title: Tunable degradation of maleimide-thiol adducts in reducing environments.
abstract: Addition chemistries are widely used in preparing biological conjugates, and in particular, maleimide-thiol adducts have been widely employed. Here, we show that the resulting succinimide thioether formed by the Michael-type addition of thiols to N-ethylmaleimide (NEM), generally accepted as stable, undergoes retro and exchange reactions in the presence of other thiol compounds at physiological pH and temperature, offering a novel strategy for controlled release. Model studies ((1)H NMR, HPLC) of NEM conjugated to 4-mercaptophenylacetic acid (MPA), N-acetylcysteine, or 3-mercaptopropionic acid (MP) incubated with glutathione showed half-lives of conversion from 20 to 80 h, with extents of conversion from 20% to 90% for MPA and N-acetylcysteine conjugates. After ring-opening, the resultant succinimide thioether did not show retro and exchange reactions. The kinetics of the retro reactions and extent of exchange can be modulated by the Michael donor's reactivity; therefore, the degradation of maleimide-thiol adducts could be tuned for controlled release of drugs or degradation of materials at time scales different than those currently possible via disulfide-mediated release. Such approaches may find a new niche for controlled release in reducing environments relevant in chemotherapy and subcellular trafficking.
authors.affiliation: Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716, United States.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Baldwin
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Kiick
mesh_terms: D002851:Chromatography, High Pressure Liquid; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008301:Maleimides / Q000737:chemistry*; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D008301:Maleimides; D013438:Sulfhydryl Compounds; C043592:maleimide