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

Abstract

SO2 is widely recognized as an air pollutant and is a known cause of acid rain. At a sufficiently high level, it also causes respiratory diseases. A much lesser known side of SO2 is its endogenous nature and possible physiological roles. There is mounting evidence that SO2 is produced during normal cellular metabolism and may possibly function as a signaling molecule in normal physiology. The latter aspect is still at the stage of being carefully examined as to the validity of classifying SO2 as a gasotransmitter with endogenous signaling roles. One difficulty in studying the biological and pharmacological roles of SO2 is the lack of adequate tools for its controllable and precise delivery. Traditional methods of using SO2 gas or mixed sulfite salts do not meet research need for several reasons. Therefore, there has been increasing attention on the need of developing SO2 donors or prodrugs that can be used as tools for the elucidation of SO2's physiological roles, pharmacological effects, and possible mechanism(s) of action. In this review, we aim to review basic sulfur chemistry in the context of sulfur signaling and various chemical strategies used for designing SO2 donors. We will also discuss potential pharmacological applications of SO2 donors, lay out desirable features for such donors and possibly prodrugs, analyze existing problems, and give our thoughts on research needs.

Post-translational Modifications of IκBα: The State of the Art

“…For example, endogenous sulfur dioxide (SO 2 ) is found to play extensive regulatory roles in the cardiovascular system as a novel gasotransmitter ( Huang et al, 2016 ). Along with the increasing studies on the pathophysiological significance of endogenous SO 2 in the cardiovascular diseases, SO 2 donors and prodrugs with different triggering mechanisms, such as thiol-activated SO 2 prodrugs, thermally activated SO 2 prodrugs and hydrolysis-based SO 2 prodrugs, were designed in recent years ( Day et al, 2016 ; Wang and Wang, 2018 ). The abovementioned studies might provide useful evidence for the drug design targeting the inhibition of NF-κB pathway.…”

Endogenous sulfur dioxide is a novel inhibitor of hypoxia-induced mast cell degranulation

“…However, the levels of SO 2 in VSMC was lower than that of MC. We speculated that there might be other impactors involved in the regulation of endogenous SO 2 content such as non-enzymatic SO 2 generation, SO 2 consumption and clearance according to a comprehensive review about SO 2 metabolism and SO 2 donor [37] , which merits to be investigated in the future.…”

“…SO 2 gas dissolved in water forms a hydrated SO 2 complex (SO 2 ·H 2 O) that dissociates twice to generate HSO 3 − and SO 3 2− . The formation of SO 2 from a NaHSO 3 /Na 2 SO 3 (1:3 M/M) solution depends on the complex kinetics of the dynamic equilibrium between gaseous SO 2 and HSO 3 − /SO 3 2− [37] . Therefore, whether a SO 2 gas solution or NaHSO 3 /Na 2 SO 3 (1:3 M/M) solution is administrated to cells or animals, they may exist in the form of SO 2 and HSO 3 − /SO 3 2− .…”

“…Therefore, whether a SO 2 gas solution or NaHSO 3 /Na 2 SO 3 (1:3 M/M) solution is administrated to cells or animals, they may exist in the form of SO 2 and HSO 3 − /SO 3 2− . However, there exist the differences in the amount of SO 2 releases, release rate, delivery rate to tissues or cells, action efficiency and clearance rate between the SO 2 gas solution and NaHSO 3 /Na 2 SO 3 mixtures [37] . For instance, a previous study demonstrated that gaseous SO 2 might have a stronger vasodilator effect compared with a NaHSO 3 /Na 2 SO 3 mixture [28] .…”

“…Previous studies reported that endogenously generated gaseous signal molecules are widely present in mammals and involved in the fine and continuous regulation of disease development [13] , [14] . Sulfur dioxide (SO 2 ), a novel endogenous sulfur-containing gaseous signaling molecule catalyzed by aspartate aminotransferase (AAT) with the substrate of cysteine [15] , significantly reduced the levels of inflammatory factors in endothelial cells [16] . Also, it was reported that SO 2 pretreatment reduced serum IL-1 and IL-6 levels in rats with acute lung injury induced by lipopolysaccharide [17] .…”