SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs.

Gabriel Gojon,Guillermo A Morales

doi:10.1089/ars.2020.8060

Abstract

Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H2S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H2S/SS in blood and/or tissues, and are amenable to treatment by H2S supplementation, development of safe and efficacious H2S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents.Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S8) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer.Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ring-substituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H2S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation.Future Directions: SG1002 is likely to emerge as the H2S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H2S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H2S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H2S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new “supramolecular tuning” paradigm.

Highlights

The present review focuses on a handful of catenated divalent sulfur molecules of low toxicity that contain sulfane sulfur (SS), are able to release hydrogen sulfide (H2S) via chemical or enzymatic reduction, and have—at least in principle—the potential to be developed into H2S prodrugs
diallyl trisulfide (DATS), dibenzyl trisulfide (DBTS), TC-2153, and SG1002 have the potential to become safe and effective pharmacological therapeutic agents that collectively will prove to be invaluable in humanity’s fight against the ravages of hundreds of disease conditions related to oxidative stress and cellular damage inflicted by reactive oxygen species (ROS): These conditions include most agingrelated diseases
To realize the therapeutic potential of these four agents, it will be necessary to invest considerable resources to carry out the required clinical trials, since—to the best of our knowledge—only in one case (SG1002) has safety been demonstrated in a formal Phase 1 clinical study

Summary

Introduction

The present review focuses on a handful of catenated divalent sulfur molecules of low toxicity that contain sulfane sulfur (SS), are able to release hydrogen sulfide (H2S) via chemical or enzymatic reduction, and have—at least in principle—the potential to be developed into H2S prodrugs. DADS and DATS are the most widely used and studied H2S donors, usually in the context of cancer prevention and treatment [100, 142, 199, 203, 276, 284]; their low toxicity, multiple targets (tubulin, ER, histone deacetylases, endothelial–mesenchymal transition-related proteins, angiogenesis, metastasis, cancer cell stemness), and broad effectiveness against cardiometabolic dysfunction and a large number of cancer types in different stages have been demonstrated in vitro and in animal models and xenografts It seems that H2S does not trigger cancer cell apoptosis in these cases; substantial experimental evidence supporting selective protein S-thiolation as an apoptosis trigger was presented in the preceding section. In the three Cochrane reviews on ‘‘Antioxidants for male subfertility’’ [221, 222, 228], the authors assessed the effects of oral antioxidants on men with documented sperm DNA damage and/or with impaired semen parameters on the basis of clinical trials wherein the participants were randomly assigned to antioxidant versus placebo, an alternative antioxi-

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