reduce the overall cost of the synthesis. Further derivatizations allowed to characterize, for the first time, the structure of a BCN analogue by X-ray crystallography and obtain a library of derivatives potentially useful for applications in metal free click chemistry
Bioorthogonal drug release from nanometric micelles in living cells
International audienceAbstract We explored a bioorthogonal approach to release drugs from stimuliâresponsive micelles inside tumor cells. The concept relies on sydnonimineâbased micelles that undergo quantitative cleavage in presence of cyclooctynes, hence releasing their content within living cells. Four cleavable micelles were developed to allow massive burst release of Entinostat, a potent histone deacetylase inhibitor, following their internalization inside cancer cells. A comparative study on the influence of the bioorthogonalâmediated versus passive drug release from micelles was carried out. The results indicated that a fast release of the drug triggered a stronger antiproliferative activity on tumor cells compared to the passive diffusion of the drug from the micelles core. These finding may be of great interest for the development of new nanomedicines
Copper-Catalyzed Aza-Iminosydnone-Alkyne Cycloaddition Reaction Discovered by Screening
International audienceThe chemistry and reactivity of mesoionic compounds represent a chemical space largely unexploited. Using a MS-based screening approach, the reactivity of mesoionics toward terminal alkynes under copper catalysis has been explored. This approach led to the discovery of new reactions allowing chemoselective ligation of the two reaction partners and, simultaneously, the release of a fragment molecule. The reactivity of aza-iminosydnones allowing the selective formation of 1,2,3 triazoles or hydrazineylidene-propanal derivatives from alkynes was revealed. This copper-catalyzed reaction was found to be under the control of copper-ligand and alkyne structures. The scope of the reactions and mechanistic investigations are presented
StrainâPromoted 1,3âDithioliumâ4âolates/Alkyne Cycloaddition
International audienceWe report the reactivity of mesoionic 1,3-dithiolium-4-olates towards strained alkynes leading to thiophene cycloaddition products. In the process, we discovered the potential of these dipoles towards orthogonal reaction with azides allowing efficient double ligation reactions. We also developed a versatile process to access benzo[c]thiophenes in an unprecedented divergent fashion, which provides a new entry to unconventional poly-aromatic thiophenes
Repositioning of FDA-Approved antifungal agents to interrogate Acyl-CoA synthetase long chain family member 4 (ACSL4) in ferroptosis
Ferroptosis, first coined in 2012, is an iron-dependent regulated cell death (RCD) characterized by the accumulation of lipid peroxides to toxic levels. This mechanism is currently being evaluated as a target for a variety of diseases offering new opportunities for drug design and development. Recent reports uncovered acyl-CoA synthetase long-chain 4 (ACSL4) as a critical contributor to ferroptosis execution. Therefore, ACSL4 inhibitors are emerging as attractive anti-ferroptotic agents. Herein, we developed a robust screening cascade with orthogonal biophysical and biochemical techniques to identify original human ACSL4 inhibitors. By screening an FDA-approved drug library, we were able to identify and validate new inhibitors with micromolar-range activities against ACSL4. With an IC50 of 280 nM against hACSL4, antifungal agent sertaconazole is to our knowledge, the most potent ACSL4 inhibitor identified so far. In addition, sertaconazole significantly reduced lipid peroxidation and ferroptosis in human differentiated dopaminergic neurons (Lund human mesencephalic LUHMES cells), demonstrating that it is a valuable chemical tool for further investigating the role of ACSL4 in ferroptosis. This study highlights the phenethyl-imidazole scaffold as a novel and promising starting point for the development of anti-ferroptotic agents targeting ACSL4