Synthesis of Sphingomyelin Carbon Analogues as Sphingomyelinase Inhibitors

Hakogi, Toshikazu; Monden, Yoshiko; Taichi, Misako; Iwama, Seiji; Fujii, Shinobu; Ikeda, Kiyoshi; Katsumura, Shigeo

doi:10.1021/jo025529o

Cited by 42 publications

(18 citation statements)

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“…The syntheses of several sphingomyelinase inhibitors have been reported previously (20,21,23). Such inhibitors could potentially be used to alter the growth of cancer cells, modulate inflammation, or, in the case of ASM inhibitors, as molecular chaperones for the treatment of NPD.…”

Section: Discussionmentioning

confidence: 99%

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A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death

Darroch

Dagan

Granot

et al. 2005

Journal of Lipid Research

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We report the synthesis and characterization of a novel thiourea derivative of sphingomyelin (AD2765). In vitro assays using pure enzyme and/or cell extracts revealed that this compound inhibited the hydrolysis of BODIPY-conjugated or 14 C-labeled sphingomyelin by acid sphingomyelinase and Mg 2 ؉ -dependent neutral sphingomyelinase. Studies in normal human skin fibroblasts further revealed that AD2765 was taken up by cells and inhibited the hydrolysis of BODIPY-conjugated sphingomyelin in situ. In situ and in vitro studies also showed that this compound inhibited the synthesis of sphingomyelin from BODIPY-conjugated ceramide. The specificity of AD2765 for enzymes involved in sphingomyelin metabolism was demonstrated by the fact that it had no effect on the hydrolysis of BODIPY-conjugated ceramide by acid ceramidase or on the synthesis of BODIPY-conjugated glucosylceramide from BODIPY-conjugated ceramide. The overall effect of AD2765 on sphingomyelin metabolism was concentration-dependent, and treatment of normal human skin fibroblasts or cancer cells with this compound at concentrations Ͼ 10 M led to an increase in cellular ceramide and cell death. Thus, AD2765 might be used to manipulate sphingomyelin metabolism in various ways, potentially to reduce substrate accumulation in cells from types A and B Niemann-Pick disease patients, and/or to affect the growth of human cancer cells.

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Section: Discussionmentioning

confidence: 99%

“…For example, various synthetic sphingomyelin analogues (20)(21)(22), as well as analogues of naturally occur-ring inhibitors, such as ␣ -mangostin, a natural product derived from Garcinia mangostana , have been developed (23). In addition, the lipid phosphatidylinositol-3,5-bisphosphate has been shown to inhibit ASM activity (24).…”

mentioning

confidence: 99%

A lipid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death

Darroch

Dagan

Granot

et al. 2005

Journal of Lipid Research

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“…Other natural inhibitors of mammalian nSMase include macquarimicin A [106], alutenusin [107], chlorogentisylquinone [108], and manumycin A [109]. Some synthetic substrate analogues can also be used as SMase inhibitors [110][111][112]. Arenz and Giannis [113] have produced the first synthetic irreversible inhibitor of nSMase.…”

Section: Sphingomyelinase Inhibitorsmentioning

confidence: 99%

Sphingomyelinases and Their Interaction with Membrane Lipids

Goñi

Alonso

2004

Lipases and Phospholipases in Drug Development

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This chapter is devoted to sphingomyelinases, enzymes that catalyze the hydrolysis of sphingomyelin (ceramide phosphorylcholine) into ceramide and phosphorylcholine. The reaction is formally similar to that of a phospholipase C. Sphingomyelinases have long been known [1, 2], but the last decade has seen renewed interest after the discovery of the sphingomyelin signal transduction pathway [3][4][5][6]. Ceramide appears to be a lipid second messenger in programmed cell death (apoptosis), cell differentiation and cell proliferation [reviews in 7-12; for the opposite point of view see 13], and sphingomyelinase is probably a major source of ceramide in the cells, although this is also a debated point. This contribution is based on a recent review [14] that we have modified according to several suggestions and criticisms received, and to which we have added what we consider as the most significant novel data to have appeared since.Two main aspects of sphingomyelinases are covered here, one corresponds to "classical enzymology", with a description of the known sphingomyelinases, and of their properties. The second is more directly related to our experimental work, and describes the interaction of sphingomyelinases with phospholipid bilayers, and the mutual influence of enzyme and substrate properties. One important function of sphingomyelinases may be related to changing membrane properties (charge, fluidity, permeability) by transforming sphingomyelin into ceramide. The present work does not cover the cell physiological effects of sphingomyelinases and/or ceramides, which are described in detail in the above-mentioned reviews.

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“…Several synthetic inhibitors, such as a carbamate analog, carbon-analog or fluorinated carbon-analog, that mimic the phosphate ester moiety of phosphocholine by substituting it with stable functional groups have also been developed [29][30][31][32][33][34] . We previously developed an inhibitor (RY221B-a) that is based on the crystal structure of Bc-SMase 6,34 .…”

Section: Introductionmentioning

confidence: 99%