Sphingomyelinase inhibitors

Uchida R, Tomoda H, Arai M, Omura S (2001) Chlorogentisylquinone, a New Neutral Sphingomyelinase Inhibitor, Produced by a Marine Fungus. J Antibiot 54 882... 

Nara F, Tanaka M, Masuda-Inoue S, Yamasato Y, Doi-Yoshioka 119. H, Suzuki-Konagai K, Kumakura S, Ogita T. Biological activities of scyphostatin, a neutral sphingomyelinase inhibitor from... 

Soeda S, Tsuji Y, Ochiai T, Mishima K, Iwasaki K, et al. Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress. Neurochem. Int. 2004 45 619-626. Hakogi T, Taichi M, Katsumura S. Synthesis of a nitrogen analogue of sphingomyelin as a sphingomyelinase inhibitor. Org. Lett. 2003 5 2801-2804. 

Claus RA, Wtistholz A, Muller S, Bockmeyer CL, Riedel NH, Kinscherf R, Deigner HP. Synthesis and antiapoptotic activity of a novel analogue of the neutral sphingomyelinase inhibitor scyphostatin. ChemBioChem 2005 6 726-737. 

Recently, it was published (Sakata et ak, 2007a,b) that a sphingomyelinase inhibitor has a beneficial effect in a murine model of DSS-induced colitis, an... 

Total synthesis of (-t-)-scyphostatin, a neutral sphingomyelinase inhibitor 07Y358. 

The enantioselective synthesis of phosphonothioate (146) and fluoromethylene phosphonate (147) analogues of cyclic phosphatidic acid, the novel antagonists of lysophosphatidic acid receptors, has been presented. Synthesis of difluoromethy-lene analogue of sphingomyelin (148) in optically active form as a new sphingomyelinase inhibitor has been achieved. The synthesis and biological evaluation of 9-(5, 5 -difluoro-5 -phosphonopentyl)guanine derivatives (149), for use as a purine nucleoside phosphorylase inhibitor, has been described. 

Mansat, V., Laurent, G. Levade, T., Bettaieb, A., and Jaffrezou, J.P., 1997a, The protein kinase C inhibitors phorbol ester and phosphatidylserine block neutral sphingomyelinase activation, ceramide generation and apoptosis triggered by daunorubicin. Cancer Res. 57 5300-5304. 

Figure 5 Structures of small-molecule inhibitors of nonapoptotic cell death. Inhibitors of (a-e) PARP-1, (f) HSP90, (i, j) mitochondrial respiratory complexes I and (k) complexes 2, (I) phosphatidylcholine-specific phospholipase C, (m) acid sphingomyelinase, (n) NADPH oxidase, (o) JNK kinase, (p-s) necroptosis, (t-w) MPTP, and (g, h) antioxidants, (a) 3-aminobenzamide, (b) benadrostin, (c) Nu1025, 8-hydroxy-2-methylquinazolin-4(3H)-one,...

The fungal metabolite scyphostatin (Fig. 7) is a potent, reversible inhibitor of membrane-bound Mg +-dependent neutral sphingomyelinase (nSMase), thereby interfering with the generation of ceramide (102, 103). The activity of nSMases is sensitive to the cellular redox state, for example, the ratio of glutathione in the reduced versus the oxidized form (104, 105). The famesyltransferase inhibitor manumycin A, a polyenamide produced by the Streptomyces species, also inhibits nSMase irreversibly (106). 

HJ, Giannis, A. Manumycin A and its analogues are irreversible inhibitors of neutral sphingomyelinase. ChemBioChem. 2001 2 141-143. 123. 

Yasuda S, Kitagawa H, Ueno M, Ishitani H, Fukasawa M, Nishijima M, Kobayashi S, Hanada K. A novel inhibitor of ceramide trafficking from the endoplasmic reticulum to the site of sphingomyelin synthesis. J. Biol. Chem. 2001 276 43994-44002. Lister MD, Ruan ZS, Bittman R. Interaction of sphingomyelinase with sphingomyelin analogs modified at the C-1 and C-3 positions of the sphingosine backbone. Biochim. Biophys. Acta 1995 1256 25-30. 

Wascholowski V, Giannis A. Sphingolactones selective and irreversible inhibitors of neutral sphingomyelinase. Angew. Chem. Int. Ed. 2006 45 827-830. 

A similar incorporation of a P-CF2 unit as a P-0 bond surrogate to sphingomyelin was reported [134] for the development of nonhydrolyzable inhibitors of sphingomyelinase (SMase), which cleaves sphingomyelin to release ceramide. As Figure 1.23 shows, difluoromethylene analogue 42b is twice as potent as methylene analogue 42a in the inhibition of SMase from B. cereus [134],... 

Tanaka M, Nara F, Yamasato Y, Ono Y, Ogita T. F-l 1334s, new inhibitors of membrane-bound neutral sphingomyelinase. J Antibiot 52 827-830, 1999. 

Mention of sphingomyelinase further brings up a study conducted at Lund University in Lund, Sweden. A thesis or dissertation by Erik Hertervig, abstracted in 2000, the title is Alkaline Sphingomyelinase A Potential Inhibitor in Colorectal... 

Luberto, C., Hassler, D. F., SignoreUi, P., Okamoto, Y., Sawai, H., Boros, E., Hazen-Martin, D. J., Obeid, L. M., Hannun, Y. A., and Smith, G. K. Inhibition of Tumor Necrosis Factor-induced Cell Death in MCF7 by a Novel Inhibitor of Neutral Sphingomyelinase. J Biol Chem 277 (2002) 41128 1139. 

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