Disulfide and multisulfide antitumor agents and their modes of action

Abstract

A variety of natural products that contain disulfide or multisulfide bonds were found to display potent biological activities, including antitumor activities. At the center of these biological activities are disulfide or multisulfide moieties. The importance of disulfide or multisulfide groups in the areas of chemistry, biology, and pharmacology has been well recognized. Among these agents, especially noteworthy are mitomycin disulfides, leinamycin, thiarubrines, varacins, calicheamicins, and esperamicins. Their general features, including their biological profiles, peculiar structures, and related chemistries, were summarized and more importantly, their working mechanisms were elucidated in detail in this review. Mechanistic studies of these compounds have provided evidence of the key role of disulfide or multisulfide groups. In general, the cleavage of disulfide or multisulfide bonds produces thiol (or thiolate), which triggers an activation cascade leading to the generation of highly reactive electrophile(s) or cytotoxic species that may cause DNA strand scission. The main concerns with the mode of action are the reactivity and stability of disulfide and multisulfide bonds, their cleavage conditions, and the generation of toxic species. A range of studies for each agent was executed to gather important information on their activation, and the obtained information was gradually integrated to give some clues to the agents' working mechanisms. Such information may be further used to generate biomechanistically designed and more potent derivatives.

Disulfide bond based polymeric drug carriers for cancer chemotherapy and relevant redox environments in mammals

“…Disulfide bonds are covalent bonds that form via the oxidation of two sulfhydryl (SH) residues of cysteines or other substances. Disulfide bonds have already been discovered in proteins as well as multiple natural products, including therapeutic drugs . They play an important role in the folding of proteins and enhancing protein stability because they can reduce the entropy of the denatured state .…”

4,4′-Azopyridine as an easily prepared and recyclable oxidant for synthesis of symmetrical disulfides from thiols or alkyl halides(tosylates)/thiourea

“…[1][2][3][4][5][6][7][8] Owing to the increasing importance of the disulfides (disulfanes) in chemistry [9][10][11][12][13][14] and biology, [15][16][17] synthetic approaches for their preparation have been extensively studied. [18][19][20][21][22] According to the literature, disulfides can be obtained directly from *Corresponding author.…”

Drug Metabolism and Pharmacokinetics of Organosulfur Compounds from Garlic

“…Garlic (Allium sativum) has been used in medicines and foodstuff for almost three thousand years as evidenced by ancient writings from China, Egypt, Greece, and India [1,2]. Epidemiological studies have shown that the enhanced dietary intake of garlic could reduce the incidence of various types of tumors such as colon, breast, lung, prostate, and stomach [3][4][5][6][7][8][9]. Garlic gives other beneficial effects including anti-atherosclerosis [10], blood lipids and sugar modulation [11], antifungal [12], antimicrobial [13], antithrombotic [14], cardiovascular disease treatment [15] and stimulating immune system [16].…”