- Natural product inspired allicin analogs as novel anti-cancer agents
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A series of novel analogs of Allicin (S-allyl prop-2-ene-1-sulfinothioate) present in garlic has been synthesized in high yield. Synthesized 23 compounds were evaluated against different breast cancer cells (MDA-MB-468 and MCF-7) and non-cancer cells (WI38). Four compounds (3f, 3h, 3m and 3u) showed significant cytotoxicity against cancer cells whereas nontoxic to the normal cells. Based on the LD50 values and selectivity index (SI), compound 3h (S-p-methoxybenzyl (p-methoxyphenyl)methanesulfinothioate) was considered as most promising anticancer agent amongst the above three compounds. Further bio-chemical studies confirmed that compound 3h promotes ROS generation, changes in mitochondrial permeability transition and induced caspase mediated DNA damage and apoptosis.
- Bhaumik, Ishani,Pal, Kunal,Debnath, Utsab,Karmakar, Parimal,Jana, Kuladip,Misra, Anup Kumar
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p. 259 - 272
(2019/02/07)
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- Selective Oxidation of Sulfides in Flow Chemistry
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A packed-bed reactor with oxone has been employed for selective oxidations of sulfur compounds. Various sulfides containing different functional groups are efficiently oxidized to the corresponding sulfoxides without formation of sulfones or other side products.
- Silva, Filipa,Baker, Alastair,Stansall, James,Michalska, Weronika,Yusubov, Mehkman S.,Graz, Michael,Saunders, Robert,Evans, Gareth J. S.,Wirth, Thomas
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supporting information
p. 2134 - 2137
(2018/05/31)
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- Synthesis and in vitro biological evaluation of thiosulfinate derivatives for the treatment of human multidrug-resistant breast cancer
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Organosulfur compounds derived from Allium vegetables have long been recognized for various therapeutic effects, including anticancer activity. Allicin, one of the main biologically active components of garlic, shows promise as an anticancer agent; however, instability makes it unsuitable for clinical application. The aim of this study was to investigate the effect of stabilized allicin derivatives on human breast cancer cells in vitro. In this study, a total of 22 stabilized thiosulfinate derivatives were synthesized and screened for their in vitro antiproliferative activities against drug-sensitive (MCF-7) and multidrug-resistant (MCF-7/Dx) human adenocarcinoma breast cancer cells. Assays for cell death, apoptosis, cell cycle progression and mitochondrial bioenergetic function were performed. Seven compounds (4b, 7b, 8b, 13b, 14b, 15b and 18b) showed greater antiproliferative activity against MCF-7/Dx cells than allicin. These compounds were also selective towards multidrug-resistant (MDR) cells, a consequence attributed to collateral sensitivity. Among them, 13b exhibited the greatest anticancer activity in both MCF-7/Dx and MCF-7 cells, with IC50 values of 18.54±0.24 and 46.50±1.98 μmol/L, respectively. 13b altered cellular morphology and arrested the cell cycle at the G2/M phase. Additionally, 13b dose-dependently induced apoptosis, and inhibited cellular mitochondrial respiration in cells at rest and under stress. MDR presents a significant obstacle to the successful treatment of cancer clinically. These results demonstrate that thiosulfinate derivatives have potential as novel anticancer agents and may offer new therapeutic strategies for the treatment of chemoresistant cancers.
- Roseblade, Ariane,Ung, Alison,Bebawy, Mary
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p. 1353 - 1368
(2017/10/10)
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- A tissue homogenate method to prepare gram-scale allium thiosulfinates and their disulfide conjugates with cysteine and glutathione
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The health benefits of Allium vegetables are widely attributed to the enzyme-derived organosulfur compounds called thiosulfinates (TS). However, the lack of a suitable method to prepare TS in good yields has hampered the evaluation of their biological activities. This paper describe a simple enzymatic method using Allium tissue homogenates as a reaction system to prepare gram-scale TS, including those enriched in 1-propenyl groups, which are particularly difficult to obtain. This method is simple, easy to scale up, and requires no column purification step, making it suitable for practical large-scale production of Allium TS. The prepared TS were further utilized to prepare the disulfide conjugates with cysteine and glutathione (CySSR and GSSR, R = methyl, ethyl, propyl, 1-propenyl, and allyl), which are the presumptive metabolites of TS. Among all of the Allium CySSR and GSSR conjugates, the newly prepared glutathione conjugate with 1-propenyl TS, GSSPe, showed the most potent effect to induce quinone reductase (QR, a representative phase II enzyme) in murine hepatoma cells (Hepa 1c1c7) and inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated macrophage cells (RAW 264.7).
- Zhang, Guodong,Parkin, Kirk L.
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p. 3030 - 3038
(2013/08/25)
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- First insights into the mode of action of a "lachrymatory factor synthase" - Implications for the mechanism of lachrymator formation in Petiveria alliacea, Allium cepa and Nectaroscordum species
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A study of an enzyme that reacts with the sulfenic acid produced by the alliinase in Petiveria alliacea L. (Phytolaccaceae) to yield the P. alliacea lachrymator (phenylmethanethial S-oxide) showed the protein to be a dehydrogenase. It functions by abstracting hydride from sulfenic acids of appropriate structure to form their corresponding sulfines. Successful hydride abstraction is dependent upon the presence of a benzyl group on the sulfur to stabilize the intermediate formed on abstraction of hydride. This dehydrogenase activity contrasts with that of the lachrymatory factor synthase (LFS) found in onion, which catalyzes the rearrangement of 1-propenesulfenic acid to (Z)-propanethial S-oxide, the onion lachrymator. Based on the type of reaction it catalyzes, the onion LFS should be classified as an isomerase and would be called a "sulfenic acid isomerase", whereas the P. alliacea LFS would be termed a "sulfenic acid dehydrogenase".
- He, Quan,Kubec, Roman,Jadhav, Abhijit P.,Musah, Rabi A.
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experimental part
p. 1939 - 1946
(2012/01/13)
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- Allicin and derivates are cysteine protease inhibitors with antiparasitic activity
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Allicin and derivatives thereof inhibit the CAC1 cysteine proteases falcipain 2, rhodesain, cathepsin B and L in the low micromolar range. The structure-activity relationship revealed that only derivatives with primary carbon atom in vicinity to the thiosulfinate sulfur atom attacked by the active-site Cys residue are active against the target enzymes. Some compounds also show potent antiparasitic activity against Plasmodium falciparum and Trypanosoma brucei brucei.
- Waag, Thilo,Gelhaus, Christoph,Rath, Jennifer,Stich, August,Leippe, Matthias,Schirmeister, Tanja
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supporting information; experimental part
p. 5541 - 5543
(2010/12/25)
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- Formation of α-Disulfoxides, Sulfinic Anhydrides, and Sulfines during the m-Chloroperoxybenzoic Acid Oxidation of Symmetrical S-Alkyl Alkanethiosulfinates
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The m-chloroperoxybenzoic acid (MCPBA) oxidation of S-methyl methanethiosulfinate (33), S-propyl propanethiosulfinate (34), S-2-propyl 2-propanethiosulfinate (35), S-butyl butanethiosulfinate (36), and S-(phenylmethyl)phenylmethanethiosulfinate (37) has been at low temperatures and compared with the MCPBA oxidation of S-(2-methyl-2-propyl)-2-methyl-2-propanethiosulfinate (26) and S-(2,2-dimethylpropyl)-2,2-dimethylpropanethiosulfinate (30).Diastereomeric α-disulfoxides are observed with 33-36 at -40 deg C, sulfinic anhydrides are observed with 33, 35, and 36 at -40 deg C, and sulfines are observed on warming the product mixtures from 34-37 from -40 deg C to -20 deg C.The lachrymatory factor ((Z)-propanethial S-oxide, 47) of the onion was observed during the oxidation of 35.The absence of thiosulfonates at -40 deg C and their presence at higher temperature suggest that they are not formed in the initial oxidation process but from subsequent reactions of thiosulfinates and sulfinic acids.Various mechanisms for the formation of intermediates and products are discussed.
- Freeman, Fillmore,Angeletakis, Christos N.
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p. 4039 - 4049
(2007/10/02)
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