Hydrogen sulfide (H 2 S) is an endogenously produced gaseous signalling molecule with multiple biological functions. In order to visualize and quantify the endogenous in situ production of H 2 S in living cells, here we developed two new sulphide ratiometric probes (SR400 and SR550) based on fluorescence resonance energy transfer (FRET) strategy for live capture of H 2 S. The FRET-based probes show excellent selectivity toward H 2 S in a high thiol background under physiological buffer. The probe can be used to in situ visualize cysteine-dependent H 2 S production in a chiral-sensitive manner in living cells. The ratiometric imaging studies indicated that D-Cys induces more H 2 S production than that of L-Cys in mitochondria of human embryonic kidney 293 cells (HEK293). The cysteine mimics propargylglycine (PPG) has also been found to inhibit the cysteine-dependent endogenous H 2 S production in a chiral-sensitive manner in living cells. D-PPG inhibited D-Cys-dependent H 2 S production more efficiently than L-PPG, while, L-PPG inhibited L-Cys-dependent H 2 S production more efficiently than D-PPG. Our bioimaging studies support Kimura's discovery of H 2 S production from D-cysteine in mammalian cells and further highlight the potential of D-cysteine and its derivatives as an alternative strategy for classical H 2 S-releasing drugs.H ydrogen sulfide (H 2 S) is an important endogenous signalling molecule along with nitric oxide (NO) and carbon monoxide (CO) 1-3 . H 2 S has also been demonstrated to exert protective effects such as preservation of mitochondrial function, protection of neurons from oxidative stress, inhibition of apoptosis, intervention of neuronal transmission, regulation of inflammation, stimulation of angiogenesis, reduce blood pressure, etc 4-7 . The deregulation of endogenous H 2 S is correlated with the symptoms of Alzheimer's disease, Down syndrome, diabetes and liver cirrhosis [8][9][10] . Kimura et al. indicated that H 2 S is enzymatic generated from L-cysteine (L-Cys) and its derivatives in vivo 7,11 . Recently, they further reported a novel possible pathway for the production of H 2 S from D-cysteine in mammalian cells 12 . As new biogenesis and biological functions of H 2 S continue to emerge [12][13][14][15] , new biocompatible tools to selectively visualize cellular H 2 S in real-time at its site of release are urgently needed 11 .Fluorescent probes could be used for H 2 S detection in a non-invasive manner in living systems [13][14][15][16][17] . The probebased tools have been successfully used to image endogenous H 2 S production from thiol substrates including LCys and glutathione (GSH) 13 or by vascular endothelial growth factor stimulation 17 . Inspired by these work 13,17 , we are interested to image endogenous H 2 S production of all possible pathways in living cells semi-quantitatively or quantitatively, based on ratiometric probes rather than intensity-based probes, in view of that ratiometric measurements can cancel out variability caused by uneven loading and distribution of...
In order to evaluate the thiolysis of NBD (7-nitro-1,2,3-benzoxadiazole) amines for development of HS probes, herein we investigated the reactivity and selectivity of a series of NBD amines for the first time. The piperazinyl- and piperidyl-based NBD probes could react efficiently with micromolar HS in buffer (pH 7.4), while such NBD(S) (nitrobenzothiadiazole) derivatives showed much slow thiolysis even in the presence of millimolar HS. Low reactivity was also observed for thiolysis of these ethylamino-, ethanolamino- and anilino-based NBD probes. Therefore, almost all NBD amines used in bioimaging should be stable, in consideration of the presence of only micromolar endogenous HS in vivo. Moreover, the piperazinyl-NBD derivatives could be efficient in the development of fluorescent HS probes and for directly visualizing HS by paper-based detection.
Inositol phosphates, as important second messengers of signal transduction, regulate many biological functions. However, cell penetration and phospholipase stability could be two main issues faced by inositol phosphate analogues used as lead compounds for drug discovery. Inositol phosphotriester analogues could be more beneficial to diffuse across plasma membrane. In this paper, we describe the design and synthesis of a series of inositol phosphotriester analogues based on phosphatidylinositol, along with the initial antitumor activity analysis. Several compounds exhibited good cytotoxic activity against human cancer cell lines A549, HepG2, MDA-MB-231 and HeLa, especially compound 33 was cytotoxic against all the four cancer cell lines with good IC(50) values.
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