Structural investigation of cyclo-dioxo maleimide cross-linkers for acid and serum stability.
Fiche publication
Date publication
novembre 2017
Journal
Organic & biomolecular chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr WAGNER Alain
Tous les auteurs :
Tobaldi E, Dovgan I, Mosser M, Becht JM, Wagner A
Lien Pubmed
Résumé
The biochemical characteristics of hetero-bifunctional cross-linkers used in bioconjugates are of essential importance to the desired features of the final adduct (i.e. antibody-drug conjugates). These include stability in biological media, chemical and biological reactivities, cleavability under defined conditions, and solubility. In our previous work, we introduced a new amino-to-thiol linker, maleimidomethyl dioxane (MD), as an alternative to classical maleimide conjugation, with increased hydrophilicity and serum stability due to succinimidyl ring-opening. In this work, we investigate the generality of linkers containing a dioxo-ring with regard to their ability to self-hydrolyze and their surprising stability at a low pH. We synthesized four FRET probes which allowed us to address the stability of the dioxo-ring and to study the maleimide ring-opening and the thiol-exchange processes by means of detecting and measuring the generation of fluorescence. It was found that the ring expansion (from a 5- to a 6-membered ring) improved the stability of the probes in aqueous media, and the increase of the chain length between the dioxo-ring and the succinimide ring (from methylene to ethylene) decreased the rate of succinimidyl ring-opening.
Mots clés
Drug Stability, Humans, Hydrogen-Ion Concentration, Maleimides, blood, Models, Molecular, Protein Conformation, Pyrans, chemistry, Serum Albumin, Human, chemistry, Sulfhydryl Compounds, chemistry, Water, chemistry
Référence
Org. Biomol. Chem.. 2017 Nov 15;15(44):9305-9310