期刊
BIOCONJUGATE CHEMISTRY
卷 22, 期 10, 页码 1946-1953出版社
AMER CHEMICAL SOC
DOI: 10.1021/bc200148v
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资金
- Nemours Foundation
- National Science Foundation [DGE-0221651]
- National Institutes of Health [5-P20-RR016472-10]
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 (H-1 NMR, HPLC) of NEM conjugated to 4-mercaptophenylcetic 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 subecullar trafficking.
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