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Hydrogen sulfide (H2S) is now recognized as a physiologically important gasotransmitter. Compounds which release H2S slowly are sought after for their potential in therapy. Herein the synthesis of a series of phosphordithioates based on 1 (GYY4137) are described. Their H2S release profiles are characterized using 2,6-dansyl azide (2), an H2S specific fluorescent probe. Most compounds have anticancer activity in several solid tumor cell lines and are less toxic in a normal human lung fibroblast, WI38. A preferred compound, 14, with 10-fold greater anticancer activity than 1, was shown to release H2S in MCF7 cells using a cell active probe, 21. Both permeability and intracellular pH (pHi) were found to be significantly improved for 14 compared to 1. Furthermore, 14 was also negative in the AMES test for genotoxicity. Cyclization of these initial structures gave a series of 2,3-dihydro-2-phenyl-2-sulfanylenebenzo[d][1,3,2]oxazaphospholes, of which the simplest member, compound 22 (FW1256), was significantly more potent in cells. The improved therapeutic window of 22 in WI38 cells was compared with three other cell types. Potency of 22 was superior to 1 in MCF7 tumor spheroids and the mechanism of cell death was shown to be via apoptosis with an increase in cleaved PARP and activated caspase-7. Evidence of H2S release in cells is also presented. This work provides a "toolbox" of slow-release H2S donors useful for studies of H2S in biology and as potential therapeutics in cancer, inflammation, and cardiovascular disease.

Slow and continuous release of H2S by GYY4137 has previously been demonstrated to kill cancer cells by increasing glycolysis and impairing anion exchanger and sodium/proton exchanger activity. This action is specific for cancer cells. The resulting lactate overproduction and defective pH homeostasis bring about intracellular acidification-induced cancer cell death. The present study investigated the potency of H2S released by GYY4137 against invasive and radio- as well as chemo-resistant cancers, known to be glycolytically active. We characterized and utilized cancer cell line pairs of various organ origins, based on their aggressive behaviors, and assessed their response to GYY4137. We compared glycolytic activity, via lactate production, and intracellular pH of each cancer cell line pair after exposure to H2S. Invasive and therapy resistant cancers, collectively termed aggressive cancers, are receptive to H2S-mediated cytotoxicity, albeit at a higher concentration of GYY4137 donor. While lactate production was enhanced, intracellular pH of aggressive cancers was only modestly decreased. Inherently, the magnitude of intracellular pH decrease is a key determinant for cancer cell sensitivity to H2S. We demonstrated the utility of coupling GYY4137 with either simvastatin, known to inhibit monocarboxylate transporter 4 (MCT4), or metformin, to further boost glycolysis, in bringing about cell death for aggressive cancers. Simvastatin inhibiting lactate extrusion thence contained excess lactate induced by GYY4137 within intracellular compartment. In contrast, the combined exposure to both GYY4137 and metformin overwhelms cancer cells with lactate over-production exceeding its expulsion rate. Together, GYY4137 and simvastatin or metformin synergize to induce intracellular hyper-acidification-mediated cancer cell death. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H 2 S) has been investigated for its potential in therapy. Recently, we reported novel H 2 S donor molecules based on a thiophosphorus core, which slowly release H 2 S and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied H 2 S donor GYY4137 ( 1 ). Herein, we have prepared new thiophosphorus organic H 2 S donors with different ring sizes and evaluated them in two solid tumor cell lines and one normal cell line. A seven membered ring compound, 17 , was found to be the most potent with sub-micromolar IC 50s in breast (0.76 μM) and ovarian (0.76 μM) cancer cell lines. No significant H 2 S release was detected in aqueous solution for this compound. However, confocal imaging showed that H 2 S was released from 17 inside cells at a similar level to the widely studied H 2 S donor GYY4137, which was shown to release 10 μM H 2 S after 12 h at a concentration of 400 μM. Comparison of 17 with its non-sulfur oxygen analogue, 26 , provided evidence that the sulfur atom is important for its potency. However, the significant potency observed for 26 (5.94–11.0 μM) indicates that the high potency of 17 is not entirely due to release of H 2 S. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of H 2 S in cancer with potent thiophosphorus agents. [ABSTRACT FROM AUTHOR]

Retina is one of the tissues that exposed to highest oxidative stress due to its high metabolic rate, abundant photosensitizing activity and visible light exposure. With these high chances of oxidative damage, antioxidative capacity of retinal tissues is essential for maintaining the proper functions of retina. Cytoprotective roles of hydrogen sulfide (H2S) have been documented and were largely attributed to its antioxidative activity. However, whether are these three H2S-producing enzymes (cystathionine-gamma-lyase (CSE), cystathionine-beta-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) plays antioxidative roles in retinal tissue is unclear. In this study, we examined the role of CSE, CBS and MPST enzymes in human retinal pigmented epithelial cell line ARPE19. ARPE19 expressed comparatively similar protein levels of the three enzymes. Surprisingly, gene silencing of CSE sensitized the cells to hydrogen peroxide (H2O2) challenge to a much greater extent as compared to gene silencing in CBS or MPST. We also observed that loss of CSE in ARPE19 resulted in decreased level of glutathione, higher oxidative stress and accelerated senescence. Taken together, our data suggest that CSE is essential for retinal functions by maintaining its redox balance. [ABSTRACT FROM AUTHOR]