35354-74-6 Usage
Uses
Used in Pharmaceutical Industry:
Honokiol is used as a therapeutic agent for its antiangiogenic, anti-inflammatory, and antitumor properties in preclinical models, exhibiting minimal toxicity. It has been shown to inhibit the bone metastatic growth of human prostate cancer cells.
Used in Antioxidant Applications:
Honokiol is utilized as an antioxidant to study its cytoprotective role in human ovarian cancer cells (SKOV-3) and Chinese hamster ovary cells (CHOK1), as well as to explore its effects on oxidative stress and mitochondrial dysfunction via a SIRT3-dependent manner.
Used in Neurological Research:
Honokiol is employed for intracerebroventricular (ICV) cannulation to study its potential effects on neurological conditions and processes.
Used in Biochemical Research:
Honokiol is used to study its effects on plasmid hSirt3102-399 deacetylation activity, providing insights into its potential role in regulating cellular processes and its therapeutic applications.
Basic Information
Honokiol is the isomer of magnolol, being the dimer polymerized by the side chain of phenylpropane and another phenylpropyl benzene nucleus, called the neolignan. It was mainly found in the Lauraceae plants, being the active ingredients of antibacterial, anti-inflammatory of the traditional Chinese medicine Magnolia.
Honokiol and magnolol appear as colorless needle crystal, being insoluble in water, soluble in chloroform, benzene, ethanol and caustic alkali. The physical and chemical constants were honokiol, mp: 102 ° C, UV λmaxEtOHnm (ε): 294 (8200); and honokiol, mp: 87.5 ° C, UV λmaxEtOHnm (ε): 294 nm (8200).
Figure 1 shows the chemical formula of magnolol and honokiol.
Magnolia is a commonly used Chinese medicine. First contained in the "Shen Nong's Herbal Classic", as the goods.
Magnolia officinalis extract is a product derived from dried root bark, bark or shoots of Magnolia officinalis, etc. The product extracts usually standardize the contents of magnolol and honokiol.
Distribution
There were about 90 species of Magnoliaceae Magnolia plants around the world. There are about 30 species, of which there are about 20 kinds of medicinal value. Magnolia was born at fertile-soil, soil-deep sunny hillside, forest edge of an altitude of 300~1700 m.
Magnolia is mainly distributed in western Hubei, southern Sichuan, southern Shaanxi and southern Gansu. Magnolia is mainly distributed in Jiangxi, Anhui, Zhejiang, Fujian, Hunan, Guangxi and northern Guangdong. Magnolia officinalis has a large area of artificial cultivation.
Main Ingredients
Magnolia bark contains magnolol, and honokiol, isomagnolol and other ingredients. It has been isolated of the trihydroxy honokiol, degausated trihydroxy glibenol, trihydroxy thick aldehydes, poly honokiol a, c. from the ethyl acetate extract of magnolia. Bark contains about 1% volatile oil, which mainly contains β-oleyl alcohol; still contain α-pinene, β-pinene and limonene. The bark also contains lignin. Its leaves also contain magnolol and honokiol.
[Harvest and Processing] On April to June, pick off the dried bark growing for more than 15 years, and put into the boiling water for micro-cook, and put into the soil pits, covered with grass to "sweat". When the water comes from the internal seepage and the inner surface becomes purple brown or tan, further steamed soft, remove out, roll into tube-like, and dry it Root bark and branch, after being peel down, can be directly dried.
Figure 2 is Magnolia.
Extraction method
1. Magnolia extract (flow extract) production process
Take magnolia and crush it, infiltrate with ethanol for 12 hours, and place it into the percolation tube; apply 12 times the amount of ethanol for percolation; collect the percolation fluid; decompress and completely recycle the ethanol to obtain the flow extract with a yield of about 9% and the content of solid content being 85.0%. The product contains more than 11.0% of magnolol and over 5.0% honokiol.
2. Magnolol, and Honokiol extraction and separation
Take the thick and dry powder of magnolia officinalis, add 1/5 amount (W / W) of lime powder, mix well; apply 15-20 times the amount of distilled water for percolation; the percolation fluid plus hydrochloric acid was adjusted to the pH value of 2 to 3, Stand still. The precipitate was collected and washed with distilled water until the pH of the precipitate was 6 to 7. After drying, alumina (1: 10) was added and homogenized, and the extractant was extracted with cyclohexane. The cyclohexane was concentrated and allowed to cool to precipitate out the white crystals; filter to give crystals and mother liquor. Crystal is recrystallized from cyclohexane, i.e., honokiol. The mother liquor is concentrated to crystallize, further re-crystallized by cyclohexane to give colorless flaky crystals, which are magnolol crystals. The yield of honokiol was 85%, and the yield of honokiol was 74%.
Pharmacological effects
1. The role of anti-pathogenic microorganisms
Magnolia has inhibitory effect against Staphylococcus aureus, Streptococcus cholerae, Escherichia coli, Proteus, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Proteus Bacilli subtilis, diphtheria bacillus and other Gram-negative bacteria, of which it has the strongest inhibitory effect on Staphylococcus aureus. At the concentration of 15%, it has inhibitory effect against the skin fungi of experimental animals including small spore ringworm, genital trichophyton and Trichophyton rubrum. Magnolia decoctum has some effect on the improvement of parenchymal pathological damage in mice with experimental viral hepatitis. Magnolol had significant antibacterial activity against Gram-positive bacteria and acid-resistant bacteria. Magnolol had significant anti-caries effect and had a minimum inhibitory concentration of 6.3 μg / ml, and its antibacterial activity was stronger than that of typical antimicrobial alkaloids Berberine (MIC: 50 μg / ml).
The saturated aqueous solution of the volatile oil of magnesium and Magnolia officinalis has certain antibacterial effect against Staphylococcus aureus, sarcina and Bacillus subtilis.
2. The role of the cardiovascular system
Magnolol and honokiol inhibit the formation of thromboxane B2 in various cases, and the increase in intracellular Ca2 + caused by arachidonic acid or collagen is also inhibited by both of them.
Honokiol can inhibit CaM to stimulate the activity of the cyclic nucleotide phosphodiesterase. Honokiol, in the presence of Ca2 +, can bind to CaM, thereby antagonizing its activation of phosphodiesterase. In addition, honokiol has a stimulating effect on the basal activity of CaM-dependent phosphodiesterase.
3. Antitumor effect
Magnolol and its hydroxymethyl derivatives have a significant inhibitory effect against the second stage of mice skin tumors. The three extraction components of Magnolia officinalis, lignans, magnolol, and honokiol and monoterpene magnolol are the antagonist of the Epstein -Barr virus early antigen activation effect induced by the 12-O-tetradecanoyl phorbol-13-acetate (TPA).
The methanol extract of Magnolia officinalis and magnolol has significant inhibitory effect on the mouse skin tumors induced by the two-stage in vivo carcinogenicity.
The toxicity of Magnolia officinalis is relatively small. Magnolia decoction: LD50 of mice subjecting to intraperitoneal injection was 6.12 ± 0.038g / kg; the LD50 for lambda alkaloids subjecting to intraperitoneal injection was 45.55mg / kg. The MLD for cat subjecting to intravenous infusion was 4.25 ± 1.25g / kg. Under the general muscle relaxation dose, the ECG of the experimental animal is not affected. Large doses can cause respiratory depression and death.
Pharmacokinetics 14C isotope tracer studies have shown that magnolol has rapid oral administration for rat; after 15 minutes, the plasma concentration reaches the peak. After oral administration of 1 hour, liver, kidney as well as stomach contains significant radioactive. The same results were obtained in 8 hours after 1 hour, and significant radioactivity was observed in the intestine.
Magnolol, after subjecting intravenous infusion, is distributed in the brain, spinal cord, liver, stomach, intestine, kidney, lung, heart, muscle and other tissues. Intravenous administration can cause significant blacking in lungs after 1 hour. This is due to that the micro-particles of the magnolol suspension are caught in the lungs. Magnolol is mainly distributed in the liver with remarkable blacking also being found in the intestine. In other tissues, the radioactivity is basically uniform distributed. In the brain, it is also seen of a similar general distribution as muscle. 8 hours later, liver, lung and kidney still contain a number of radioactivities. Remarkable blacking could be seen in the intestine, and so for stomach.
Based on the analysis of mass spectrometry, the main metabolites of Magnolol, which excreted in the fecal matter for the rats is M1, M2, M3, M4, M5, M6 and their glucuronic acid compounds and sulfates.
Clinical efficacy
Magnolia can be used to treat acute enteritis, bacterial or amoebic dysentery and chronic gastritis.
Application overview
Magnolia is a kind of traditional Chinese medicine, and has been included in many kinds of prescriptions. In recent years, domestic and foreign scholars, through the in-depth study of the active ingredients, pharmacodynamics and clinical pharmacy of Magnolia officinalis, have developed the Magnolia caries toothpaste, antibacterial “chewing gum” made of Magnolia extract that have been already marketed.
History
In 1930, magnolol was first isolated from the bark of Cortex magnoliae officinalis
in China by Japanese Sugii, and it was also isolated from Cortex magnoliae officinalis
in Japan. In 1973, magnolol and its isomers honokiol were isolated from Cortex magnoliae officinalis in China and Japan by Japanese Fujita. The drug research and development of magnolol and honokiol remain in pharmacological activity and preclinical research. Kyung Hee University from Korea declared a preclinical study in 2003, in which allergy, anxiety, angina, and heart failure are indications for honokiol.
Indications
These compounds are recorded in the British Pharmacopoeia (2017) and European
Pharmacopoeia (8.7th ed.). They are mainly used as antibacterial and antifungal
agents.
Biochem/physiol Actions
Honokiol is a natural biphenyl neolignan from magnolia extract. It is antiangiogenic, antitumor, and anxiolytic.
Pharmacology
Magnolol and honokiol have the pharmacological effects of prolonging central
muscle relaxation, inhibition of the central nervous, anti-inflammatory, antibacterial,
antimicrobial, antiulcer, antioxidant, antitumor, hormone regulation, and antidiabetes
.
Check Digit Verification of cas no
The CAS Registry Mumber 35354-74-6 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 3,5,3,5 and 4 respectively; the second part has 2 digits, 7 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 35354-74:
(7*3)+(6*5)+(5*3)+(4*5)+(3*4)+(2*7)+(1*4)=116
116 % 10 = 6
So 35354-74-6 is a valid CAS Registry Number.
InChI:InChI=1/C18H18O2/c1-3-5-13-7-9-18(20)16(11-13)14-8-10-17(19)15(12-14)6-4-2/h3-4,7-12,19-20H,1-2,5-6H2
35354-74-6Relevant articles and documents
Efficient synthesis of neurotrophic honokiol using Suzuki-Miyaura reactions
Harada, Kenichi,Arioka, Chiharu,Miyakita, Akina,Kubo, Miwa,Fukuyama, Yoshiyasu
, p. 6001 - 6003 (2014)
Efficient synthesis of honokiol (1) was accomplished using two kinds of Suzuki-Miyaura reactions. The first Suzuki-Miyaura reaction was employed to couple 2-bromophenol (6) with 4-hydroxyphenylboronic acid (5), giving rise to biphenol 4, and the second co
Concise total synthesis of honokiol via Kumada cross coupling
Srinivas, Jada,Singh, Parvinder Pal,Varma, Yogesh Kumar,Hyder, Irfan,Kumar, Halmuthur M. Sampath
, p. 4295 - 4297 (2014)
A concise four-step efficient synthesis of honokiol 1 in 68% overall yield is described here. The present method involves tetrakis(triphenylphosphine) palladium [Pd(Ph3)4] catalyzed Kumada coupling in two key steps. First coupling generates biaryl backbone intermediate 5 and second generates 2,4′-O-dimethylhonokiol 3. Final demethylation under AlCl 3/DMS condition affords honokiol in quantitative yield.
In vitro metabolism and disposition of honokiol in rat and human livers
Boehmdorfer, Michaela,Maier-Salamon, Alexandra,Taferner, Barbara,Reznicek, Gottfried,Thalhammer, Theresia,Hering, Steffen,Huefner, Antje,Schuehly, Wolfgang,Jaeger, Walter
, p. 3506 - 3516 (2011)
The biotransformation of honokiol, a major constituent of the bark of Magnolia officinalis, was investigated in rat and human livers. When isolated, rat livers were perfused with 10μM honokiol and two metabolites, namely hydroxylated honokiol conjugated with glucuronic and sulfuric acid (M1) and honokiol monoglucuronide (M2), were quantified in bile and perfusate by high-performance liquid chromatography. The hepatic extraction ratio and clearance of honokiol was very high in rat liver (E: 0.99 ± 0.01 and 35.8 ± 0.04mL/min, respectively) leading to very low bioavailability (F = 0.007 ± 0.001). M2 formation was also highly efficient in human liver microsomes [Vmax/Km = 78.1 ± 6.73 μL/(min mg)], which appeared to be catalyzed mainly by UDP-glucuronosyltransferases 1A1, A3, 1A8, and 1A10, indicating hepatic and extrahepatic glucuronidation. Monosulfation of honokiol to the minor metabolite honokiol monosulfate [Vmax/Km = 27.9 ± 4.33 μL/(min mg)] by human liver cytosol was less pronounced and is mediated by sulfotransferases 1A1* 1, 1A1* 2, 1A2, 1A3, 1B1, and 1E1. P450-mediated oxidation of honokiol by liver microsomes, however, was below detection limit. In summary, this study established that glucuronidation and sulfation are the main metabolic pathways for honokiol in rat and human liver, suggesting their major contribution to clearance in vivo.
Total synthesis of honokiol by selective samarium-mediated allylic benzoate reduction
Wright, Alicia M.,O'Neil, Gregory W.
, p. 3441 - 3443 (2016)
The total synthesis of the biologically relevant compound honokiol has been completed featuring a samarium-mediated bis-benzoyl ester reduction to simultaneously install both allyl substituents found in the natural product. This reaction was performed after a Suzuki coupling was used to generate the biphenyl core, thereby avoiding problems associated with the acidity of these allyl groups and their propensity to isomerize. In this way, the synthesis of honokiol could be completed in 4 steps and 42% overall yield.
A concise synthesis of honokiol
Chen, Chang-Ming,Liu, Yeuk-Chuen
, p. 1151 - 1152 (2009)
A simple synthesis of the natural product honokiol 1 has been developed which proceeds in four steps and provides a 32% overall yield. Suzuki coupling of 4-allyl-2-bromoanisole 3 with 4-hydroxyphenyl boronic acid, followed by allylation, gave 5-allyl-4′-a
Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB2 receptor inverse agonists
Schuehly, Wolfgang,Paredes, Juan Manuel Viveros,Kleyer, Jonas,Huefner, Antje,Anavi-Goffer, Sharon,Raduner, Stefan,Altmann, Karl-Heinz,Gertsch, Juerg
, p. 1053 - 1064 (2011)
The cannabinoid CB2 receptor is known to modulate osteoclast function by poorly understood mechanisms. Here, we report that the natural biphenyl neolignan 4′-O-methylhonokiol (MH) is a CB2 receptor-selective antiosteoclastogenic lead structure (Ki i inverse agonist response and a strong CB2 receptor-dependent increase in intracellular calcium. The most active inverse agonists from a library of MH derivatives inhibited osteoclastogenesis in RANK ligand-stimulated RAW264.7 cells and primary human macrophages. Moreover, these ligands potently inhibited the osteoclastogenic action of endocannabinoids. Our data show that CB 2 receptor-mediated cAMP formation, but not intracellular calcium, is crucially involved in the regulation of osteoclastogenesis, primarily by inhibiting macrophage chemotaxis and TNF-α expression. MH is an easily accessible CB2 receptor-selective scaffold that exhibits a novel type of functional heterogeneity.
Transition-Metal-Free C(sp2)–C(sp2) Cross-Coupling of Diazo Quinones with Catechol Boronic Esters
Che, Chi-Ming,Wu, Kai,Wu, Liang-Liang,Zhou, Cong-Ying
supporting information, p. 16202 - 16208 (2020/07/17)
A transition-metal-free C(sp2)?C(sp2) bond formation reaction by the cross-coupling of diazo quinones with catechol boronic esters was developed. With this protocol, a variety of biaryls and alkenyl phenols were obtained in good to high yields under mild conditions. The reaction tolerates various functionalities and is applicable to the derivatization of pharmaceuticals and natural products. The synthetic utility of the method was demonstrated by the short synthesis of multi-substituted triphenylenes and three bioactive natural products, honokiol, moracin M, and stemofuran A. Mechanistic studies and density functional theory (DFT) calculations revealed that the reaction involves attack of the boronic ester by a singlet quinone carbene followed by a 1,2-rearrangement through a stepwise mechanism.
Concise and practical approach for the synthesis of honokiol, a neurotrophic agent
Khan, P. Rasvan,Mujawar, Taufiqueahmed,Shankar, G.,Shekhar, P.,Subba Reddy, BV.,Subramanyam, Ravi
supporting information, (2020/08/06)
An improved method has been developed for the synthesis of honokiol using a readily available p-bromophenol as a precursor. The key step involved in this method is ortho-lithiation facilitated by methoxymethyl ether (MOM). Other important steps are ortho-allyl phenyl ether Claisen rearrangement and a Suzuki coupling for the construction of biaryls. This method does not require pre-functionalization of aromatic ring with bromide for the generation of arylboronic acid.
SYNTHESIS OF HONOKIOL
-
, (2017/06/01)
Disclosed herein are improved methods for the synthesis of honokiol, as well as methods for the synthesis of 3,3′-di-tert-butyl-5,5′-dimethyl-[1,1′-biphenyl]-2,4′-diol, 3′,5-dimethyl-[1,1′-biphenyl]-2,4′-diol, and 2,4′-dimethoxy-3′,5-dimethyl-1,1′-biphenyl, 3,3′,5,5′-tetra-tert-butyl-[1,1′-biphenyl]-2,4′-diol, and certain tetrasubstituted bisphenols, and uses therefor.
A short and efficient synthesis of honokiol via Claisen rearrangement
Subba Reddy,Nageshwar Rao,Siva Senkar Reddy,Somaiah,Yadav,Subramanyam, Ravi
, p. 1049 - 1051 (2014/02/14)
A concise and efficient total synthesis of honokiol, a biphenyl-type neolignan is accomplished in six steps using readily available and cost-effective reagents. The synthetic route involves mainly the Grignard reaction, iodine mediated aromatization, and Claisen rearrangement as key steps. A predominant formation of honokiol (1a) was observed in the Claisen rearrangement under microwave irradiation whereas the isohonokiol (1b) was formed as a major product under conventional conditions.
