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Purity: =99.13%
| Targets |
Natural product; Akt/mTOR
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|---|---|
| ln Vitro |
Corynoxine (6.25-25 μM; 6-12 hours) increases the expression of the autophagy-specific marker LC3-II in N2a and SH-SY5Y cells in a dose-dependent manner [1]. Corynoxine (25 μM; 48 h) increases the breakdown of wild-type (WT) and mutant (A53T) α-syn in inducible PC12 cells through autophagy induction [1].
Corynoxine (10, 20, 40 μM) treatment for 24 hours significantly reduced the level of A53T α-synuclein in a stable PC12 cell model in a dose-dependent manner, as detected by Western blot analysis. [1] Corynoxine (20 μM) treatment for 24 hours increased the protein levels of the autophagy marker LC3-II and decreased the level of the autophagy substrate p62 in PC12 cells expressing A53T α-synuclein, indicating the induction of autophagy. [1] The autophagy-enhancing effect of Corynoxine was confirmed by the observation of increased numbers of GFP-LC3 puncta (autophagosomes) in HeLa cells transfected with a GFP-LC3 plasmid after treatment with 20 μM Corynoxine for 24 hours. [1] |
| ln Vivo |
The oral gavage of corynoxine (100-100 mg/kg) prolongs the thiopental-induced hypnosis in mice [2]. In Drosophila, corynoxine (10–100 μM, 12 hours) causes autophagy [1].
Cory (corynoxine) Induces Autophagy in Drosophila: To confirm the autophagy-inducing effect of Cory in vivo, we firstly crossed Cg-GAL4 fly lines to UAS-GFP-Atg8a fly lines at 25 °C, and got the 2nd instar larvae of Cg-GAL4 > UAS-GFP-Atg8a. We fed these larvae with food containing different concentrations of Cory (10-100 μM) for 12 h at 25 °C. In our previous study, Cory B was confirmed to induce autophagy in Drosophila; therefore we chose it as a positive control and using 0.4 % DMSO as a negative control. We collected the treated larvae and prepared the fat bodies for photographing through a confocal microscope. Atg8 (Autophagy-related protein), the homolog of LC3, is an ubiquitin-like protein required for the formation of autophagosomal membranes. Compared with the control, both Cory (10-100 μM) and Cory B (100 μM) induced the puncta formation of Atg8 (Fig. 3), suggesting that Cory could also induce autophagy in the fat bodies of Drosophila larvae [1]. |
| Enzyme Assay |
After treatment, N2a-GFP-LC3 stable cells were fixed with 4 % paraformaldehyde in PBS for 10 min at room temperature. Cells were mounted with FluoSave reagent and imaged with a confocal microscope [1].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: N2a and SH-SY5Y Cell Tested Concentrations: 6.25, 12.5, 25 μM Incubation Duration: 6, 12 hrs (hours) Experimental Results: Induction of autophagy in neuronal cell lines. Cell culture and treatment: PC12 cells stably expressing human A53T mutant α-synuclein were used. Cells were cultured in growth medium. For treatment, Corynoxine was dissolved in DMSO and then diluted in the cell culture medium to the final concentrations (10, 20, 40 μM). An equal volume of DMSO was used as the vehicle control. Cells were treated for 24 hours. [1] Western blot analysis: After treatment, cells were harvested and lysed. The protein concentration of the lysates was determined. Equal amounts of protein were separated by SDS-PAGE and then transferred to a membrane. The membrane was blocked and then incubated with primary antibodies against α-synuclein, LC3, p62, phospho-Akt (Ser473), Akt, phospho-mTOR (Ser2448), mTOR, and β-actin (as a loading control) overnight at 4°C. After washing, the membrane was incubated with a secondary antibody. Protein bands were visualized using an enhanced chemiluminescence detection system. [1] GFP-LC3 puncta formation assay: HeLa cells were transfected with a GFP-LC3 plasmid. After 24 hours, the cells were treated with 20 μM Corynoxine or vehicle for another 24 hours. The cells were then fixed. The formation of GFP-LC3 puncta (autophagosomes) was observed and imaged using a fluorescence microscope. Cells with more than 10 GFP-LC3 puncta were considered to have undergone autophagy. [1] |
| Animal Protocol |
Cg-GAL4 fly lines and UAS-GFP-Atg8a fly lines were raised at 25 °C on standard corn meal medium supplemented with dry yeast. Drugs were initially dissolved in DMSO then diluted in water to desired concentrations. The drug- containing water was added to instant Drosophila food and mixed thoroughly. As the control, the same amount of DMSO was also mixed with instant Drosophila food. For the treatment, Cg-GAL4 fly lines were crossed to UAS-GFP-Atg8a fly lines at 25 °C, and then transferred the 2nd instar larvae of Cg-GAL4 > UAS-GFP-Atg8a onto instant food containing different concentrations of Cory (10–100 μM), 100 μM Cory B (positive control) or 0.1 % DMSO (negative control) for 12 h at 25 °C. Treated larvae were collected and fat bodies were dissected out in PBS, and then fixed with 4 % paraformaldehyde for 10 min at room temperature. Tissues were mounted with FluorSave™ Reagent (Merck) and imaged with a confocal microscopy [1].
Hypnosis test: The alkaloid fraction from Uncaria macrophylla (containing Corynoxine, Corynoxine B, Rhynchophylline, and Isorhynchophylline) was administered intraperitoneally (i.p.) to mice. The test was conducted by injecting thiopental sodium (40 mg/kg, i.p.) 30 minutes after the administration of the alkaloid fraction. The loss of the righting reflex was used as the criterion for hypnosis. The duration of hypnosis (sleeping time) was recorded. The alkaloid fraction was dissolved in a saline solution containing a drop of Tween 80. [2] |
| Toxicity/Toxicokinetics |
No specific toxicity data (e.g., LD50, organ toxicity) for purified Corynoxine is reported in the provided literature. [2] only states that the alkaloid fraction from Uncaria macrophylla (which includes Corynoxine) did not cause any observable toxic symptoms or mortality in mice at the tested doses (5, 10, 20 mg/kg, i.p.). [2]
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| References | |
| Additional Infomation |
Corynoxine is a member of indolizines. It has a role as a metabolite.
Corynoxine has been reported in Uncaria macrophylla, Mitragyna speciosa, and Uncaria attenuata with data available. Corynoxine is a natural oxindole alkaloid isolated from the hooks of Uncaria macrophylla. [1] The study demonstrates that Corynoxine promotes the clearance of alpha-synuclein, a protein implicated in Parkinson's disease, by enhancing autophagy. [1] The mechanism of action involves the inhibition of the Akt/mTOR pathway. Corynoxine (20 μM) treatment decreased the phosphorylation levels of Akt (at Ser473) and mTOR (at Ser2448) in PC12 cells expressing A53T α-synuclein, as shown by Western blot, without affecting the total protein levels of Akt and mTOR. [1] The hypnotic effects reported in [2] are for a mixture of four alkaloids (Corynoxine, Corynoxine B, Rhynchophylline, Isorhynchophylline), not for Corynoxine alone. The mixture (20 mg/kg, i.p.) significantly prolonged thiopental-induced sleeping time in mice. The effect of the mixture was stronger than that of any single alkaloid administered at an equivalent dose. [2] |
| Molecular Formula |
C22H28N2O4
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|---|---|
| Molecular Weight |
384.4687
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| Exact Mass |
384.204
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| CAS # |
6877-32-3
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| Related CAS # |
Corynoxine B;17391-18-3;Corynoxine hydrochloride
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| PubChem CID |
10475115
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
560.8±50.0 °C at 760 mmHg
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| Melting Point |
166-168ºC
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| Flash Point |
293.0±30.1 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.596
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| Source |
Uncaria rhynchophylla
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| LogP |
3.31
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
663
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| Defined Atom Stereocenter Count |
4
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| SMILES |
O=C1[C@]2(C3=C([H])C([H])=C([H])C([H])=C3N1[H])C([H])([H])C([H])([H])N1C([H])([H])[C@@]([H])(C([H])([H])C([H])([H])[H])[C@@]([H])(/C(=C(/[H])\OC([H])([H])[H])/C(=O)OC([H])([H])[H])C([H])([H])[C@]12[H]
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| InChi Key |
DAXYUDFNWXHGBE-NRAMRBJXSA-N
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| InChi Code |
InChI=1S/C22H28N2O4/c1-4-14-12-24-10-9-22(17-7-5-6-8-18(17)23-21(22)26)19(24)11-15(14)16(13-27-2)20(25)28-3/h5-8,13-15,19H,4,9-12H2,1-3H3,(H,23,26)/b16-13+/t14-,15+,19+,22+/m1/s1
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| Chemical Name |
methyl (E)-2-[(3S,6'S,7'S,8'aS)-6'-ethyl-2-oxospiro[1H-indole-3,1'-3,5,6,7,8,8a-hexahydro-2H-indolizine]-7'-yl]-3-methoxyprop-2-enoate
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| Synonyms |
Corynoxine; 6877-32-3; CHEBI:70072; methyl (E)-2-[(3S,6'S,7'S,8'aS)-6'-ethyl-2-oxospiro[1H-indole-3,1'-3,5,6,7,8,8a-hexahydro-2H-indolizine]-7'-yl]-3-methoxyprop-2-enoate; 1443767-78-9; Methyl (E)-2-((3S,6'S,7'S,8a'S)-6'-ethyl-2-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-3,1'-indolizin]-7'-yl)-3-methoxyacrylate; CHEMBL1909424; DTXSID201318329;
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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) |
DMSO : ≥ 100 mg/mL (~260.10 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.50 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 (6.50 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 30 mg/mL (78.03 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6010 mL | 13.0049 mL | 26.0098 mL | |
| 5 mM | 0.5202 mL | 2.6010 mL | 5.2020 mL | |
| 10 mM | 0.2601 mL | 1.3005 mL | 2.6010 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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