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Description: Sinomenine HCl (Cucoline), the hydrochloride salt of Sinomenine, is a naturally occuring alkaloid isolated from the root of the plant Sinomenium acutum. It is a blocker of the NF-κB activation with anticancer and anti-inflammatory effects. Sinomenine also is an activator of μ-opioid receptor. It has been used in traditional medicine in China to treat rheumatic arthritis. Sinomenine has a wide spectrum of analgesic effect in rodent models of nociceptive, inflammatory and neuropathic pain.
Physicochemical Properties
| Molecular Formula | C19H24CLNO4 |
| Molecular Weight | 365.8512 |
| Exact Mass | 365.139 |
| Elemental Analysis | C, 62.38; H, 6.61; Cl, 9.69; N, 3.83; O, 17.49 |
| CAS # | 6080-33-7 |
| Related CAS # | Sinomenine;115-53-7 |
| PubChem CID | 5464452 |
| Appearance | White to off-white solid powder |
| Boiling Point | 513.6ºC at 760 mmHg |
| Melting Point | 231.0 to 235.0 °C |
| Flash Point | 264.4ºC |
| LogP | 2.758 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 25 |
| Complexity | 562 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | Cl[H].O(C([H])([H])[H])C1C(C([H])([H])[C@@]23C4C(=C(C([H])=C([H])C=4C([H])([H])[C@@]([H])([C@@]2([H])C=1[H])N(C([H])([H])[H])C([H])([H])C3([H])[H])OC([H])([H])[H])O[H])=O |
| InChi Key | YMEVIMJAUHZFMW-VUIDNZEBSA-N |
| InChi Code | InChI=1S/C19H23NO4.ClH/c1-20-7-6-19-10-14(21)16(24-3)9-12(19)13(20)8-11-4-5-15(23-2)18(22)17(11)19;/h4-5,9,12-13,22H,6-8,10H2,1-3H3;1H/t12-,13+,19-;/m1./s1 |
| Chemical Name | (1R,9S,10S)-3-hydroxy-4,12-dimethoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5,11-tetraen-13-one;hydrochloride |
| Synonyms | Sinomenine hydrochloride; Sinomenine HCl; 6080-33-7; Cucoline, hydrochloride; Cucoline Hydrochloride; 2J34HRJ45S; Sinomenin Hydrochloride; NSC-76,021; 683-119-6; Cucoline HCl; NSC76021; NSC 76021; NSC-76021 |
| 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) |
Biological Activity
| Targets |
NF-κB[1], μ-opioid receptor[2] - Opioid μ-receptor (EC50 not specified, but activates the receptor in cell-based assays) [2] - NF-κB (inhibited via the IL-4/miR-324-5p/CUEDC2 axis, no specific IC50 reported) [1] - STAT3 (inhibited in glioma cells, no specific IC50 reported) [5] |
| ln Vitro |
Sinomenine downregulates HIAP, Bcl-2, and survivin while activating caspase-3, caspase-8, and caspase-9 in U87 cells to cause apoptotic death. The expression of phosphorylated STAT3 (p-STAT3) is reduced by Sinomenine both in vivo and in vitro. It has protective effects against a variety of cancer types, such as breast cancer cells, esophageal carcinoma cells, hepatocellular carcinoma cells, gastric adenocarcinoma cells, lung cancer cells, and colon carcinoma cells. Treatment with Sinomenine results in a dose- and time-dependent inhibition of growth in U87, with an IC50 of SM ranging from 178 μM to 380 μM. Sinomenine obviously reduces cell viability when applied to U251, U373, Hs683 and T98G for 48 hours; the IC50 values are 342.7 μM, 430.2 μM, 189.6 μM and 270.3 μM, respectively[1]. Following pretreatment with autophagy inhibitors, the accumulation of the microtubule-associated protein light chain 3B (LC3B)-II indicates that the chemical Sinomenine HCl (SH) activates an autophagy-mediated cell death pathway, initiates autophagic flux, and improves cell viability. By blocking the Akt-mTOR pathway and activating the JNK pathway, it causes autophagy. Sinomenine HCl (SH) increases the levels of autophagy marker proteins both in vivo and in vitro while dose-dependently decreasing the phosphorylation of p70S6K, 4E-BP1, Akt, and mTOR. Sinomenine HCl increases ROS production in a dose-dependent manner, which is accompanied by an increase in autophagy in both U87 and SF767 cells. By causing the nuclear translocation of TFEB through mTOR inhibition, SH may encourage lysosomal biogenesis[2].
- In human breast cancer MDA-MB-231 cells, sinomenine (10-100 μM) dose-dependently inhibited cell invasion and migration (by 30-60% at 100 μM) via suppressing NF-κB activation. This was associated with upregulated miR-324-5p, downregulated CUEDC2, and reduced levels of p-p65 and MMP-9 (detected by Western blot) [1] - In HEK293 cells transfected with opioid μ-receptors, sinomenine (10-100 μM) increased [35S]GTPγS binding, indicating μ-receptor activation, with efficacy comparable to morphine at high concentrations [2] - In human glioma U87 and U251 cells, sinomenine (50-200 μM) inhibited cell viability (IC50 ~100 μM for U87) by suppressing STAT3 phosphorylation (Western blot) and reducing cyclin D1 expression. It also induced reactive oxygen species (ROS) generation (detected by DCFH-DA staining) and activated autophagy (increased LC3-II/LC3-I ratio and Beclin-1 expression) [5][6] - In primary microglia from rats with neuropathic pain, sinomenine (10-50 μM) reduced LPS-induced TNF-α and IL-1β secretion (ELISA), suggesting anti-inflammatory effects [3] |
| ln Vivo |
Sinomenine has anti-inflammatory, cardioprotective, and cancer-chemopreventive properties. In vivo, it demonstrates anti-glioma activity. At therapeutic doses, sinomenine is well tolerated by recipient mice and causes no discernible cytotoxicity[1]. Both in vitro and in vivo experiments show that the autophagy-lysosome pathway is started by the compound Sinomenine HCl (SH)[2].
- In rats with chronic constriction injury (CCI)-induced neuropathic pain, sinomenine (10-40 mg/kg, intraperitoneal injection, once daily for 7 days) dose-dependently increased paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in von Frey and hot plate tests, with maximum efficacy at 40 mg/kg (PWT: 12.5 ± 1.8 g vs. 3.2 ± 0.5 g in vehicle group) [4] - In mice with complete Freund's adjuvant (CFA)-induced inflammatory pain, sinomenine (20-80 mg/kg, oral gavage) reduced thermal hyperalgesia, an effect reversed by the μ-opioid receptor antagonist naloxone, confirming opioid-mediated analgesia [3] - In nude mice bearing U87 glioma xenografts, sinomenine hydrochloride (50 mg/kg, intraperitoneal injection, every other day for 21 days) reduced tumor volume (356 ± 42 mm³ vs. 689 ± 57 mm³ in control) and weight, associated with decreased p-STAT3 expression and increased LC3-II accumulation in tumor tissues [6] |
| Enzyme Assay |
- Opioid μ-receptor binding assay: Membranes from HEK293 cells transfected with human μ-opioid receptors were incubated with [3H]-diprenorphine (0.5 nM) and sinomenine (10-9-10-4 M) at 25°C for 60 min. Nonspecific binding was defined with 10 μM naloxone. Bound ligand was separated by filtration, and radioactivity was measured. Sinomenine displaced [3H]-diprenorphine with moderate affinity, indicating μ-receptor interaction [2] - NF-κB activity assay: MDA-MB-231 cells were transfected with NF-κB-luciferase reporter plasmid. After treatment with sinomenine (50 μM) and IL-4 (10 ng/mL), luciferase activity was measured. Sinomenine reduced IL-4-induced luciferase activity by 58%, indicating NF-κB inhibition [1] |
| Cell Assay |
The cells are cultured in 96-well plates at a density of 5 × 103/well and subjected to SM treatment for the predetermined period of time (24–72 hours). The microplate is then incubated at 37 °C for 4 hours after adding 10 μl of MTT solution (5 g/l) to the medium in each well. A microplate reader reads the absorbance at 570 nm. The proportion of surviving cells compared to untreated cells is how cytotoxicity is measured.
- Breast cancer invasion assay: MDA-MB-231 cells were seeded in Matrigel-coated transwell inserts with sinomenine (10-100 μM) in serum-free medium. After 24 h, invaded cells were fixed, stained, and counted. Sinomenine (100 μM) reduced invasion by 62% vs. control [1] - Glioma autophagy assay: U87 cells were treated with sinomenine (50-200 μM) for 24 h. Autophagosomes were visualized by LC3 immunofluorescence staining. Western blot analysis showed increased LC3-II/LC3-I ratio (2.8-fold at 100 μM) and Beclin-1 expression, confirming autophagy activation [6] - Microglia cytokine assay: Primary rat microglia were pretreated with sinomenine (10-50 μM) for 1 h, then stimulated with LPS (1 μg/mL) for 24 h. TNF-α and IL-1β levels in supernatants were measured by ELISA, showing 40-60% reduction at 50 μM [3] |
| Animal Protocol |
- Neuropathic pain model (CCI): Male rats underwent sciatic nerve ligation. From day 7 post-surgery, sinomenine (10-40 mg/kg) was administered intraperitoneally once daily. PWT (von Frey filaments) and PWL (hot plate, 52°C) were measured on days 7, 10, 14 [4] - Glioma xenograft model: Nude mice were subcutaneously injected with U87 cells (1×10⁶). When tumors reached 100 mm³, sinomenine hydrochloride (50 mg/kg) or vehicle (saline) was injected intraperitoneally every other day. Tumor volume was measured twice weekly, and mice were euthanized on day 21 for tissue analysis [6] - Inflammatory pain model: Mice received CFA (20 μL, intraplantar) on day 0. Sinomenine (20-80 mg/kg) was administered orally on days 1-7. Thermal hyperalgesia was assessed using a radiant heat source, measuring paw withdrawal time [3] Nude mice (male, 5-week-old BALB/c) 50 mg/kg and 100 mg/kg i.p. |
| Toxicity/Toxicokinetics | 5464452 mouse LD50 subcutaneous 4830 ug/kg BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD; LUNGS, THORAX, OR RESPIRATION: CYANOSIS; LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 52(157), 1956 |
| References |
[1]. Sinomenine inhibits breast cancer cell invasion and migration by suppressing NF-κB activation mediated by IL-4/miR-324-5p/CUEDC2 axis. Biochem Biophys Res Commun. 2015 Aug 28;464(3):705-10. [2]. Activation of opioid mu-receptor by sinomenine in cell and mice.Neurosci Lett. 2008 Oct 10;443(3):209-12. [3]. Analgesic effect of sinomenine in rodents after inflammation and nerve injury. Eur J Pharmacol. 2013 Dec 5;721(1-3):5-11. [4]. Antinociceptive effects of sinomenine in a rat model of neuropathic pain. Sci Rep. 2014 Dec 1;4:7270. [5]. Sinomenine inhibits the growth of glioma cells through STAT3 signal pathway. Journal of Applied Biomedicine2018, 16, 22-28. [6]. Sinomenine Hydrochloride Inhibits Human Glioblastoma Cell Growth through Reactive Oxygen Species Generation and Autophagy-Lysosome Pathway Activation: An In Vitro and In Vivo Study. Int J Mol Sci. 2017 Sep 11;18(9):1945. |
| Additional Infomation |
- Sinomenine is an alkaloid isolated from the Chinese herb Sinomenium acutum, traditionally used for anti-inflammatory and analgesic effects [3][4] - Its mechanisms include μ-opioid receptor activation (analgesia), NF-κB inhibition (anti-invasion in breast cancer), STAT3 suppression, and ROS-mediated autophagy induction (glioma growth inhibition) [1][2][5][6] - The hydrochloride salt (sinomenine hydrochloride) shows improved water solubility and is used in in vivo studies for better bioavailability [6] |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~273.3 mM) H2O: ~16.67 mg/mL (~45.6 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.69 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 (5.69 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (5.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. Solubility in Formulation 4: 25 mg/mL (68.33 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7334 mL | 13.6668 mL | 27.3336 mL | |
| 5 mM | 0.5467 mL | 2.7334 mL | 5.4667 mL | |
| 10 mM | 0.2733 mL | 1.3667 mL | 2.7334 mL |