Kinetics study of degradation of maleimide-thiol conjugates in reducing environments
Date
2017
Authors
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Publisher
University of Delaware
Abstract
The retro-Michael addition and thiol exchange of thioether succinimide click linkages in response to thiol-containing environments offers a novel and well-established strategy for the design of glutathione-sensitive degradable hydrogels for controlled drug delivery. Here we demonstrate that the kinetics and extent of the retro Michael-type addition and thiol exchange are significantly dependent on the nature of both thiols and N-substituents of maleimides. A series of N-substituted succinimide thioethers were prepared through typical Michael-type addition. Model studies (1H NMR, HPLC) of 4-mercaptophenylacetic acid (MPA, pKa 6.6) conjugated to N-ethyl maleimide (NEM), N-phenyl maleimide (NPM) or N-aminoethyl maleimide (NAEM) incubated with glutathione showed half-lives of conversion from 3.1 h to 18 h, with extents of conversion from 12.3% to 89.5%. Rapid thiol exchange is attributed to the resonance effect of the N-phenyl group for NPM conjugates, while the electron-withdrawing inductive effect of groups such as protonated N-aminoethyl group favors a higher level of ring-opening than retro reaction. Further model studies of 4-mercaptohydrocinnamic acid (MPP, pKa 7.0), N-acetyl-L-cysteine (NAC, pKa 9.5) conjugated to selected N-substituted maleimides incubated with glutathione showed half-lives of conversion from 3.6 h to 258 h, with extents of conversion from 0.8% to 90.7%. Higher pKa of thiols decreased the rate of the exchange reaction and limited the impact of other electronic effects of N-substituents on the extents of conversion. Additional factors affecting the degradation kinetics were studied on NEM conjugates. The kinetics of retro and exchange reaction was not hindered in thiol traps of lower pKa but retarded in conditions of lower pH. These studies shed light into details of thiol and maleimide design that could be used to tune the rates of degradation of drug and polymer conjugates for a variety of applications.
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Keywords
Applied sciences, Glutathione-mediated degradation, N-substituted maleimide, Retro Michael-type addition, Thiol pKa