| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
GM1 ( IC50 = 14 nM ); glucosylceramide (GlcCer) synthase; GL1 synthase; glucosylceramide synthase
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|---|---|
| ln Vitro |
Cytotoxic anticancer medications have a greater ability to kill tumor cells when cells are exposed to nontoxic amounts of Genz-123346 and other GCS inhibitors. P-gp (ABCB1, gP-170) and other multidrug resistance efflux pumps are substrates of Genz-123346 and certain other GCS inhibitors. The primary reason for the chemotherapeutic sensitization of Genz-123346 in cell lines that have been chosen to overexpress or endogenously express P-gp is the impact on P-gp function [2]. An amplifier of autophagy flux is Genz-123346 (Genz) [3].
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| ln Vivo |
In Zucker diabetic obese rats, Genz-123346 increased glucose tolerance and lowered glucose and A1C levels. Additionally, medication maintenance maintains the animals' capacity to release insulin and avoids the loss of pancreatic beta cell function. Treatment with Genz-123346 corrected A1C levels and enhanced glucose tolerance in mice produced obese by diet. This medication has a 30–60 minute plasma half-life and an oral bioavailability of 10% and 30% in mice and rats, respectively [1]. Treatment with Genz-123346 significantly inhibited cystic disease by causing a dose-dependent drop in kidney GlcCer and GM3 levels. Genz-123346 has been shown to directly affect the Akt-mTOR signaling pathway, which results in a decrease in Akt and ribosomal protein S6 phosphorylation [4]. After two weeks of feeding, the renal Gb3 of a group of WT mice given Genz-123346 (final concentration 0.11% in ordinary chow) was roughly 50% lower than that of a group of WT mice fed chow alone [5].
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| Enzyme Assay |
Glucosylceramide synthase (GCS) is a key enzyme engaged in the biosynthesis of glycosphingolipids and in regulating ceramide metabolism. Studies exploring alterations in GCS activity suggest that the glycolase may have a role in chemosensitizing tumor cells to various cancer drugs. The chemosensitizing effect of inhibitors of GCS (e.g. PDMP and selected analogues) has been observed with a variety of tumor cells leading to the proposal that the sensitizing activity of GCS inhibitors is primarily through increases in intracellular ceramide leading to induction of apoptosis. The current study examined the chemosensitizing activity of the novel GCS inhibitor, Genz-123346 in cell culture. Exposure of cells to Genz-123346 and to other GCS inhibitors at non-toxic concentrations can enhance the killing of tumor cells by cytotoxic anti-cancer agents. This activity was unrelated to lowering intracellular glycosphingolipid levels. Genz-123346 and a few other GCS inhibitors are substrates for multi-drug resistance efflux pumps such as P-gp (ABCB1, gP-170). In cell lines selected to over-express P-gp or which endogenously express P-gp, chemosensitization by Genz-123346 was primarily due to the effects on P-gp function. RNA interference studies using siRNA or shRNA confirmed that lowering GCS expression in tumor cells did not affect their responsiveness to commonly used cytotoxic drugs.[2]
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| Cell Assay |
Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons[3]
In this study, researchers identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol and Genz-123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT-mammalian target of rapamycin (mTOR) signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on-target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant α-synuclein in neurons, it does so, according to our data, through autophagy-independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease. Inhibition of GlcCer synthase enhances autophagy by inhibiting AKT-mTOR signaling, and increases the number and size of lysosomal/late endosomal structures. Furthermore, inhibition of GlcCer synthase decreased levels of mutant α-synuclein in neurons, which may represent a potential therapeutic target for Parkinson's disease.
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| Animal Protocol |
Rats: In water, Genz-123346 dissolves. After receiving Genz-123346 (75 mg/kg) for six weeks, Zucker diabetic fatty rats are fasted for the entire night. The fasted rats are put under anesthesia and given five human insulin shots into their hepatic portal veins the next morning. Two minutes after injection, the liver and quadriceps muscle are removed and instantly frozen in liquid nitrogen. The immunoprecipitated insulin receptor By using immunoblotting, the immunoprecipitates are examined[1].
Mice: For eight weeks, C57BL/6 mice are given a high-fat (45% of kcal) diet. Obese mice with similar body weight gain, insulin, and glucose levels are placed in the treated or control groups. After that, the mice are given water or Genz-123346 every day for ten weeks[1].
Beneficial effect of pharmacologic inhibition of Gb3 synthesis in the glycerol-induced AKI model: The glucosylceramide synthase inhibitor Genz-123346 has been shown to effectively reduce renal GSLs as well as provide protection against STx-induced renal damage in rodents. We used this inhibitor to diminish Gb3 levels in the kidneys of mice. A group of WT mice received Genz-123346 (0.11% final concentration in regular chow); after 2 weeks of feeding, renal Gb3 was reduced by approximately 50%, in comparison with WT mice fed with chow diet only ( Figure 9 a). After 3 weeks of Genz-123346 administration, we assessed renal albumin excretion. Genz-123346–treated WT mice manifested a significant increase in 24-hour urinary albumin excretion compared with untreated WT mice ( Figure 9 b). In addition, at 24 hours after glycerol administration, Genz-123346–treated WT mice showed preserved renal morphology, with most of the PTs having an intact BB together with significantly lower values of serum creatinine and serum urea, in contrast to glycerol-injected control mice ( Figure 9 c–f). Thus, pharmacologic inhibition of Gb3 in WT mice confirmed a role for Gb3 in urinary albumin excretion and corroborated the protective effects of genetic Gb3 deficiency, as observed in Gb3S−/− and Ugcgf/f Pax8Cre mice, in myoglobin-induced AKI.[5] |
| References |
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| Additional Infomation |
Our results show an involvement of Gb3 in the reabsorption of proteins and xenobiotics by PTECs; Gb3 abolishment, which can be partially achieved by pharmacologic treatment with GENZ-123346, protects against myoglobin-induced AKI and also shows a decrease in gentamicin-induced AKI. Gb3 thus serves as a bimodal function in proximal tubule (PT) epithelia, contributing to the reabsorption of albumin and low-molecular-weight (LMW) proteins filtered into the primary urine, and to the tubulotoxic effect of endogenous proteins such as myoglobin and xenobiotics such as gentamicin.[5]
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| Molecular Formula |
C52H82N4O14
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|---|---|
| Molecular Weight |
987.22589635849
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| Exact Mass |
986.582
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| CAS # |
943344-58-9
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| Related CAS # |
Genz-123346 free base;491833-30-8
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| PubChem CID |
92044364
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
8
|
| Hydrogen Bond Acceptor Count |
16
|
| Rotatable Bond Count |
27
|
| Heavy Atom Count |
70
|
| Complexity |
631
|
| Defined Atom Stereocenter Count |
6
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| SMILES |
CCCCCCCCC(N[C@H](CN1CCCC1)[C@@H](C2=CC=C(OCCO3)C3=C2)O)=O.CCCCCCCCC(N[C@H](CN4CCCC4)[C@@H](C5=CC=C(OCCO6)C6=C5)O)=O.O=C(O)[C@H](O)[C@@H](O)C(O)=O
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| InChi Key |
ZRGZTIAIHNUMCZ-DQKXIDSGSA-N
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| InChi Code |
InChI=1S/2C24H38N2O4.C4H6O6/c2*1-2-3-4-5-6-7-10-23(27)25-20(18-26-13-8-9-14-26)24(28)19-11-12-21-22(17-19)30-16-15-29-21;5-1(3(7)8)2(6)4(9)10/h2*11-12,17,20,24,28H,2-10,13-16,18H2,1H3,(H,25,27);1-2,5-6H,(H,7,8)(H,9,10)/t2*20-,24-;1-,2-/m111/s1
|
| Chemical Name |
N-[(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl]nonanamide;(2R,3R)-2,3-dihydroxybutanedioic acid
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| Synonyms |
Genz-123346; 943344-58-9; GQH5N7U72P; UNII-GQH5N7U72P; Genz123346; N-((1R,2R)-1-(2,3-Dihydro-1,4-benzodioxin-6-yl)-1-hydroxy-3-pyrrolidin-1-ylpropan-2-yl)nonanamide;(2R,3R)-2,3-dihydroxybutanedioic acid; Nonanamide, N-((1R,2R)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-hydroxy-1-(1-pyrrolidinylmethyl)ethyl)-, (2R,3R)-2,3-dihydroxybutanedioate (2:1); GENZ-123346 HEMITARTRATE;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0129 mL | 5.0647 mL | 10.1294 mL | |
| 5 mM | 0.2026 mL | 1.0129 mL | 2.0259 mL | |
| 10 mM | 0.1013 mL | 0.5065 mL | 1.0129 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.
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