Click and Release: SO₂ Prodrugs with Tunable Release Rates

Abstract

Employing an intramolecular cycloaddition reaction, we have developed a series of SO prodrugs with tunable release rates with half-lives ranging from minutes to days.

Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide

“…Herein we describe a novel concentration-sensitive platform approach to prodrug activation based on controls by reaction kinetics using bioorthogonal click chemistry, which has been applied in prodrug preparation with excellent success. 12 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 Ideally, one would like to use linker chemistry that tethers the active drug to the targeting molecule in a stable fashion, and allow for selective cleavage at the desired site of action. 20 , 26 , 27 , 28 , 29 Through the use of click chemistry and the concept of co-localization, 30 , 31 the linker can be very stable until enrichment-triggered release (ETR).…”

SO2 Donors and Prodrugs, and Their Possible Applications: A Review

“…Inspired by their previous work developing CO prodrugs, Wang's group developed click-reaction-based SO 2 donors and prodrugs (Wang D. et al, 2014 ; Ji et al, 2017 ; Wang W. et al, 2017 ). A bimolecular system consisted of a tetra-substituted thiophene dioxide with a low LUMO and a strained alkyne/alkene with a high HOMO was first developed as a proof-of-concept (Scheme 5 ).…”

“…To overcome these problems, Wang's group carried the “click-and-release” strategy further by combining the diene (thiophene dioxide) and dienophile (alkyne) into one single molecule (Ji et al, 2017 ). They reasoned that intramolecular cycloaddition reaction will be entropy-favored and therefore allow the compounds to release SO 2 under mild conditions.…”

Small molecule generators of biologically reactive sulfur species

“…143 This reaction was carried out with two independent reactants and a follow-up on this work had an intramolecular reaction. 144 The latter strategy has been used to tune release of sulfur dioxide from a few minutes to days. Binghe Wang and co-workers recently reported a sulfone that was a candidate for Julia olenation reaction (Scheme 12).…”