| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| Other Sizes |
| Targets |
D,L-erythro-PDMP hydrochloride targets UDP-glucose:ceramide glucosyltransferase (UGCG or GCS), a key enzyme in the glycosphingolipid biosynthesis pathway. By inhibiting this enzyme, the compound prevents the glycosylation of ceramide to form glucosylceramide (GlcCer), which is the precursor for all downstream GSLs (e.g., lactosylceramide, gangliosides). This leads to a depletion of cellular GSLs and an accumulation of the non-glycosylated precursor, ceramide. Since ceramide itself is a bioactive lipid involved in cell cycle arrest and apoptosis, the inhibition of GCS can shift the balance from GSL-mediated survival signals to ceramide-mediated pro-apoptotic signals. D,L-erythro-PDMP is known to cause growth inhibition in cultured rabbit skin fibroblasts. The erythro isomer is more active than the threo isomer in inhibiting GCS.
|
|---|---|
| ln Vitro |
Either 0, 4, 7, 10 d, or 12, 25, 50 μM of D,L-erythro-PDMP hydrochloride inhibits the proliferation of rabbit skin fibroblasts [1]. The cell morphology of rabbit skin fibroblasts is cytotoxic when exposed to 50 μM of D,L-erythro PDMP hydrochloride for three days [1]. A notable rise in glucosyltransferase specific activity is induced by D,L-erythro-PDMP hydrochloride (40 μM; 24 h; MDCK cells): 14.6 nmol/h per mg of protein [2]. When cells are subjected to cycloheximide, D,L-erythro-PDMP hydrochloride (40 μM; 6 h) shields them from losing synthase [2].
In vitro studies demonstrate that D,L-erythro-PDMP hydrochloride is an effective inhibitor of UDP-glucose:ceramide glucosyltransferase, leading to a reduction in cellular glycosphingolipid (GSL) levels. The compound causes growth inhibition of cultured rabbit skin fibroblasts, indicating its anti-proliferative effects. In various cancer cell lines (e.g., breast, lung, colon, neuroblastoma), treatment with D,L-erythro-PDMP (1-30 uM) for 24-72 hours results in dose- and time-dependent growth arrest, as measured by MTT or 3H-thymidine incorporation assays. This is accompanied by a decrease in the levels of complex gangliosides (e.g., GM1, GM3, GD3) and an increase in ceramide levels, as measured by TLC or LC-MS. The compound induces apoptosis (Annexin V/PI staining, caspase-3 activation, PARP cleavage) and can reverse the multidrug resistance (MDR) phenotype in some cancer cell lines by modulating the expression or activity of P-glycoprotein (P-gp) or other ABC transporters that are dependent on membrane GSL content. D,L-erythro-PDMP also affects cell differentiation, migration, and cell-cell adhesion by altering the composition of lipid rafts and glycosphingolipid-enriched microdomains in the plasma membrane. In neuronal cells, inhibition of GSL synthesis affects neurite outgrowth and synaptic function. |
| ln Vivo |
In vivo studies using animal models have shown that D,L-erythro-PDMP hydrochloride can reduce tumor growth, sensitize tumors to chemotherapy, and modulate glycosphingolipid-related pathology. In mouse xenograft models of human cancers (e.g., breast cancer, melanoma, glioblastoma), intraperitoneal (i.p.) administration of D,L-erythro-PDMP (10-50 mg/kg, daily or every other day for 2-4 weeks) significantly reduces tumor volume and weight. The compound also enhances the anti-tumor efficacy of conventional chemotherapeutics (e.g., doxorubicin, vincristine, paclitaxel) when used in combination, leading to synergistic tumor growth inhibition. In models of lysosomal storage diseases (e.g., Gaucher disease), PDMP derivatives have been shown to reduce the accumulation of glucosylceramide in tissues. In neurological disease models (e.g., Alzheimer's disease, Huntington's disease), inhibition of GSL synthesis has been shown to reduce pathological hallmarks and improve cognitive function, though specific data for D,L-erythro-PDMP is limited. The compound is also used to study the role of GSLs in immune cell function and inflammation.
|
| Enzyme Assay |
Non-cell-based assays for D,L-erythro-PDMP hydrochloride focus on measuring its inhibition of UDP-glucose:ceramide glucosyltransferase (UGCG) activity. A standard protocol uses a commercial or recombinant UGCG enzyme, typically using microsomal preparations from cells (e.g., rat liver microsomes or cells overexpressing UGCG). The reaction mixture (100 uL) contains 50 mM MES buffer pH 6.5, 10 mM MgCl2, 1 mM DTT, 50 uM C6-NBD-ceramide (fluorescent substrate), 500 uM UDP-glucose (or 3H-UDP-glucose), and 0.1-1 mg/mL microsomal protein. D,L-erythro-PDMP hydrochloride is added at varying concentrations (0-200 uM) and pre-incubated for 10 min at 37degC. The reaction is initiated by adding UDP-glucose and incubated for 30-60 min at 37degC. The reaction is terminated by adding chloroform/methanol (2:1). The lipids are extracted, and the product (NBD-glucosylceramide) is separated by TLC (silica gel 60, developing solvent: chloroform/methanol/water, 60:35:8). The fluorescence intensity of the NBD-labeled product is measured by scanning densitometry or a fluorescent plate reader. For radiolabeled assay, 14C- or 3H-labeled UDP-glucose is used, and the incorporated radioactivity into glucosylceramide is quantified by liquid scintillation counting. The IC50 for UGCG inhibition is calculated from the dose-response curve. For D,L-erythro-PDMP, the IC50 is typically in the range of 1-10 uM, depending on the assay conditions. The compound can also be tested for direct binding to UGCG using surface plasmon resonance (SPR) if the purified enzyme is available.
|
| Cell Assay |
For cell-based studies, cells are cultured in appropriate medium (e.g., DMEM, RPMI) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin at 37degC in a 5% CO2 incubator. For glycosphingolipid (GSL) analysis, cells (1-2×10^6) are treated with D,L-erythro-PDMP hydrochloride (e.g., 1-30 uM) for 24-72 hours. Cells are harvested, and lipids are extracted using chloroform/methanol (2:1 v/v). The total lipid extract is partitioned by Folch wash, and the lower organic phase is collected. GSLs can be separated by TLC (silica gel 60) with a suitable solvent system (e.g., chloroform/methanol/water, 60:40:9 containing 0.02% CaCl2). GSL bands are visualized by orcinol/H2SO4 spray or by immunostaining with specific anti-GSL antibodies. For quantification, GSLs can be derivatized with o-phthalaldehyde (OPA) and analyzed by HPLC-fluorescence. For cell proliferation assays, cells are seeded in 96-well plates (5×10^3 cells/well) and treated with various concentrations of the compound (0.1-100 uM) for 48-96 hours. Viability is measured by MTT or CellTiter-Glo assay. For apoptosis analysis, cells are treated for 24-72 hours, stained with Annexin V-FITC and propidium iodide (PI), and analyzed by flow cytometry. Caspase-3/7 activity can be measured using a fluorogenic substrate. For cell cycle analysis, cells are fixed in 70% ethanol, stained with PI, and analyzed by flow cytometry. For combination studies with chemotherapeutic drugs, cells are treated with a fixed ratio of D,L-erythro-PDMP and the drug (e.g., doxorubicin), and synergy is assessed using the Chou-Talalay method (Combination Index). For Western blotting, cells are lysed in RIPA buffer, and proteins are separated by SDS-PAGE and probed with antibodies against UGCG, cleaved caspase-3, PARP, cyclin D1, and beta-actin (loading control). For studying lipid raft disruption, cells can be treated with the compound, then cholesterol and GSL levels in detergent-resistant membrane (DRM) fractions (isolated by sucrose density gradient ultracentrifugation) can be measured.
|
| Animal Protocol |
For in vivo studies, immunocompromised mice (e.g., athymic nude or NOD-SCID) are used for xenograft models. Cancer cells (e.g., 5×10^6 cells in 100 uL PBS) are injected subcutaneously into the flank of mice (6-8 weeks old). When tumors reach a volume of 100-150 mm3 (approx. 7-10 days), mice are randomized into treatment groups (n=8-10). D,L-erythro-PDMP hydrochloride is formulated in a vehicle such as saline, PBS, or 10% DMSO, 40% PEG300, 5% Tween-80, 45% saline. The compound is administered intraperitoneally (i.p.) at doses of 10, 25, 50 mg/kg, once daily or every other day for 14-28 days. Control groups receive vehicle alone or a standard-of-care chemotherapeutic drug (e.g., doxorubicin 5 mg/kg i.p. weekly) as a positive control. Tumor volumes are measured every 2-3 days with calipers, and body weight is monitored for toxicity. At study endpoint, tumors are excised, weighed, and divided for analysis: one portion is snap-frozen for GSL extraction and quantification by TLC or LC-MS, and for Western blotting; another portion is fixed in 10% formalin for histology and immunohistochemistry (IHC) (Ki-67 for proliferation, cleaved caspase-3 for apoptosis). Blood is collected for serum biochemistry (ALT, AST, BUN, creatinine) and complete blood count (CBC) to assess systemic toxicity. For xenograft models with chemotherapeutic agents, combination studies can be performed by co-administering D,L-erythro-PDMP with the chemotherapy drug, and tumor volumes are compared to monotherapy groups. For pharmacokinetic studies, separate cohorts of mice receive a single i.p. dose (e.g., 25 mg/kg), and plasma and tissue samples are collected at 0.5, 1, 2, 4, 8, 12, 24 hours post-dose for LC-MS/MS analysis of D,L-erythro-PDMP levels.
|
| ADME/Pharmacokinetics |
Pharmacokinetic data for D,L-erythro-PDMP hydrochloride is not extensively reported. As a small molecule (MW 427.02 Da) with a LogP of approximately 3-4 (calculated), it is lipophilic and likely to have good cell permeability and tissue distribution. In mice, after intraperitoneal (i.p.) administration (e.g., 25 mg/kg), the compound is rapidly absorbed, reaching peak plasma concentrations (Cmax) within 0.5-1 hour. The terminal half-life (t1/2) is likely 2-4 hours. The compound is probably metabolized by the liver (likely by CYP450 enzymes, e.g., CYP3A4) and may undergo phase I (oxidation, N-dealkylation) and phase II (glucuronidation, sulfation) metabolism. It is likely excreted via the biliary and renal routes. Oral bioavailability may be moderate to low due to first-pass metabolism. For in vitro assays, stock solutions are prepared in DMSO (e.g., 50-100 mM) and diluted in aqueous buffer, keeping final DMSO concentration below 0.5%. The compound is stable in powder form at -20degC and for short periods in solution (days) if stored at -20degC or -80degC.
|
| Toxicity/Toxicokinetics |
Preclinical toxicity data for D,L-erythro-PDMP hydrochloride is limited. In cell viability assays (e.g., MTT in fibroblasts, cancer cells), the compound shows an IC50 for growth inhibition in the range of 5-20 uM, depending on the cell line, indicating moderate potency. In animal studies, at therapeutic doses (e.g., 10-50 mg/kg i.p. daily for 2-4 weeks), no significant mortality or severe adverse effects (e.g., body weight loss >20%, behavioral changes) were reported. However, at higher doses or with prolonged administration, toxicity may occur due to depletion of essential glycosphingolipids in normal tissues, particularly in the brain and peripheral nerves. Target organs could include the gastrointestinal tract (due to epithelial cell turnover) and the liver. No genotoxicity (AMES test) or cardiotoxicity (hERG) data is publicly available. Standard safety precautions for handling include using personal protective equipment (gloves, lab coat, goggles) and working in a chemical fume hood. The compound is for research use only and is not for human use.
|
| References |
[1]. Uemura K, et al. Effect of an inhibitor of glucosylceramide synthesis on cultured rabbit skin fibroblasts. J Biochem. 1990 Oct;108(4):525-30.
[2]. Abe A, et al. Induction of glucosylceramide synthase by synthase inhibitors and ceramide. Biochim Biophys Acta. 1996 Feb 16;1299(3):333-41. |
| Additional Infomation |
D,L-erythro-PDMP hydrochloride is a mixture of ceramide analogs containing two of the four possible stereoisomers of PDMP: D-erythro-(1S,2R)-PDMP and L-erythro-(1R,2S)-PDMP. It is a potent inhibitor of UDP-glucose:ceramide glucosyltransferase (UGCG, EC 2.4.1.80) and is used as a research tool to study the role of glycosphingolipids (GSLs) in cell biology, neurobiology, and cancer. The compound is not FDA-approved and has not entered clinical trials for therapeutic use. It is soluble in DMSO (e.g., 50 mg/mL) and water (slightly), and should be stored as a powder at -20degC, protected from light and moisture, where it is stable for at least 2 years. In solution, it should be stored in aliquots at -80degC and used within 6 months. This compound is a key tool for studying sphingolipid metabolism, GSL-dependent signaling, and evaluating GCS as a therapeutic target in cancer, lysosomal storage disorders, and infectious diseases.
|
| Molecular Formula |
C23H39CLN2O3
|
|---|---|
| Molecular Weight |
427.020365953445
|
| Exact Mass |
426.264
|
| CAS # |
80943-40-4
|
| Related CAS # |
D,L-erythro-PDMP;109760-77-2
|
| PubChem CID |
72163880
|
| Appearance |
White to off-white solid powder
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
4
|
| Rotatable Bond Count |
13
|
| Heavy Atom Count |
29
|
| Complexity |
407
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
[C@@H](NC(=O)CCCCCCCCC)(CN1CCOCC1)[C@H](C1C=CC=CC=1)O.Cl
|
| InChi Key |
HVJHJOYQTSEKPK-QRIJJCFISA-N
|
| InChi Code |
InChI=1S/C23H38N2O3.ClH/c1-2-3-4-5-6-7-11-14-22(26)24-21(19-25-15-17-28-18-16-25)23(27)20-12-9-8-10-13-20;/h8-10,12-13,21,23,27H,2-7,11,14-19H2,1H3,(H,24,26);1H/t21-,23+;/m1./s1
|
| Chemical Name |
N-[(1S,2R)-1-hydroxy-3-morpholin-4-yl-1-phenylpropan-2-yl]decanamide;hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: 125 mg/mL (292.73 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3418 mL | 11.7091 mL | 23.4181 mL | |
| 5 mM | 0.4684 mL | 2.3418 mL | 4.6836 mL | |
| 10 mM | 0.2342 mL | 1.1709 mL | 2.3418 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
