Sulforaphane

Biocatalytic access to both antipodal sulfoxides was exploited in total syntheses of bioactive compounds, which is outlined in some representative examples. Biooxidation of functionalized dialkyl sulfides was utilized in the direct synthesis of both enantiomers of sulforaphane and some analogs in low to good yields and stereoselectivities (Scheme 9.27) [206]. This natural product originates from broccoli and represents a potent inducer of detoxification enzymes in mammalian metabolism it might be related to anticarcinogenic properties of plants from the cruciform family. All four possible stereoisomers of methionine (R = Me) and ethionine sulfoxides... 

HT29 AITC > BITC > PEITC > sulforaphane Limd et al. (90)... 

In general, isothiocyanates cause disruption to the cell cycle in vitro, but the evidence that they actually induce apoptosis under these conditions is less clear-cut. It is interesting to note, however, that, even with respect to the cell cycle, they do not all act in the same way. Sulforaphane causes a block in cell cycle at Gl/S, whereas PEITC and AITC cause a block at G2/M ... 

Like sulforaphane, however, PEITC-NAC (N-acetylcysteine) conjugate appears to block in Gl. Studies by Lund et al. show that in the case of the colorectal cell line HT29, which lacks wild type p53, treatment with AITC causes the cells to detach from the substratum but, at least in the short-term, they do not then enter apoptosis . Where it does occur, induction of apoptosis by isothiocyanate appears to be a p53-dependent process. However, this statement must also be qualified, because the effect appears to depend on which metabolite is considered. For example, sulforaphane does appear to be able to induce apoptosis in HT29 cells, which express a mutated form of the protein. 

FAHEY J W, HARISTOY X, DOLAN P M, KENSLER T W, SCHOLTUS I, STEPHENSON K K, TALALAY p and LOZNIEWSKI a (2002) Sulforaphane inhibits extracellular, intracellular and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors , Proc Natl Acad Sci USA, 99 7610-15. 

CHUNG F L, CONAWAY c c, RAO c V and REDDY B s (2000) Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate . Carcinogenesis, 21 2287-91. 

TULLiEZ J and terce f (2000) Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells . Cancer Res, 60 1426-33. 

Petri, N., Tannergren, C., Bennett, R. N., Holst, B., Bao, Y. et al., Intestinal absorption and metabolism of sulforaphane and quercetin as well as regulation of phase II enzymes in human jejunum in vivo and in Caco-2 cells, Drug Metab. Dispos. 2003 (in press). 

Scheme 9 Formation of (S)-(-)-goitrin 24 and structure of sulforaphane. In 25, e represents a lone pair of electrons...

These reactions to 4-methylthiobutyl glucosinolate, the precursor for sulforaphane formation, have been extensively studied in Eruca sativa (arugula, rocket).64 A gene controlling variation in the glucosinolates of Arabidopsis is part of the methionine elongation pathway just described.65... 

Barcelo S, Gardiner JM, Gesher A and Chipman JK. 1996. CYP2El-mediated mechanism of anti-genotoxicity of the broccoli constituent of sulforaphane. Carcinogenesis 17 277—282. 

Ritz SA, Wan J, Diaz-Sanchez D (2007) Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extractAm J Physiol 292(1 ) L33-L39. 

Matusheski NV, Swamp R, Juvik JA, Mithen R, Bennett M, Jeffery EH (2006) Epithiospecifier protein from broccoli Brassica oleracea L. ssp. Italica) inhibits formation of the anticancer agent sulforaphane. J Agric Food Chem 54 2069-2076... 

Five known natural product HDAC inhibitors can be consumed in the human diet butyrate, diallyl disulfide (DADS), flavones, pomiferin, and sulforaphane (SFN). These compounds are found in fiber, garlic, broccoli, and various fruits. The first clinical use of HDAC inhibitors come from the butyrate class. 

Fig. 6. Biotransformation of sulforaphane through mercapturic acid metabolic pathway. It is hypothesized that SFN-NAC or SFN-Cys are active FIDAC inhibitors. The structures of SFN-Cys and SFN-NAC are also shown.

Ho E, Clarke ID, Dashwood RH. (2009) Dietary Sulforaphane, a histone deacetylase inhibitor for cancer prevention. J Nutr 139 2393-2396. 

Kassahun K, Davis M, Hu P, Martin B, Baillie T. (1997) Biotransformation of the naturally occurring isothiocyante sulforaphane in the rat Identification of phase I metabolities and glutathione conjugates. Chem Res Toxicol 10 1228-1233. 

Myzak MC, Karplus PA, Chung FL, Dashwood RH. (2004) A novel mechanism of chemoprotection by sulforaphane Inhibition of histone deacetylase. Cancer Res 64 5161-511 A. 

Anwar-Mohamed A, El-Kadi, AOS. (2009) Sulforaphane induces CYPlAl mRNA, protein, and catalytic activity levels via an AhR-dependant pathway in murine hepatoma Hepa IclcV and human Hep62 cells. Cancer Lett 275 93-101. 

Nian H, Delage B, Ho E, Dashwood RH. (2009) Modulation of histone deacetylase activity by dietary isothio-cyanates and allyl sulfides Studies with sulforaphane and garlic organosulfur compounds. Environ Mol Mutagen 50 213-221. 

Pledgie-Tracy A, Sobolewski MD, Davidson NE. (2007) Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther 6 1013-1021. 

Matsui TA, Murata H, Sakabe T, Sowa Y, Horie N, Nakanishi R, Sakai T, Kubo T. (2007) Sulforaphane induces cell cycle arrest and apoptosis in murine osteosarcoma cells in vitro and inhibits tumor growth in vivo. Oncol Rep 18 1263-1268. 

Myzak MC, Tong P, Dashwood WM, Dashwood RH, Ho E. (2007) Sulforaphane retards the growth of human PC-3 xenographs and inhibits HDAC activity in human subjects. Exp Biol Med 232 227-234. 

Singh AV, Xiao D, Lew KL, Dhir R, Singh SV. (2004) Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo. Carcinogenesis 25 83-90. 

Zhang Y, Kensler TW, Cho CQ Posner GH, Tallalay P. (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbomyl isothiocyanates. Proc Natl Acad Sci USA 91 3147-3150. 

Myzak MC, Dashwood WM, Omer GA, Ho E, Dashwood, RH. (2006) Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorige-nesis in Ape-minus mice. EASEB J 20 506-8. 

In 2005, Haristoy and coworkers investigated the activities of 12 isothiocyanates (ITC) and L-sulforaphane isolated from Cruciferous plant species in 25 strains of HP. Medicinal plants from the Cruciferae are well known to have chemopreventative effects on the GI tract, and are... 

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