N1-Glutathionyl-spermidine disulfide

Bioresponsive polymers have been widely used in drug delivery because of their degradability. For example, poly(disulfide)s with repeating disulfide bonds in the main chain have attracted considerable research attention. The characteristics of the disulfide bonds, including their dynamic and reversible properties and their responsiveness to stimuli such as reductants, light, heat, and mechanical force, make them ideal platforms for on-demand drug delivery. This review introduces the synthesis methods and applications of poly(disulfide)s. Furthermore, the synthesis methods of poly(disulfide)s are classified on the basis of the monomers used: oxidative step-growth polymerization with dithiols, ring-opening polymerization with cyclic disulfides, and polymerization with linear disulfides. In addition, recent advances in poly(disulfide)s for the delivery of small-molecule or biomacromolecular drugs are discussed. Quantum-dot-loaded poly(disulfide) delivery systems for imaging are also included. This review provides an overview of the various design strategies employed in the construction of poly(disulfide) platforms to inspire new applications in the field of drug delivery.

To find their potential use in protein research, direct addition of a disulfide compound to alkyne (namely disulfide-yne reaction) and S-arylation with arenediazonium salt (namely disulfide-diazonium reaction) were investigated in aqueous or protic solutions. The reaction of dimethyl disulfide with 5-hexynol performed best under 300 nm irradiation in the presence of sodium acetate to afford 5,6-bis(methylthio)-5-hexenol in 60% yield. Without the prior reduction of a disulfide bond to thiols, the disulfide-yne reactions have the advantage of 100% atom economy. Disulfide-diazonium reaction was triggered by sodium formate and accelerated by photoirradiation with a 450 nm LED lamp (5 W). The reaction of 3,4-dihydroxy-1,2-dithiane with 2-(prop-2-yn-1-yloxy)benzene-1-diazonium tetrafluoroborate (8b) afforded 2-(benzofuran-3-yl)-1,3-dithiepane-5,6-diol (13), confirming that both S substituents originate from the same disulfide molecule. The trastuzumab antibody was incubated with diazonium 8b, followed by α-lytic protease digestion, LC-ESI-MS/MS analysis, and Mascot search, to verify that the proximal C229 and C232 residues on the same heavy chain were reconnected with a (benzofuranyl)methine moiety that originated from 8b, unlike the expected disulfide rebridging across two heavy chains. Nonetheless, disulfide-diazonium reactions still have potential for rebridging disulfide bonds if appropriate proteins and diazonium agents are chosen.

The major function of disulfide bonds is not only the stabilization of protein structures. Over the last 30 years, a change in perspective took place driven by groundbreaking experiments, which promoted disulfide bonds to central players in essential thiol-disulfide exchange reactions involved in signal transduction, thiol protection, and redox homeostasis regulation. This new view stimulated redox research and led to the discovery of novel redox pathways, redox enzymes, and new low-molecular-weight thiols. These redox-sensitive molecules operate along diverse pathways via a dynamic thiol-disulfide mechanism in which disulfide bonds are reversibly formed and reduced, thereby switching the molecules between different conformational and functional states. It is now clear that disulfide bonds play a pivotal role in cellular reduction and oxidation processes. However, in spite of the fundamental cell biological and medical importance of the thiol-disulfide exchange switches, we are only beginning to understand their principles of specificity, their mechanism of action, and their role in signal transduction. Our further progress in understanding the thiol-disulfide switches will strongly depend on the chemical tools and on the technological advances that will be made in the development of new methodologies.