Rhein | 478-43-3, Rhein Formula

Description

Rhein is a lipophilic anthraquinone extensively found in medicinal herbs, and has many pharmacological effects, including epatoprotective, nephroprotective, anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. IC50 value:Target:In vitro: Rhein (0.1 and 1 mg/mL) evidently suppressed cell proliferation and mitogen-activated protein (MAP) kinase activation in human colon adenocarcinoma cells (Caco-2) but significantly lessened H2O2-induced DNA damage and the elevated MD

Rhein appears as yellow needles (from methanol) or yellow-brown powder. (NTP, 1992)|Solid

Rhein appears as yellow needles (from methanol) or yellow-brown powder. (NTP, 1992)|Rhein is a dihydroxyanthraquinone.|Rhein is an anthraquinone metabolite of rheinanthrone and senna glycoside is present in many medicinal plants including Rheum palmatum, Cassia tora, Polygonum multiflorum, and Aloe barbadensis. It is known to have hepatoprotective, nephroprotective, anti-cancer, anti-inflammatory, and several other protective effects.

Rhein Basic Attributes

Molecular Weight：

284.22

Exact Mass：

284.22

EC Number：

207-521-4

UNII：

YM64C2P6UX

NSC Number：

38629

DSSTox ID：

DTXSID4026000

HScode：

2918990090

Characteristics

PSA：

112

XLogP3：

2.2

Appearance：

Rhein appears as yellow needles (from methanol) or yellow-brown powder. (NTP, 1992)

Density：

1.7±0.1 g/cm3

Melting Point：

321-321.5 °C (sublm)

Boiling Point：

Sublimes (NTP, 1992)

Flash Point：

329.4±26.6 °C

Refractive Index：

1.761

Water Solubility：

H2O: <0.1 g/100 mL at 17 ºC

Storage Conditions：

2-8°C

Air and Water Reactions：

Insoluble in water.

Reactive Group：

Acids, Carboxylic

Reactivity Profile：

RHEIN forms a red potassium salt and a pink sodium salt.

Safety Information

Transport codes：

NONH for all modes of transport

wgk germany：

2

hazard class code：

36/37/38

safety instructions：

26-37/39

RTECS Number：

CA9516000

Marks：

Xi

Precautionary statement(s)：

P305 + P351 + P338

Hazard Statements：

H315-H319-H335

Fire Hazards：

Flash point data for this chemical are not available; however, it is probably combustible. (NTP, 1992)

Fire Fighting：

Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

Nonfire Spill Response：

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material under ambient temperatures. (NTP, 1992)

Personal Protective Equipment：

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Toxicity

Toxicity Summary：

Oral LD50 of >5000mg/kg in mice [MSDS].

Protein Binding：

99% bound to plasma proteins.

Drug Information

Drug Indication：

No approved indication.

Pharmacology：

**Liver: **Reverses animal models of non-alcoholic fatty liver disease by lowering liver lipids and reducing inflammation. Also reverses and prevents fibrosis in liver injury. **Kidney: **Protects against fibrosis in nephropathy models and improves epithelial tight junction function. **Bone and joint:** Decreases inflammation and cartilage destruction and also corrects altered osteoblast acitivity. **Lipid lowering and anti-obesity:** Reduces body weight and fat content, and lowers high density lipoprotein and low density lipoprotein. May prevent adipocyte differentiation. **Anti-oxidant/Pro-oxidant**: Reduces levels of reactive oxygen species (ROS) at concentrations of about 2-16 microM but induces the generation of ROS at concentrations of 50 microM and above. **Anti-cancer:** Rhein has been observed to produce DNA damage and suppress DNA repair in cancer cells. It induces apoptosis via ER stress, calcium, and mitochondria mediated pathways. Rhein also prevents cancer cell invasion into systemic circulation by preventing angiogenesis and breakdown of the extracellular matrix. Finally, rhein suppresses the activation of several tumor promoting signalling pathways. **Anti-inflammatory: ** Suppresses the production of pro-inflammatory cytokines such as interleukin-1beta and interleukin-6. **Anti-diabetic: **Lowers plasma glucose and increases survival of islet beta cells in type 2 diabetes mellitus models. **Anti-microbial:** Inhibits arylamine N-acteyltransferase and cell growth in Helicobacter pylori. Rhien also appears to be effective against many genotypes of Staphylococcus aureus. **Anti-allergenic:** Inhibits production of leukotrienes and the release of histamine from mast cells.

MeSH：

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

Absorption：

Tmax of 1.6-2.6 hours.|37% is excreted in urine and 53% in feces as estimated in rats.|15-60L.|Total CL is 1.5 L/h and renal CL is 0.1 L/h.

Metabolism/Metabolites：

Metabolized primarily to rhein glucuronide and rhien sulfate.

Biological Half-Life：

4-10h.

Mechanism of Action：

**Liver: **The reversal of non-alcoholic fatty liver disease stems from rhien's lipid lowering and anti-obesity actions which result in an overall decrease in body weight, high density lipoprotein, and low density lipoprotein as well as its anti-inflammatory action. The reversal of hepatic fibrosis is thought to be due to rhien's anti-inflammatory and anti-oxidant action which suppresses the pro-fibrotic signalling from macrophages and further damage from reactive oxygen species respectively. Ultimately this results in reduced expression of alpha-smooth muscle actin (Alpha-SMA) which is indicative of decreased hepatic stellate cell and myofibroblast activation. Rhein also appears to suppress the expression of transforming growth factor-Beta (TGF-Beta) **Kidney: **The protection from fibrosis in the kidney also appears to stem from rhien's anti-inflammatory action resulting in less inflammatory cell infiltration along with suppression of alpha-SMA and fibronectin expression. These indicate a reduction in the activation of interstitial fibroblasts which are responsible for excess production of extracellular matrix components. Rhien may also suppress TGF-beta expression in the kidney. The anti-fibrotic mechanism of rhien may involve the upregulation of bone morphogenetic protein 7 and hepatic growth factor. In diabetic nephropathy rhein appears to suppress the expression of integrin-linked kinase leading to a reduction in the matrix metalloproteinase-9/tissue inhibitor of matrix metalloproteinase-1 ratio. The improvement of epithelial tight junction function seems to involve upregulation of zona occludins protein-1 and occludin expression. **Bone and joint:**Rhein reduces cartilage destruction by decreasing expression of matrix metalloproteinase (MMP)-1 and -3 as well as upregulating tissue inhibitor of matrix metalloproteinases which serve to reduce the activity of several MMPs. The anti-inflammatory action of rhein reduces the level of interleukin-1beta activity which plays a large role in reduction of extracellular matrix production, MMP activity, and continued inflammation. Rhein reduces abnormal osteoblast synthetic activity through an unknown mechanism. **Lipid lowering and anti-obesity: **Rhein is known to bind and inhibit liver X receptor alpha and beta with Kd values of 46.7 microM and 31.97 microM respectively. This decreases the expression of genes such as that of sterol regulatory element binding transcription factor 1 (SREBP1c) and its downstream genes for fatty acid synthase (FAS), steroyl-coenzyme A desaturase 1 (SCD1), and acetyl CoA carboxylase 1 (ACC1). SREBP1c, FAS, SCD1, and ACC1 are all involved in adipogenesis and their suppression results in less fat content. The genes for ABCA1 and ABCG1 are also suppressed. These correspond to cholesterol efflux trasporters and likely explain the reductiion in HDL and LDL seen with rhein. The inhibition of LXR by rhien relieves the inhibition on uncoupling protein 1 expression in brown adipose tissue. The result of this is increased thermogenesis which likely plays a role in the reduction of body weight produced by rhien. Additionally, rhein may downregulate peroxisome proliferator-receptor gamma and its downstream genes to inhibit adipocyte differentiation. **Anti-oxidant/Pro-oxidant:** The antoxidant mechanism is unknown. The pro-oxidant action of rhien may involve the inhibition of mitochondrial respiratory complex 1 and subsequent facilitation of NADH and NADPH dependent lipid peroxidation. **Anti-cancer:** The exact mechanism of rhein's ability to damage DNA and supress the expression of DNA repair enzymes ADR and MGMT is unknown. The mechanism through which rhien induces ER stress is unknown but likely involves its pro-oxidant properties. Rhein has been observed to produce increases in cytosolic calcium, reductions in mitochondrial membrane potential, and upregulation of pro-apoptotic proteins as well as leakage of cytochrome C which would induce apoptosis via the intrinsic pathway. The reduction of matrix metalloproteinase-9 serves to prevent extra cellular matrix breakdown by cancer cells and hinders their invasion into surrounding tissue. Rhein also decreases vascular endothelial growth factor expression through an unknown mechanism to prevent cancer cells from stimulating agiogenesis. Rhein reduces the activity of the nuclear factor kappa (NFkappaB) pathway by preventing the destruction of IKBalpha. The activity of the phosphoinositol 3-kinase/Akt pathway is also reduced by rhien. Rhein's inhibition of the mitogen-activated protein kinase pathways (particularly those involving extracellular signal regulated kinase) appears to follow a U-shaped dose response curve. ERK phosphorylation is inhibited at low concentrations of around 3microM but activated at higher concentrations of around 30microM. Furthermore, ERK phosporylation is again inhibited at extremely high concentrations in excess of 100 microM. The suppression of these three pathways is likely involved in the anti-proliferative effects of rhein. **Anti-inflammatory:** The mechanism of rhein's anti-inflammatory effect likely involves its inhibition of the NFkappa B pathway which plays a role in the production of many pro-inflammatory cytokines. Rhein's anti-oxidant activity may also play a role in preventing damage during inflammation. **Anti-diabetic:** Rhein is thought to increase islet beta cell survival by suppressing the expression of dynamin-related protein 1 and thereby preventing mitochondrial fission. Rhein's anti-oxidant properties are also thought to play a role in protecting islet beta cells. The reduction in plasma glucose is likely due to increased survival of islet beta cells and subsequent increases in insulin secretion. Rhein's anti-inflammatory action may also serve to reduce insulin resistance. **Anti-microbial:** Rhien inhibits H. pylori arylamine N-acetyltransferase in a dose dependent manner. The mechanism of rhein's anti-microbial effect on H. pylori and S. aureus are unknown. **Anti-allergenic:** Rhien inhibits 5-lipoxygenase with an IC50 of 13.7microM. Rhien also inhibits mast cell degranulation although the specific mechanism is unknown.

Health Hazards：

SYMPTOMS: This chemical is an irritant. ACUTE/CHRONIC HAZARDS: This compound may cause irritation. (NTP, 1992)

First Aid：

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

MeSH Entry Terms：

1,8-dihydroxy-3-carboxyl-9,10-anthraquinone

Rhein Use and Manufacturing

Methods of Manufacturing

Diacerein (150 g, 0.41 mol) was stirred in 10percent (w/w) Na2CO3 solution (4 L) resulting in a red mixture. After stirring overnight the mixture was acidified to pH2 with 5M HCI solution to give a yellow precipitate. This was filtered and dried in a vac-oven at 50 °C (168 g, >100percent). 'H NMR (400 MHz, DMSO): 7.40 (1H, d J=8 Hz), 7.71-7. 76 (2H, m), 7.82 (1 H, t J=8 Hz), 8.11 (1 H, d J=1. 6 Hz).Diacerein (0.012 M, 4.5 g) was dispersed in 80 ml of 10percent aqueous sodium hydroxide solution. The solution was heated on a boiling water bath for 30 min and then poured into 120 mL of 10percent HCl. Rhein was obtained in the form of yellow flakes which were recrystallized twice with pyridine. Rhein. mp 318–319 °C, R6g of chrysophanol was added to 150ml of mixed solution of anhydride and pyridine (1:1), overnight at room temperature. The reaction mixture was put into cold water for crystallization , then filtered and dried, was put into 300 ml of acetic anhydride and glacial acetic acid mixture (1:1). Chromium trioxide solution was dropped at 45°C, and then was stirred for 8 hours at 65°C. The reaction mixture was put into water, crystallized, filtered, added into 1000 ml of 25percent sodium carbonate solution, extracted by chloroform for three times. Sodium carbonate solution was heated to boiling, cooled, added into hydrochloric acid for acidification. Until a large amount of gas is drained off, the solution was heated to boiling for 1 hour, cooled, crystallized, filtered and washed by water, recrystallized with glacial acetic acid, thus 2g of rhein was obtained. The product yield was above 98percent.6 g of chrysophanol was added to 150 ml of mixed solution of anhydride and pyridine (1:1), overnight at room temperature. The reaction mixture was put into cold water for crystallization, then filtered and dried, was put into 300 ml of acetic anhydride and glacial acetic acid mixture (1:1). Chromium trioxide solution was dropped at 45° C., and then was stirred for 8 hours at 65° C. The reaction mixture was put into water, crystallized, filtered, added into 1000 ml of 25percent sodium carbonate solution, extracted by chloroform for three times. Sodium carbonate solution was heated to boiling, cooled, added into hydrochloric acid for acidification. Until a large amount of gas is drained off, the solution was heated to boiling for 1 hour, cooled, crystallized, filtered and washed by water, recrystallized with glacial acetic acid, thus 2 g of rhein was obtained. The product yield was above 98percent.Oxidizing medium was prepared by dissolving sodium nitrite (255 g) in sulphuric acid (1.2 I). The oxidizing medium was heated to 120A mixture of compound A1 (1 mmol, 0.27 g), PCC (2 mmol, 0.45 g), DMF (100 ml) and 2 mL of water were stirred at room temperature for 24 h, monitored by TLC. After the completion of reaction, 100 mL of ice water was added under stirring to afford orange precipitate. The orange precipitate was filtered, washed and dried. Recrystallization of the orange precipitate from ethanol gave compound B7 as brown acicular crystals, yield 62percent; mp 310–313 °C; IR νA mixture of compound 1 (1 mmol, 0.27 g), PCC (2 mmol, 0.45 g), DMF (100 ml) and 2 mL of water were stirred at room temperature for 24 h, monitored by TLC. 5g of raw Diacerein containing about 300 ppm of Aloemodine derivatives is dissolved in 40ml of methanol and, under magnetic agitation, 40ml of water and 5g of KOH are added. In the presence of a condenser, heating to 60-65°C is performed for 30 minutes; after this period, 35ml of 6N HCL are added; dilution with about 35ml of water is performed and the solution is boiled for about 30 minutes. After cooling, the suspension is filtered under vacuum, the residue washed with water and dried under vacuum at constant weight. 4.5g of Rhein are thus obtained. 2g of Rhein thus obtained are transformed into the corresponding potassium salt as described for the Diacerein in Example 1. 2g of Potassium Salt of Rhein are dissolved in 200ml of water (final pH of the solution 6.2). This solution, after filtration under vacuum, is percolated through a 7.5cm-diameter 10cm-high column, packed with 180g of Diaion SP207.(R). (Mitsubishi). Washing with a volume corresponding to the volume of the column of acetone and then elution with a water/ethanol mixture are performed until the complete elution of the Rhein. 4 elution steps are performed: the two first elutions are performed by using ethanol/water mixture 20percent/80percent and the two last elutions are performed by using ethanol/water mixture 60percent/40percent. The fraction containing the Rhein is then brought to pH 4.5-5 with 10percent sulphuric acid. The suspension is cooled to 5-10°C, the precipitate recovered by filtration under vacuum, washed with cold water and dried under vacuum. The precipitate, after drying, is acetylated using pyridine and acetic anhydride in a ratio of 1:1 (alternatively, other conventional acetylating agents may be used). After drying under vacuum, 1.5g of Diacerein are obtained which under HPLC analysis are shown to be free of impurities. The yield of the process, from the Potassium Salt of Rhein, is 87percent.In a three-necked flask equipped with a magnetic stirrer and reflux condenser, intermediate product IV and toluene were added, Heating to reflux, dropping 30percent hydrobromic acid, dropping complete, keep reflux for 10 hours, vacuum distillation of toluene, filtration, filter cake alkali solution, filter to remove insoluble impurities, the filtrate and hydrochloric acid precipitation products, Filtration, filter cake drying to rhein, the yield of 56percent.DMSO (300 g) was added to the reactor.Formula II (33.5 g, 125 mmol), Stir for 30 minutes, The internal temperature is controlled at 5 °C.Rapid dropwise addition of sodium dihydrogen phosphate solution(anhydrous sodium dihydrogen phosphate 45g, 0.375mol, 28.9g purified water), Control the dropping temperature below 20 °C, Sodium chlorite solution (sodium chlorite 45.2 g, 0.5 mol, 180 g water) was added dropwise.Control the dropping temperature below 10 °C, After the addition is completed, the temperature is raised to 25 ° C.Stir for 4.5 hours, HPLC detection, The residual of 3.4percent of formula II is complete.Cool down to 15 ° C, Quickly add 550mL of water, The internal temperature does not exceed 40 °C during the addition process.After the addition is completed, Stir for 2 hours, The reaction solution is filtered, The filter cake ethanol (210g) is beaten once, Drying at 60 ° C for 8 hours, 15.5 g of a yellow solid were obtained.98.3percent purity, The calculated yield is based on aloe-emodin.The yield was 82.9percent.

Uses

Found in the free state and as glucoside in Rheum spp, Polygonaceae (rhubarb) and in Senna leaves.A potential antioxidant resource: endophytic fungi from medicinal plants.

Use Classification：

Polyketides [PK] -> Aromatic polyketides [PK13] -> Anthracenes and phenanthrenes [PK1304]

Computed Properties

Molecular Weight:284.22
XLogP3:2.2
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:284.03208797
Monoisotopic Mass:284.03208797
Topological Polar Surface Area:112
Heavy Atom Count:21
Complexity:487
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

Drug Function and Efficacy

Regulates gut microbiota to achieve laxative and antibacterial dual effects

This ingredient has been used in drugs with the following functions (note: it does not mean that the ingredient itself has the following health functions)

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