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D-Tetrandrine
Calculate chemical data
1. Reference value for hydrophobic parameter calculation (XlogP): 6.4
2. Number of hydrogen bond donors: 0
3. Number of hydrogen bond acceptors: 8
4. Number of rotatable chemical bonds: 4
5. Number of tautomers: None
6. Topological molecule polarity surface area 61.9
7. Number of heavy atoms: 46
8. Surface charge: 0
9. Complexity: 979
10. Number of isotopic atoms: 0
11. Determine the number of atomic stereocenters: 2
12. Uncertain number of atomic stereocenters: 0
13. Determine the number of chemical bond stereocenters: 0
14. Number of uncertain chemical bond stereocenters: 0
15. Number of covalent bond units: 1 [2]
purpose
1. Hanfangjijia, an immune system disease, can significantly inhibit the development of arthritis and has a stronger effect than aspirin, making it suitable for the treatment of rheumatoid arthritis.
2. Tetracycline not only has a calcium antagonistic effect on cardiovascular diseases, but also inhibits T - and L-type calcium channels in ventricular myocytes. It interacts with M receptors and can block calcium activated potassium channels, making it a treatment for paroxysmal supraventricular tachycardia.
3. Tetracycline in the digestive system plays a certain role in protecting liver cells and preventing liver fibrosis.
4. Hanfangjijia is used for the treatment of ocular inflammation, including uveitis, keratitis, and the resulting retinal lesions.
5. Other tetracyclines have a significant antagonistic effect on the acute nephrotoxicity caused by streptomycin, which can reduce apoptosis and proliferation of renal tubular epithelial cells, protect renal function, and have a protective effect on acute ischemia-reperfusion kidney injury. They can significantly reduce serum creatinine and urea nitrogen levels, improve glomerular filtration rate and renal plasma flow, and delay the development of glomerulosclerosis.
| D-Tetrandrine Basic information |
| Product Name: | D-Tetrandrine |
| Synonyms: | [4aS-(4aR*,16aR*)]-3,4,4a,5,16a,17,18,19-Octahydro-12,21,22,26-tetramethoxy-4,17-dimethyl-16H-1,24:6,9-dietheno-11,15-metheno-2H-pyrido[2',3':17,18][1,11]dioxacycloeicosino[2,3,4-ij]isoquinoline;(S S)-(+)-TETRANDRINE 98%;Conba;Jinake;(1β)-6,6',7,12-tetramethoxy-2,2'-dimethylberbaman;TETRANDRINE, (S,S)-(+)-(RG);Trandrine;16H-1,24:6,9-Dietheno-11,15-metheno-2H-pyrido[2',3':17,18][1,11]dioxacycloeicosino[2,3,4-ij]isoquinoline,3,4,4a,5, 16a,17,18,19-octahydro-12,21,22,26- |
| CAS: | 518-34-3 |
| MF: | C38H42N2O6 |
| MW: | 622.75 |
| EINECS: | 683-095-7 |
| Product Categories: | chemical reagent;pharmaceutical intermediate;phytochemical;reference standards from Chinese medicinal herbs (TCM).;standardized herbal extract;Inhibitors;Alkaloids;reference substance |
| Mol File: | 518-34-3.mol |
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| D-Tetrandrine Chemical Properties |
| Melting point | 219-222 °C(lit.) |
| alpha | 285 º (c=1, CHCl3) |
| Boiling point | 662.81°C (rough estimate) |
| density | 1.1528 (rough estimate) |
| refractive index | 1.5300 (estimate) |
| storage temp. | 2-8°C |
| solubility | Chloroform (Slightly), Methanol (Slightly, Heated) |
| pka | 7.70±0.20(Predicted) |
| form | solid |
| color | Off-White |
| λmax | 283nm(EtOH)(lit.) |
| Merck | 14,9231 |
| LogP | 3.550 (est) |
| Safety Information |
| Hazard Codes | Xi |
| Risk Statements | 36/37/38 |
| Safety Statements | 22-24/25-36-26 |
| WGK Germany | 3 |
| RTECS | XE9350000 |
| HS Code | 29349990 |
| D-Tetrandrine Usage And Synthesis |
| Description | Recently it has been discovered that pronounced drug-dependence and related toxic effects occur in both dogs and rhesus monkeys with this alkaloid on intravenous injection with a dose of 10-150 mg/kg. When rapidly injected, the acute hypotensive effect is very marked and fatal at once. Following drug administration at toxic levels it is found that severe local tissue reaction heptaotoxicity and lymphoid necrosis occurs. At the highest dosage level there is a very definite nephrotoxicity in monkeys and some indications of this in dogs. The evidence available suggests that monkeys are less sensitive to hepatotoxicity with this drug than dogs. |
| Description | Tetrandrine is a bis-benzylisoquinoline alkaloid that has been found in R. stephania roots and has diverse biological activities. It induces autophagy in HeLa, MCF-7, and human foreskin fibroblast (HFF) cells when used at a concentration of 5 μM, an effect that can be reversed by the autophagy inhibitor 3-methyladenine . Tetrandrine inhibits PAF-, thrombin-, collagen-, ADP-, or epinephrine-induced aggregation of isolated human platelets. Priming of mesenchymal stem cells (MSCs) with tetrandrine (5 and 10 μM) reduces TNF-α secretion by RAW 264.7 cells in co-culture. Ear skin transplantation of tetrandrine-primed MSCs decreases ear levels of TNF-α in a mouse model of ear skin inflammation. Tetrandrine (1 mg/kg) increases soleus muscle levels of glucose transporter 4 (Glut4) and decreases plasma glucose levels in a rat model of diabetes induced by streptozotocin . |
| Chemical Properties | White powder |
| Physical properties | Appearance: Needle-like crystals (ether). Solubility: Hardly soluble in water and petroleum ether; soluble in ether and some organic solvents. Melting point: 219– 222?°C. Specific optical rotation: 285° (c?=?1, CHCl3); sensitive to light. |
| History | Recent studies have shown that tetrandrine has a variety of biological effects and very good applicational prospects in the treatment of fibrosis and portal vein and pulmonary hypertension, the regulation of immunologic function, as well as the prevention and treatment of tumor. As early as 1988, tetrandrine has been found having the effect on blocking the Ca2 + channel and was quickly applied into the pharmacological research in the field of cardiovascular and inflammatory diseases. Results from a large number of studies have shown that tetrandrine has good effects on antihypertension, arrhythmia, myocardial ischemia, inflammation, and so on. As a traditional Chinese calcium antagonist, tetrandrine has a broad prospects in clinical applications of cardiovascular and inflammatory diseases.In the early 1990s, the application of tetrandrine was extended. During that time, researchers conducted many studies about its protective effects on liver, lung, and mitochondria, which opened a new field for the treatment of liver disease. In 2002, it was found that tetrandrine can inhibit the synthesis of DNA and RNA in tumor cells, which provided a new method for the treatment of cancer. At present, the prevention and treatment effects of hypertension, fibrosis, digestive diseases, tumors, rheumatoid arthritis, and other autoimmune diseases of tetrandrine have been confirmed, as well as the function of reducing portal hypertension and pulmonary hypertension, while its other pharmacological effects are to be explored in further study. |
| Uses | Tetrandrine is a lipopolysaccharide-induced microglial suppressor, effectively reducing the production of bacterial inflammatory mediators. Anti-inflammatory, anti-nociceptive. Tetrandrine is used in China to treat high blood pressure. This drug blocked the TPC2 calcium channel required for the Ebola infection process (Robert A. Davey et al., Science 2015, DOI: 10.1126/science.1258758). |
| Uses | analgesic, antineoplastic, antihypertensive, lymphotoxin |
| Indications | This product is included in national standards for chemical drugs (Volume 14), British Pharmacopoeia (2017), and European Pharmacopoeia (9.0th ed.). Tetrandrine is used for the treatment of mild to moderate hypertension and hypertensive crisis, rheumatism, silicosis, etc. |
| Definition | ChEBI: (+)-Tetrandrine is a member of isoquinolines and a bisbenzylisoquinoline alkaloid. |
| Pharmacology | Tetrandrine has analgesic, anti-inflammatory, and anti-allergic effects and has a wide range of usage on the cardiovascular system owing to its antihypertensive, anti-myocardial ischemia/reperfusion injury and antiarrhythmic effects. It can inhibit the platelet aggregation induced by ADP, collagen, and arachidonic acid in?vitro and can also restrain the platelet adhesion and thrombosis (in rabbits). Tetrandrine also has anticancer effects. Studies have shown that tetrandrine has a strong inhibitory effect on the DNA and RNA synthesis in L7712 and S180 (cancer cells), which can significantly suppress the growth of Wacker sarcoma W256. Besides that, tetrandrine has the ability to relax the striated muscle, and its methyl iodide or methyl bromide derivatives can also affect the muscles. Notably, tetrandrine can prevent silicosis and has a preferable outcome on the clinical treatment of such disease. In addition, tetrandrine also owns antipyretic, diuretic, and antiallergic shock effects. |
| Clinical Use | Tetrandrine is used for the treatment of hypertension, angina, termination of paroxysmal supraventricular tachycardia, pulmonary fibrosis, and other diseases in clinical application, and it also has strong antitumor effects. Tetrandrine was also approved for lowering blood glucose and free radical damage; its treatment effect on silicosis is significant and superior to conventional immunosuppressive and cytotoxic drugs. |
| References | Gralla, Coleman, Jonas, Cancer Chemother. Rep., Pt. 3, 5(1), 79 (1974) |
1. Hanfangjijia, an immune system disease, can significantly inhibit the development of arthritis and has a stronger effect than aspirin, making it suitable for the treatment of rheumatoid arthritis.
2. Tetracycline not only has a calcium antagonistic effect on cardiovascular diseases, but also inhibits T - and L-type calcium channels in ventricular myocytes. It interacts with M receptors and can block calcium activated potassium channels, making it a treatment for paroxysmal supraventricular tachycardia.
3. Tetracycline in the digestive system plays a certain role in protecting liver cells and preventing liver fibrosis.
4. Hanfangjijia is used for the treatment of ocular inflammation, including uveitis, keratitis, and the resulting retinal lesions.
5. Other tetracyclines have a significant antagonistic effect on the acute nephrotoxicity caused by streptomycin, which can reduce apoptosis and proliferation of renal tubular epithelial cells, protect renal function, and have a protective effect on acute ischemia-reperfusion kidney injury. They can significantly reduce serum creatinine and urea nitrogen levels, improve glomerular filtration rate and renal plasma flow, and delay the development of glomerulosclerosis.
pharmacological action
This product has a significant antihypertensive effect on both normal and hypertensive animals. The antihypertensive effect is mainly due to the dilation of resistance vessels, which reduces peripheral resistance. The initial hypotension may be related to its inhibition of left ventricular systolic function. Its principle of action is also caused by calcium antagonism, which can directly relax vascular smooth muscle. It has negative inotropic effects, negative frequency, and negative conduction effects on the heart, reduces oxygen consumption, prolongs myocardial refractory period and atrioventricular conduction, and is also related to its calcium antagonistic effect [4].
Anti allergic effect
Bian Rulian and others have shown through animal experiments that Hanfangjijia can counteract the action and release of allergic mediators. It exhibits inhibitory effects on guinea pig asthma induced by histamine and acetylcholine, as well as spasmodic contraction of isolated ileum smooth muscle. Its effect is dose-dependent, and both 32 and 48ug/ml of medication have significant inhibitory effects on the increase of 5-hydroxytryptamine in rat skin vascular permeability. In addition, it also has a significant inhibitory effect on the release of histamine from rat peritoneal cells induced by dextran. Based on the above results, it is believed that Hanfangjijia is both an allergy mediator antagonist and an allergy mediator blocker, with reliable antagonistic and therapeutic effects on allergic reactions [5].
The preventive and therapeutic effects on liver fibrosis
Tet can significantly reduce serum type III procollagen, serum and liver HA, and decrease collagen deposition in the liver, indicating that Tet can be used to treat liver fibrosis in chronic liver disease.
The effect on hypoxic pulmonary hypertension
In dogs with hypoxic pulmonary hypertension, Tet can significantly reduce elevated pulmonary arterial pressure and pulmonary vascular resistance, and improve CO and oxygen transport capacity, while having no significant effect on systemic circulation and blood gas levels. Tet mainly inhibits the proliferation of collagen fibers in pulmonary arterioles and suppresses the thickening and muscle formation of pulmonary blood vessels caused by hypoxia, significantly reducing the narrowing of pulmonary arterioles and lowering pulmonary artery pressure, thereby partially inhibiting the development of pulmonary arterial hypertension.
The therapeutic effect on silicosis
On the basis of preparing Pro α 1 (I) and Pro α 1 (III) collagen cDNA probes, spot and in situ molecular hybridization techniques were used to observe the effect of Tet on mRNA expression of type I and III collagen genes in silicosis tissues. It is believed that the accumulation of collagen in silicosis tissue is caused by the increased expression of collagen genes induced by quartz dust. TET can directly or indirectly inhibit the transcription of collagen genes, thereby reducing the synthesis of collagen in the diseased tissue.
The therapeutic effect on hypertension
Tet has a significant antihypertensive effect and can significantly reduce the levels of lipid peroxides (LPO) and thromboxane (TXB2) in the blood of hypertensive patients, significantly increase the levels of SOD and prostacyclin (6-keto-PGF1 α), and reduce the TXB2/6-keto-PGF1 α ratio. The antihypertensive mechanism of Hanfangjijia is caused by blocking voltage dependent calcium channels in the myocardium and vascular smooth muscle, as well as increasing the level of 6-keto-PGF1 α.
The therapeutic effect on angina pectoris
Tet has a significant effect on reducing myocardial oxygen consumption index, with no significant difference compared to n . Therefore, Tet is an effective drug for treating angina pectoris, preventing myocardial infarction, and reducing myocardial ischemia-reperfusion injury.
The therapeutic effect on ophthalmic diseases
(1) The therapeutic effect of Tet on experimental uveitis: Tet inhibits experimental uveitis, which is not only related to its anti-inflammatory effect, but also to its inhibition of humoral and cellular immune responses.
(2) The effect on hyperpigmentation membrane inflammation: The mechanism of Tet's anti hyperpigmentation membrane inflammation may be related to its ability to reduce intracellular levels.
(3) The effect of Tet on retinoblastoma: At low doses (0 At a concentration of 1 μ g/mL, although there was no direct inhibitory effect on Rb44 cells, it significantly increased the killing effect of radiation on Rb44 cells. As the drug concentration increases, the cell killing rate increases, and there is no significant difference in administration before and after radiation. Tet mainly increases the efficacy of radiotherapy by inhibiting the repair of potentially lethal cell damage.
Enhance the efficacy of anticancer drugs
MTT assay was used to detect the toxic effects of d (DNR) and homosophocarpine (HHT) on leukemia cells, and the effect of Tet on the cytotoxicity of the two chemotherapy drugs was observed. As a result, Tet can significantly enhance the toxic effects of DNR and HHT on drug-resistant cells (K562/AO2, K562/HHT). [3]
Other functions
Someone observed the effect of Hanfangjijia on myocardial infarction through animal experiments and found that this drug can reduce the size of myocardial infarction. The CPK enzyme released by the myocardium was lower than that in the control group. There are also reports that this drug has a good muscle relaxation effect, and its mechanism may be related to blocking the motor nerve source - the muscle spindle system. In addition, Hanfangjijia has good therapeutic effects on leukemia, neuropathic pain, arrhythmia and other diseases.
Usage and dosage
(1) Hypertension: This medication can dilate peripheral blood vessels, especially resistance vessels, and has a significant and long-lasting antihypertensive effect, which is effective for all types and stages of hypertension. Mild to moderate hypertension, take orally 0.19 times a day, 3 times a day; Severe hypertension and hypertensive crisis can be treated by intravenous injection, with a dosage of 0.12-0.189 per session, diluted with physiological saline twice a day. Generally, it takes effect 1 minute after intravenous injection. The effect reaches its peak in 10 minutes and can last for 1.5 to 2 hours.
(2) Arrhythmia: This drug is a calcium antagonist that can prevent calcium ions from entering myocardial cells and has an anti arrhythmic effect similar to v . Treat paroxysmal supraventricular tachycardia, 0.125-0.189 per session, with 30ml of physiological saline or 10% glucose solution added intravenously.
(3) Angina pectoris: This medication can reduce myocardial contractility, dilate coronary arteries, increase coronary blood flow, and thus increase myocardial oxygen supply; At the same time, it can dilate surrounding blood vessels, reduce the pre - and post cardiac load, and lower myocardial oxygen consumption, thus treating angina pectoris. Add 0.12-0.18 to 20ml of physiological saline for intravenous injection twice a day for a total of 2 weeks, and use low-dose aspirin in combination. Suitable for exertional angina.
(4) Cirrhotic portal hypertension and esophageal variceal bleeding: This drug is a calcium antagonist that can relax vascular smooth muscle, reduce resistance in peripheral blood vessels and portal blood vessels inside and outside the liver, thereby lowering portal pressure and esophageal variceal pressure. After one week of medication, esophageal variceal pressure significantly decreases and stabilizes after three months, thus preventing and treating this disease. Oral administration of 50rag each time, 3 times a day, p l 151 times 20mg each time, 3 times a day. Long term oral administration of Hanfangjijia not only continuously reduces portal pressure, but also improves liver and kidney function.
(5) Rheumatoid pain, joint pain, neuralgia, muscle pain: 20mg of Hanfangjisu orally each time, 3 times a day; Or intramuscular injection of 30mg each time, 1 day. Twice.
(6) Antiallergy: Hanfangjijia is both an allergy neurotransmitter antagonist and an allergy neurotransmitter blocker, so it can be used to treat allergic diseases.
(7) Antitumor: Tetracycline 20-100mg per dose, 3 times a day, when used in combination with other anti-tumor drugs, can enhance the therapeutic effect on lung cancer and leukemia.
(8) Silicosis: Tetracycline can inhibit the formation of collagen fibers in silicosis, relieve vascular spasm, improve local circulation, and accelerate the absorption of lesions, so it can be used as an adjuvant treatment for silicosis. Take 0.1g orally three times a day, with one course of treatment every six months.
[1]. Wang G, et al. Tetrandrine blocks a slow, large-conductance, Ca(2+)-activated potassium channel besides inhibiting a non-inactivating Ca2+ current in isolated nerve terminals of the rat neurohypophysis. Pflugers Arch. 1992 Sep;421(6):558-65. [Content Brief] [2]. Zhang Z, et al. The plant alkaloid tetrandrine inhibits metastasis via autophagy-dependent Wnt/β-catenin and metastatic tumor antigen 1 signaling in human liver cancer cells. J Exp Clin Cancer Res. 2018 Jan 15;37(1):7. [Content Brief]
