Metallocarbonyl bromomaleimide derivatives for thiol bioconjugation and disulfide bridging: spectroscopic and biological properties

Abstract

Mono- and dibromomaleimides have been introduced as useful reagents for the modification of cysteine residues, disulfide rebridging and peptide stapling. Herein, we investigate the reaction of the organometallic compounds CpFe(CO)₂(η¹-2-bromomaleimidato) and CpFe(CO)₂(η¹-2,3-dibromomaleimidato) and their organic analogs 2-bromomaleimide and 2,3-dibromomaleimide with the bioactive thiols N-acetyl cysteine methyl ester and 1-thio-β-D-glucose tetraacetate, along with the disulfide-containing protein bovine insulin. Substitution and/or addition products were isolated and characterized by NMR, IR and MS and the molecular structure of two reaction products was confirmed by X-ray diffraction. In the case of the organic derivatives, formation of the dithiomaleimide adducts was also assessed by the emission of fluorescence in the green region. Visible light irradiation of the metallocarbonyl dithiomaleimides resulted in the decomposition of the organometallic fragment and generation of fluorescent products. This feature greatly helped to delineate the transformations operated by the metallocarbonyl compounds within cancer cells and provided clues to their molecular mechanism of action.