Novel GSH/enzyme-responsive anti-hyperthyroidism prodrugs designed for transdermal delivery of 2-sulfonyl-1- methylimidazole (MMI) were synthesized by a Michael addition reaction of MMI with propiolic acid (PA) followed by esterification with three long chain fatty alcohols and their structures were characterized by 1H NMR, 13C NMR and mass spectrometry. Their maximum steady state flux through rat skin in the PG/W solution was found to be more than 37-times faster than that of MMI. The result may be attributed to the improved lipophilicity of prodrug and rapid bioconversion. The prodrugs were hydrolyzed by esterase on passing through the skin and appeared mainly as intermediate MMI-PA in the receiver compartment and accompanied by a small amount of MMI and intact prodrug. The prodrugs did not release any MMI in the media without GSH or with 100 µM GSH, while the obvious MMI release could be observed within 6.4 h in the media containing 2 mM and 10 mM GSH, and their maximum cumulative release rates reached 95.07% for lauryl alcohol ester prodrug (MMI-PA-OLa). MMI-PA-OLa exhibited a significant inhibition effect on lactoperoxidase (LPO) after being incubated in millimolar GSH media, whose inhibition rate was very similar to that of free MMI with an equivalent dose. These results suggested that MMI-PA-OLa could pass efficiently through the skin and release MMI in response to the intracellular environment.
Keywords: GSH/enzyme responsiveness; Methylimidazole; Prodrug; Transdermal delivery.
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