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Purity: ≥98%
SKF-96365 HCl (SKF-96365 hydrochloride) is a novel, potent and selective TRPC channel blocker that is commonly used to characterize the potential functions of TRPC channels in different systems. SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway. SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes. SKF 96365 inhibits glioblastoma cell growth by enhancing reverse mode of the Na(+) /Ca(2+) exchanger and increasing intracellular Ca(2+). SKF-96365 attenuates toxin-induced neuronal injury through opposite regulatory effects on Homer1a and Homer1b/c in cultured rat mesencephalic cells.
| Targets |
TRP channel; store-operated Ca2+ entry (SOCE)
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|---|---|
| ln Vitro |
SKF-96365 induces cell-cycle arrest and death in colorectal cancer cells, demonstrating strong anti-neoplastic action. hERG current is inhibited by SKF-96365 in a concentration-dependent manner[1]. By inhibiting the release of cytochrome c (cyt c) from the mitochondria into the cytoplasm, SKF-96365 can delay apoptosis by inducing cytoprotective autophagy. AKT signaling cascade and calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ) are inhibited mechanistically by SKF-96365 administration. The effects of SKF -96365 on cancer cells are eliminated by overexpressing CaMKIIγ or AKT, indicating a crucial function for the CaMKIIγ/AKT signaling pathway in the biological actions of SFK -96365[2].
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| ln Vivo |
In vivo CRC cell proliferation is inhibited by SKF-96365. In mice treated with SKF-96365, p-CaMKII and p-AKT are decreased, while LC3-II, cleaved PARP, caspase-3, and caspase-9 are increased[2].
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| Enzyme Assay |
Measurements of intracellular Ca2+ concentration and SOCE[2]
The iCa2+ concentration was monitored using a Ca2+-sensitive fluorescence indicator, fluo-3/AM, following a previously published procedure. ER Ca2+ stores were depleted by treatment with 2 µM thapsigargin in BSS solution (140 mM NaCl, 2.8 mM KCl, 2 mM MgCl2, 10 mM HEPES, pH 7.4) containing 1 mM EGTA. Ca2+ entry was accomplished by addition of CaCl2 (2 mM). The iCa2+ concentration in colon cancer cells was monitored by a Nikon A1 confocal microscopy at an excitation of 488 nm and an emission of 530 nm. Changes of intracellular fluorescence intensity compared with the baseline were indicative of the changes in iCa2+. Images were obtained at a rate of one image per 4 s and were analyzed with Nikon confocal software. Mitochondrial membrane potential assay[2] The mitochondrial membrane potential was measured using JC-1 as previously described. Briefly, the treated cells were incubated with an equal volume of JC-1 staining solution (5 µg/ml) at 37 °C for 20 min, rinsed twice with PBS, and analyzed by flow cytometry. Intracellular signaling array[2] Intracellular signaling molecules were detected using a PathScan intracellular signaling array kit according to the manufacturer’s instructions. |
| Cell Assay |
SKF-96365 is a TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in different systems, which was recently reported to induce QTc prolongation on ECG by inhibiting TRPC channels. The present study investigates whether the blockade of cardiac repolarization currents would be involved in the increase of QTc interval. Cardiac repolarization currents were recorded in HEK 293 cells stably expressing human ether-à-go-go-related gene potassium (hERG or hKv11.1) channels, hKCNQ1/hKCNE1 channels (IKs) or hKir2.1 channels and cardiac action potentials were recorded in guinea pig ventricular myocytes using a whole-cell patch technique. The potential effect of SKF-96365 on QT interval was evaluated in ex vivo guinea pig hearts. It was found that SKF-96365 inhibited hERG current in a concentration-dependent manner (IC50, 3.4μM). The hERG mutants S631A in the pore helix and F656V of the S6 region reduced the inhibitory sensitivity with IC50s of 27.4μM and 11.0μM, suggesting a channel pore blocker. In addition, this compound inhibited IKs and hKir2.1currents with IC50s of 10.8 and 8.7μM. SKF-96365 (10μM) significantly prolonged ventricular APD90 in guinea pig ventricular myocytes and QTc interval in ex vivo guinea pig hearts. These results indicate that the TRPC channel antagonist SKF-96365 exerts blocking effects on hERG, IKs, and hKir2.1 channels. Prolongation of ventricular APD and QT interval is related to the inhibition of multiple repolarization potassium currents, especially hERG channels[1].
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| Animal Protocol |
Five to six-week-old female athymic BALB/c mice were inoculated into the right oxter with HCT116 cells. When the diameter of the subcutaneous tumor reached approximately 0.5 centimeters, animals were randomly assigned to the vehicle, SKF-96365 alone, HCQ alone or SKF-96365 + HCQ. SKF-96365 was applied (20 mg/kg) and HCQ was applied (60 mg/kg) daily for 14 successive days by intraperitoneal injection. Tumor sizes were determined by measuring 2 diameters with a caliper. Tumor volume (V) was estimated using the equation V = ab2 /2, where a is the largest diameter and b is the smallest diameter. Eight mice were included in each group. Mice were sacrificed 24 h after the last treatment. The tumors were weighed and processed for western blot analysis or paraffin embedding. This animal study was approved by the Institutional Animal Ethics Committee of Zhejiang University with Approval No. zju-2013-1-01-066.[2]
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| References |
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| Additional Infomation |
SKF-96365 hydrochloride is the hydrochloride salt of SKF-96365. It is a TRP channel blocker. It has a role as a TRP channel blocker, an apoptosis inducer, an autophagy inducer, a GABA antagonist, an antineoplastic agent, a calcium channel blocker and a platelet aggregation inhibitor. It contains a SKF-96365 free base(1+).
See also: SKF-96365 free base (annotation moved to). |
| Molecular Formula |
C22H26N2O3.HCL
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|---|---|
| Molecular Weight |
402.91438
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| Exact Mass |
402.171
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| Elemental Analysis |
C, 65.58; H, 6.75; Cl, 8.80; N, 6.95; O, 11.91
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| CAS # |
130495-35-1
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| Related CAS # |
130495-35-1 (HCl);162849-90-3;
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| PubChem CID |
104955
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| Appearance |
Typically exists as White to light yellow solids at room temperature
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| Boiling Point |
556ºC at 760mmHg
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| Melting Point |
119 °C
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| Flash Point |
290.1ºC
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| Vapour Pressure |
7.86E-12mmHg at 25°C
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| LogP |
5.093
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
28
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| Complexity |
393
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=CC=C(CCCOC(C2=CC=C(OC)C=C2)CN3C=CN=C3)C=C1.[H]Cl
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| InChi Key |
FWLPKVQUECFKSW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H26N2O3.ClH/c1-25-20-9-5-18(6-10-20)4-3-15-27-22(16-24-14-13-23-17-24)19-7-11-21(26-2)12-8-19;/h5-14,17,22H,3-4,15-16H2,1-2H3;1H
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| Chemical Name |
1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl]imidazole;hydrochloride
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| Synonyms |
SKF-96365 hydrochloride; SKF 96365 HYDROCHLORIDE; SKF-96365; SKF96365; SK&F 96365; SKF-96365 (hydrochloride); 1-(2-(3-(4-Methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole hydrochloride;
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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 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)
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| Solubility (In Vitro) |
H2O : ~100 mg/mL (~248.19 mM)
DMSO : ~100 mg/mL (~248.19 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.20 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 25.0 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: ≥ 2.5 mg/mL (6.20 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 25.0 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: ≥ 2.5 mg/mL (6.20 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (248.19 mM) in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4819 mL | 12.4097 mL | 24.8194 mL | |
| 5 mM | 0.4964 mL | 2.4819 mL | 4.9639 mL | |
| 10 mM | 0.2482 mL | 1.2410 mL | 2.4819 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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