Sulfagenix, Inc., Tucson, Arizona, USA.
Antioxid Redox Signal. 2020 Nov 10;33(14):1010-1045. doi: 10.1089/ars.2020.8060. Epub 2020 Jun 11.
Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (HS) 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 HS/SS in blood and/or tissues, and are amenable to treatment by HS supplementation, development of safe and efficacious HS 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. Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S) 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. 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 HS and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. SG1002 is likely to emerge as the HS donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate HS without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of HS donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic HS 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.
硫在所有生物体的蛋白质结构/功能和氧化还原状态/信号转导中都起着关键作用。虽然氢硫化物 (HS) 和亚硫酸硫 (SS) 现在被认为是生理学和病理生理学的核心参与者，但硫代谢组对人类健康和健康长寿的全面和深度影响还远远没有被低估，现在才刚刚开始被理解。由于许多病理状况与血液和/或组织中 HS/SS 水平异常降低有关，并且可以通过 HS 补充来治疗，因此，安全有效的 HS 供体的开发应该具有紧迫感；这些前药也有望成为广泛用于疾病预防和抗衰老的药物。
对包含硫原子链的已知分子（二烯丙基三硫化物 [DATS]，S）的性质进行超分子调节，导致了更好的供体的产生，例如负载 DATS 的聚合物纳米颗粒和 SG1002。在心力衰竭、动脉粥样硬化、缺血性损伤和杜氏肌营养不良症中，SG1002 在动物模型中获得了令人鼓舞的结果；在阿尔茨海默病、精神分裂症、与年龄相关的记忆减退、脆性 X 综合征和可卡因成瘾中，TC-2153 获得了令人鼓舞的结果；在脑、结肠、胃和乳腺癌中，DATS 获得了令人鼓舞的结果。
对烯丙基多硫化物、苄基多硫化物、ajoene 和 12 位取代的有机二硫化物和硫代硫酸盐的作用模式研究使几组研究人员得出结论，这些化合物的抗癌作用不是由 HS 介导的，而是仅由活性氧物质调节的，它们的中心作用模式是选择性蛋白质 S-巯基化。
SG1002 很可能成为 HS 供体的首选，用于在动物模型中获得对这种气体递质作用的知识，因为它具有独特的能力，能够以无副产物的方式高效生成 HS，并且以缓慢而持续的方式进行，这种方式与剂量和酶无关。不仅通过对先导分子进行常规结构修饰，而且通过新的“超分子调节”范例，还将实现 DATS、二苄基三硫化物和其他疏水性 HS 前药的 HS 供体特性的有效调节，用于口服和肠胃外给药。
