L-threo-Dihydrosphingosine

Name: L-threo-Dihydrosphingosine
SKU: ACM15639506
Rating: 5 (1 reviews)

CAS

15639-50-6

Catalog Number

ACM15639506

Category

Main Products

Molecular Weight

301.0

Molecular Formula

C18H39NO2

COA MSDS SDS Spec Sheet

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Specification

Synonyms

L-threo-Sphinganine

Melting Point

103 - 114 °C

Appearance

Solid

How L-threo-sphinganine Induces Autophagy in Solid Tumor Cells?

Coward, Jesse, et al. Autophagy, 2009, 5(2), 184-193.

L-threo-sphinganine (safingol), a L-threo stereoisomer of endogenous (D-erythro) sphingosine, is an in vitro inhibitor of protein kinase C and sphingosine kinase. In this work, it was found that l-threo-sphinganine drives autophagy directly by blocking PKCs and PI3k, not by changing native sphingolipids.
Mechanism of Action
· Safingol inhibits PKCβ-I, PKCδ, and PKCε, as well as the phosphorylation of key components in the PI3K/Akt/mTOR pathway (including Akt, p70S6k, and rS6) and the MAPK pathway (ERK). While blocking PI3K with LY294002 or silencing PKCδ and PKCε using siRNA in HCT-116 cells promotes autophagy, the effect is less pronounced than that caused by safingol. In contrast, activating PKCs with phorbol 12,13-dibutyrate (PDBu) or introducing a constitutively active form of Akt diminishes safingol's autophagic effect, although not entirely, suggesting that both Akt- and PKC-dependent pathways partially and independently contribute to safingol-induced autophagy.
· Notably, combining siRNA-mediated depletion of PKCε with LY294002 inhibition of PI3K produces a level of autophagy similar to that induced by safingol. Liquid chromatography and electrospray tandem mass spectrometry analyses revealed that safingol does not increase the levels of any known endogenous sphingolipids (such as ceramide, sphingosine-1-phosphate, and dihydroceramide) that are known to promote autophagy, indicating that these effects may stem from safingol itself or another metabolite.

Safingol Combined with Cisplatin for Advanced Solid Tumors

Dickson, Mark A., et al. Clinical Cancer Research, 2011, 17(8), 2484-2492.

Safingol (l-threo-dihydrosphingosine) is a putative inhibitor of SphK. In this work, a phase I trial of safingol (S) alone and in combination with cisplatin (C) was conducted. The results showed that Safingol can be safely used in combination with cisplatin. Reversible dose-dependent hepatotoxicity was observed. Safingol achieved targeted inhibition by downregulating S1P.
Evaluation of results
A total of 43 patients underwent treatment, with 41 assessed for toxicity and 37 for response. The maximum tolerated dose (MTD) was 840 mg/m² of S administered over 120 minutes, combined with 60 mg/m² of C, every three weeks. Dose-limiting toxicities (DLTs) associated with cisplatin included fatigue and hyponatremia, while S caused elevated hepatic enzymes. The pharmacokinetics of S were linear across the dosage range, showing no significant interaction with C. Patients receiving doses at or near the MTD exhibited S levels exceeding 20 μmol/L, maintaining levels of at least 5 μmol/L for four hours. The most favorable outcomes included stable disease in six patients, lasting an average of 3.3 months (ranging from 1.8 to 7.2 months). One patient with adrenal cortical cancer experienced significant regression of liver and lung metastases, while another had prolonged stable disease. Additionally, S was linked to a dose-dependent decrease in plasma S1P levels.

Metabolic Fate and Sphingolipid Biosynthetic Activity of L-threo-Dihydrosphingosine (Safingol) in Cultured Cells

Time course of the incorporation of tritiated safingol into different lipid species in primary cultured cerebellar neurons.

Dragusin, Mihaela, et al. Journal of Lipid Research 44.9 (2003): 1772-1779

This study investigated the metabolism of L-threo-dihydrosphingosine (safingol), an unnatural anticancer sphingoid base, in primary cultured cerebellar neurons, B104 neuroblastoma cells, and Swiss 3T3 fibroblasts, compared to its natural stereoisomer D-erythro-dihydrosphingosine. Radioactive labeling experiments showed that safingol is preferentially metabolized via the sphingolipid biosynthetic pathway rather than catabolic cleavage. Unlike the natural isomer (20-66% catabolized), only <5% of safingol was directed to the catabolic pathway in neurons and fibroblasts (22.47% in neuroblastoma cells). Safingol was N-acylated to L-threo-dihydroceramide, which accumulated in cells (up to 52.35% in neurons) and was partially converted to L-threo-dihydrosphingomyelin (up to 45.60% in neuroblastoma cells) and minor amounts of glycosphingolipids (~5%). Notably, safingol-derived dihydroceramide was insensitive to fumonisin B1 (FB1, a dihydroceramide synthase inhibitor) and not desaturated to ceramide, unlike the natural isomer. These studies demonstrate that safingol is recognized by sphingolipid biosynthetic enzymes, producing stable metabolites, which may reduce its cytotoxic potential by avoiding formation of bioactive ceramide.The in vitro metabolic analysis was conducted using radiolabeled safingol ([³H]-L-threo-dihydrosphingosine) and D-erythro-dihydrosphingosine. Cells were metabolically labeled for 24 hours, and lipids were extracted, separated by thin-layer chromatography (TLC), and quantified via autoradiography. Sphingolipid identification was confirmed by enzymatic digestion (acid sphingomyelinase for sphingomyelin, sialidase for gangliosides) and electrospray mass spectrometry. The effect of FB1 (25 μM) on N-acylation was assessed by pre-treating cells prior to labeling. Desaturation of dihydroceramide was evaluated by acid hydrolysis of TLC-isolated fractions and TLC analysis of released sphingoid bases. Protein concentration was measured via Bradford assay to normalize lipid-associated radioactivity. All experiments were performed in triplicate, with statistical comparison of metabolic fractions between stereoisomers.

Competitive Inhibition of Sphingosine Kinase by L-threo-Dihydrosphingosine in Vitro and in Human Platelets

Buehrer, Benjamin M., and Robert M. Bell. The Journal of Biological Chemistry 267.5 (1992): 3154-3159

This study investigated the inhibitory activity of L-threo-dihydrosphingosine against sphingosine kinase, a key enzyme in sphingolipid metabolism, using rat brain microsomes and human platelets. Sphingosine kinase exhibits strict substrate specificity for erythro-enantiomers of sphingosine and dihydrosphingosine, while L-threo-dihydrosphingosine (and other threo-enantiomers) do not serve as substrates but act as potent competitive inhibitors. In vitro assays using a mixed micelle system (β-octyl glucoside/sphingosine) showed L-threo-dihydrosphingosine inhibited rat brain sphingosine kinase with a Ki of 0.40 mol% and human platelet sphingosine kinase with a Ki of 0.23 mol%. In whole human platelets, DL-threo-dihydrosphingosine (a mixture of D- and L-enantiomers) inhibited sphingosine-1-phosphate production in a dose-dependent manner, prolonging the inhibitory effect of D-erythro-sphingosine on thrombin-induced 47-kDa protein phosphorylation (a protein kinase C-dependent process). This prolongation occurred because L-threo-dihydrosphingosine blocked sphingosine metabolism, maintaining inhibitory levels of D-erythro-sphingosine. These studies demonstrate that L-threo-dihydrosphingosine is a specific competitive inhibitor of sphingosine kinase, making it a valuable tool for investigating sphingosine metabolism and signal transduction pathways.The in vitro and in vivo evaluation of L-threo-dihydrosphingosine was conducted through enzymatic and cellular assays. Sphingosine kinase was partially purified from rat brain microsomes, and activity was measured using a mixed micelle assay with [γ-³²P]ATP, converting sphingosine-1-phosphate to N-caproyl-sphingosine-1-phosphate for extraction and TLC quantification. Substrate specificity and inhibition kinetics were determined via double reciprocal plots. In human platelets, sphingosine-1-phosphate production was monitored in ³²P-labeled platelets, and thrombin-induced 47-kDa protein phosphorylation was analyzed by SDS-PAGE and autoradiography. DL-threo-dihydrosphingosine was tested at concentrations of 5-20 μM, with BSA complexation to enhance solubility. All experiments were performed in triplicate, with statistical analysis of kinetic parameters and inhibitory effects.

What is the molecular formula of L-threo-Dihydrosphingosine?

The molecular formula of L-threo-Dihydrosphingosine is C18H39NO2.

What are the synonyms for L-threo-Dihydrosphingosine?

The synonyms for L-threo-Dihydrosphingosine include SAFINGOL, 15639-50-6, and (2S,3S)-2-aminooctadecane-1,3-diol.

What is the molecular weight of L-threo-Dihydrosphingosine?

The molecular weight of L-threo-Dihydrosphingosine is 301.5 g/mol.

What is the structure of L-threo-Dihydrosphingosine?

The structure of L-threo-Dihydrosphingosine is a saturated derivative of sphingosine.

What is the IUPAC name of L-threo-Dihydrosphingosine?

The IUPAC name of L-threo-Dihydrosphingosine is (2S,3S)-2-aminooctadecane-1,3-diol.

What is the InChI key of L-threo-Dihydrosphingosine?

The InChI key of L-threo-Dihydrosphingosine is OTKJDMGTUTTYMP-ROUUACIJSA-N.

What is the CAS number of L-threo-Dihydrosphingosine?

The CAS number of L-threo-Dihydrosphingosine is 15639-50-6.

What is the UNII of L-threo-Dihydrosphingosine?

The UNII of L-threo-Dihydrosphingosine is OWA98U788S.

What is the ChEMBL ID of L-threo-Dihydrosphingosine?

The ChEMBL ID of L-threo-Dihydrosphingosine is CHEMBL1442934.

What are the physical properties of L-threo-Dihydrosphingosine?

The physical properties of L-threo-Dihydrosphingosine include a molecular weight of 301.5 g/mol, an XLogP3-AA value of 5.8, a hydrogen bond donor count of 3, and a hydrogen bond acceptor count of 3.

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