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神經醯胺(原液)

神經醯胺(原液)

標準用量:2%-4%.進口品質優良純度好的原提萃取物料.凍晶,經過水解:成份定量生產標準製成.供應合乎國際標準的萃取液.GMP認證

  • 售價: $1,760

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神經醯胺(原液)

What is Ceramide

Nerve  (Ceramide) is One kind of natural existence to in vivoSkinCuticle intercellular spaceLipinBy the nerve after  is mellow (sphingosine) and the fatty acid (fatty Acid) connects the fat body which becomes, for  lipin (sphingolipid) one kind of typeIs in the skin cuticle lipin is most important also the proportion highest ingredient, the total content approximately intercellular space lipin 40~55%Because the age and the date exposes to the sun can destroySkinCuticleFat, but the fat is precisely the skin natural moisture content barrier essential ingredient,Affiliation by maintenanceCuticleLipinIntegrityCeramide can form one kind of thin film on the skin, can prevent the moisture content evaporating, lets  the cell lock in the moisture content, and achieves the heat preservation, prevented raises function which the share drains, soft causes the flesh maintenance to be smooth, has the elasticity and the tensity.

CeramideIs in the cuticle lipin is most important also the proportion highest ingredient, the content approximately intercellular space lipin

CeramideIs Molecular nailFunction

CeramideTemporarily stores by the epidermal cell production in a  cell, at the right moment releases to  the intercellular space, forms the integrity the intercellular space lipin to be cut off the system, when age increase, its manufacture quantity can reduce, creates the cuticle to link not good, causes the skin to produce , the thick crack. But cleans or takes orally the supplement nerve by way of exterior, can increase the cell cohesive force, decreases the moisture content disappearing. Has regarding the sensitive flesh guarantees the wet effect.

Ceramide (green dot) saves to  the intercellular space, forms the integrity the lipin to be cut off the system, decreases the hydrone disappearing, therefore is calledMolecular

Introduction


Ceramide structure

Ceramide (N-Acyl-D-erythro-sphingosine,is a structural component of mammalian glycolipids and of a phospholipid, sphingomyelin . Ceramide derivatives attracted attention as potential therapeutic agents for the treatment of cancer, allergy, and other diseases originating from cell regulation disorders Ceramide itself is a signaling substance that can be released from sphingomyelin in response to extracellular and intracellular stimuli. In general, it mediates antimitogenic cellular effects like differentiation, apoptosis, or cellular senescence. Details of this pathway including the identity of the presumed ceramide binding proteins are not entirely clear. One reason for this is the metabolic coupling of ceramide with other bioactive lipids like ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. For investigation and triggering ceramide metabolism and signaling, we are interested in ceramide analogs and derivatives of enhanced metabolic stability.


Ceramide metabolism. Potential inhibition sides by the target compounds 1 and 2 are indicated.

The major metabolic reactions of exogenous and endogenous  ceramides are the formation of sphingomyelin and glucosylceramide Both reactions require the presence of the 1-OH group of ceramide. A modification that prevents formation of sphingomyelin, glucosylceramide, but also of ceramide-1-phosphate and galactosylceramide is the replacement of the 1-hydroxyl group by a suitable substitute. Earlier studies indicated that this is possible without eliminating the signaling properties of the lipid: dihydroceramide analogs bearing an alkyl residue instead of the 1-hydroxyl group show suitable properties in different lines of cultured cells .


1-Deoxy-1-fluoroceramide 1

Consideration of the bioisosteric replacement of a hydroxyl group by fluorine (see for review) led us to the design of 1-deoxy-1-fluoroceramide 1 (fig. 3).
Besides metabolic elongation of 1-OH-group, ceramide can also be degraded by several ceramidases to sphingosine. These enzymes of different subcellular localization, cofactor requirement, and pH-optima, cleave the amide linkage within the lipid.


Sulfonamide analogue 2

Replacement of the amide moiety by a sulfonamide-group is one possibility to enhance the metabolic stability of the parent compound . We attempted to achieve enhanced catabolic stability by incorporation of this modification into the ceramide structure, leading to 2 . This should also prevent formation of sphingosine-1-phosphate which is an additional signalling substance metabolically derived from ceramide .

We report the synthesis of 1 and 2 as ceramide analogues of enhanced metabolic stability with high similarity to the parent lipid.


Results


Undesired reaction of DAST with sphingosine derivatives

Various synthetic routes to ceramide, or its preparative precursor, sphingosine, have been reported Many of them lead to protected long chain 2-tert.-butyloxycarbonylamino-1,3-diols. Reaction of urethane-protected b-aminoalcohols, however, with diethylaminosulfur trifluoride (DAST) leads to heterocyclic products instead of a fluorine for hydroxyl exchange and also in our hands, N-acyl- and N-urethane-protected sphingosine derivatives gave not the desired 1-fluoro-derivatives on reaction with DAST .


6. Azidosphingosine strategy to the fluoro derivative 1

Therefore, we decided to apply the following strategy . Starting point is the MPM (= p-methoxyphenylmethyl) -protected azidosphingosine 3 which is accessible from Diethyl-D-tartrate , but is more conveniently prepared from D-galactose according to a modification of the procedure by Zimmermann and Schmidt .


Route to azidosphingosine derivative 7

The preparation of this starting material is summarized in Replacement of the 1-hydroxyl group in 3 by fluorine is achieved with DAST .The moderate yields in this key step are accompanied by recovery of considerable amounts of starting material 3. The fluorinated azidosphingosine building block 4 is deprotected to 5 using Ceric ammonium nitrate in good yield. Staudinger reaction of 5 with triphenylphosphine in THF / water leads to 1-deoxy-1-fluorosphingosine 6 . 6 can be selectively acylated with lauroyl chloride in methanol in the presence of triethylamine at low temperatures to yield the target compound 1.


Fig. 8. Synthesis of the sulfonamide derivative 2

The synthesis of 2 starts from compound 7, which is also available from D-galactose.Staudinger reduction of the azide, acylation with an appropriate sulfuryl chloride, and the subsequent deprotection under acidic conditions with toluenesulfonic acid leads to the target compound 2 .

We investigated the ceramide analogs 1 and 2 on their influence on the incorporation of a biosynthetic precursor, L-serine, into ceramide-containing lipids of primarily cultured cerebellar cells of mice.

In brief,the cells were treated with the target compounds 1 and 2 for 24 h. Radiolabelled 3-serine was added to the culture medium and incorporation into newly synthesized sphingolipids was analyzed after labelling. Lipids were extracted, separated by thin layer chromatography, and visualized with the aid of  a phosphoimager. Radioactivity found in the selected lipids were expressed in relation to untreated cells . The results of two independent experiments are given .




Fig. 9. Effect of 1-deoxy-1-fluoroceramide 1 on the incoroporation of 3-serine into glucosylceramide and sphingomyelin. Radioactivity found in the tlc spots of untreated cells were set equal 100%. The results of 2 experiments were given , in which the cells were treated with bwith varying concentrations of the target compound.

1-deoxy-1-fluoroceramide 1 led to a concentration dependent decrease of labelled sphingomyelin. Surprisingly, the level of glucosylceramide seems not to be significantly influenced by 1.


Effect of the sulfonamide derivative 2 on the incoroporation of 3serine into glucosylceramide and sphingomyelin. Radioactivity found in the tlc spots of untreated cells were set equal . The results of 2 experiments were given , in which the cells were treated with bwith varying concentrations of the target compound.

The dose dependent effect of 2 on serine incorporation into sphingomyelin and glucosylceramide is shown in . Incorporation of radioactivity into downstream metabolites of ceramide is significantly decreased in a dose dependent manner. Sphingomyelin formation was reduced.The decrease of glucosylceramide is not as drastic as in the case of sphingomyelin; the de novo synthesis is reduced 2. Also the levels of lactosylceramide and of the higher gangliosides GT1b and GD1a are decreased compared to the control (data not shown).
Discussion

The described method provides access to ceramide analogues 1 and 2 and also to the sphingosine derivatives 5 and 6 . The present approach provides access to the 1-fluoro-analog of ceramide in its natural occurring configuration and with the 4,5-trans-double bond which is required for the signaling properties of ceramide . The synthesis presented here makes use of slightly modified intermediates commonly used in the preparation of glycolipids and avoids the unfavorable reaction of urethane- or acyl-protected b-amino alcohols with DAST. An alternative approach leading to 5 has been reported starting from (R)-fluoroalanine , which in turn is prepared from (S)-serine .

Ceramide analogs with a fluoro-substituent in 3-position have already been prepared. They show apoptogenic properties and have been investigated as inhibitors of protein kinase C.The bioisosteric hydroxyl to fluorine replacement and the substitution of the amide to sulfonamide within the ceramide structure constitutes a valuable addition to the known sphingolipid analogues and derivatives .

The initial results of cell culture studies in murine cerebellar neurons indicate a competition of the synthetic derivatives with the endogenously formed parent compound. As can be expected from Fig. 2, the steady state levels of the downstream metabolites were decreased. Due to the low absolute radioactivity found in the ceramide bound, large derivation were observed in the presence of 1 and 2 between the two experiments. It can be concluded that GlcCer synthase shows a higher substrate selectivity than sphingomyelin synthase. Surprisingly, the fluoro substitution is less active towards GlcCer synthase than expected. Albeit further studies are necessary to confirm the enhanced metabolic resistance of 1 and 2, their application to living cells should lead to elevated concentrations of endogenous ceramide. Elevation of this proapoptotic lipid in humans e. g. achieved by intake of nonsteroidal antiinflammatory drugs, seems to lead to protection from colon cancer. In general, several attempts have been made to pharmacologically increase ceramide levels for cancer treatment. Our approach utilizes the bioisosteric replacement for enhancement of metabolic stability.

Acknowledgment

We thank Prof. Dr. K. Sandhoff, Bonn, the Deutsche Forschungsgemeinschaft (SFB) and the Fonds der Chemischen Industrie for the support of this work, J. Hörnschemeyer for recording the MALDI mass spectra, U. Damen for IR-spectra, U. Weynand and C. Schmidt for the NMR spectra.

The tapioca raises the face cosmetology decipher!

The expert public figures all should know that, the tapioca principal constituent besides the well known calcium and the many kinds of trace elements, the amino acid, most important raises the face cosmetology ingredient is the phosphoric acid ethanolamine(phosphorylethanolamine), actually also is one kind of typeNerve (Ceramide)

Nerve +Bolivian uric acid = sensitive flesh maintenance best quality goods

Ceramide can form one kind of thin film on the skin, can prevent the moisture content evaporating, lets the cell lock in the moisture content, causes the flesh to have the elasticity and the tensity, matches the use with the Bolivian uric acid, can strengthen guarantees the wet effect, prevented the flesh is rough, the skin scratches with the finger , is the summer and the season indispensable maintenance best quality goods.

In the market condition has some levels well-known brand , frequently can increase Ceramide, promotes the flesh regeneration, causes the skin nature to reveal smoothly, simultaneously provides guarantees the wet effect, strengthens the flesh the natural protection barrier,For exampleElizabeth is elegant the space and time tension which recently promotedDepartmentRow product, so-calledHighly effective nourishes the molecular nail science and technology (Ceramide Triple Complex) Is Ceramide.

Nerve (ceramdie) isSebum compositionThe important ingredient, can increase along with the age reduces, supplements not easily. When ceramide drains outside, the intercellular space archery target moisture content also is unable to detain, is easy to create in the oil the dry situation. This formula specially increases precious ceramide, can effectively improve the phenomenon which sheds skin,The in-depth guarantees wet

PlantOriginEdible levelCeramide

Takes orallyCeramide guarantees the wet effect to be more than approximately 2~3 to double!

Ceramide except utilization in high price positionOutside , Japan also has recently promoted from the natural plant (the origin:Rice, corn, mushroom class) after special fermentation extract edible levelCeramide, passes through healthy public figures in a year the season, the clinical experiment compares spreads wipes containsCeramide with takes orallyContainsCeramide nutrition lozenge guaranteeingThe wet ability discovered that,

1.Spreads wipes containsCeramide After three weeks,The skin moisture the quantity obviously reduces compared to the comparison group

2.Takes orallyContainsCeramide nutrition lozenge lozengeAfter three weeks,The skin guaranteesThe wet ability increases compared to the comparison

3.Takes orallyContainsCeramide nutrition lozenge lozengeAfter three weeks,The skin guaranteesThe wet ability increases compared to the comparison