Stabilizing p-dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release.

Stabilizing p-dithiobenzyl Urethane Linkers without Rate-Limiting Self-Immolation for Traceless Drug Release.
ChemMedChem. 2019 Apr 24;:
Authors: Zheng Y, Shen Y, Meng X, Wu Y, Zhao Y, Wu C
Abstract
Exploiting the redox-sensitivity of disulfide bonds is a prevalent strategy adopted in targeted prodrug designs. Compared with aliphatic disulfides, the p-thiobenzyl-based disulfides have rarely been used for prodrug designs due to their intrinsic instability caused by the low pKa of aromatic thiols. Here, we examined the interplay between steric hindrance and the low-pKa effect on the thiol-disulfide exchange reactions and uncovered a new thiol-disulfide exchange process for the self-immolation of p-thiobenzyl-based disulfides. We observed a central-leaving group shifting effect in our DMTB-linkers, which leads to >2 orders of magnitude increase in disulfide stability, an extent that is significantly larger than that observed from the typical aliphatic disulfides. Particularly, the DMTB-linkers display not only a high stability, but also rapid self-immolation kinetics due to the low pKa of the aromatic thiol, which can be used as a general and robust linkage between targeting reagents and cytotoxic drugs for targeted prodrug designs. The unique and promising stability characteristics of the present DMTB-linker would inspire the development of novel targeted prodrugs to achieve traceless release of drugs into cells.
PMID: 31020...

Source: ChemMedChem - April 23, 2019 Category: Chemistry Authors: Zheng Y, Shen Y, Meng X, Wu Y, Zhao Y, Wu C Tags: ChemMedChem Source Type: research