Chemistry:Honokiol

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Honokiol
Honokiol.png
Names
Preferred IUPAC name
3′,5-Di(prop-2-en-1-yl)[1,1′-biphenyl]-2,4′-diol
Other names
houpa, hnk
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
UNII
Properties
C18H18O2
Molar mass 266.334 g/mol
Appearance White solid
sparingly (25 °C)
Related compounds
Related biphenols
 diethylstilbestrol,
dihydroxyeugenol
Related compounds
 magnolol.
4-O-Methylhonokiol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Honokiol is a lignan isolated from the bark, seed cones, and leaves of trees belonging to the genus Magnolia. It has been identified as one of the chemical compounds in some traditional eastern herbal medicines along with magnolol, 4-O-methylhonokiol, and obovatol.

Biology

Honokiol has been extracted from a number of species of Magnolia native to many regions of the globe. Magnolia grandiflora, which is native to the American South, as well as Mexican species like Magnolia dealbata have been found to be sources of honokiol.[1] Traditionally in Asian medicine, the Magnolia biondii, Magnolia obovata, and Magnolia officinalis are commonly used.[2] The compound itself has a spicy odor.

Because of its physical properties, honokiol can readily cross the blood brain barrier and the blood-cerebrospinal fluid barrier.[1][3] As a result, honokiol is a potentially potent therapy with high bioavailability.

Chemistry

Structure

Honokiol belongs to a class of neolignan biphenols. As a polyphenol it is relatively small and can interact with cell membrane proteins through intermolecular interactions like hydrogen bonding, hydrophobic interactions, or aromatic pi orbital co-valency.[1] It is hydrophobic and readily dissolved in lipids. It is structurally similar to propofol.[1]

Purification

There are several methods for purifying and isolating honokiol. In nature, honokiol exists with its structural isomer magnolol, which differs from honokiol only by the position of one hydroxyl group. Because of the very similar properties of magnolol and honokiol, purification has often been limited to a HPLC or electromigration. However, methods developed in 2006 by workers in the lab of Jack L. Arbiser, took advantage of the proximity of the phenolic hydroxyl groups in magnolol, which form a protectable diol, to generate a magnolol acetonide (Figure 1), with a subsequent simple purification via flash chromatography over silica.[4]

Figure 1

Magnolol and Honokiol are normally inseparable. Honokiol is easily separable from the protected magnolol acetonide

Additionally a rapid separation approach was published in the Journal of Chromatography A in 2007. The process uses high-capacity high-speed countercurrent chromatography (high-capacity HSCCC).[5] Through this method honokiol can be separated and purified to above 98% purity with a high yield in under an hour.

History

Traditional medicine

Seed Cone

Extracts from the bark or seed cones of the Magnolia tree have been widely used in traditional medicine in China, Korea, and Japan.[2]

Magnolia bark has traditionally been used in Eastern medicine as analgesic and to treat anxiety and mood disorders.[2][6] In traditional Chinese medicine, magnolia bark is called Houpu and is most commonly taken from two species, Magnolia obovata and Magnolia officinalis.[7] Some Chinese traditional formulas containing Houpu include Banxia Houpu Tang (半夏厚朴丸), Xiao Zhengai Tang, Ping Wei San(平胃散) and Shenmi Tang.[2] Japanese Kampo formulas include, Hange-koboku-to (半夏厚朴湯) and Sai-boku-to (柴朴湯).[2][6]

Seeds

Western medical research

Honokiol is a pleiotropic compound, meaning it is able to act on the body through a number of pathways. This diversity of interaction makes it a viable therapy for a number of conditions in the central nervous system, cardiovascular system, and gastrointestinal system. It has been shown to have antitumorigenic, anti-inflammatory, and antioxidant effects as well.[1][8][9]

Side effects and contraindications

Research has shown a limited side effect profile for honokiol, and it appears to be well tolerated. However, its antithrombotic effects could cause hemorrhage especially in patients with conditions that would put them at a higher risk like hemophilia or Von Willebrand disease.[1] Additionally, patients already taking anticoagulants should talk to their doctor before taking honokiol supplements. In a 2002 study, researchers induced cell death in fetal rat cortical neurons by directly applying 100μM in vitro.[10]

Pharmacology

Antitumorigenic activities

Honokiol has shown pro-apoptotic effects in melanoma, sarcoma, myeloma, leukemia, bladder, lung, prostate, oral squamous cell carcinoma,[11] in glioblastome multiforme cells [12] and colon cancer cell lines.[13][14][15][16] Honokiol inhibits phosphorylation of Akt, p44/42 mitogen-activated protein kinase (MAPK), and src. Additionally, honokiol regulates the nuclear factor kappa B (NF-κB) activation pathway, an upstream effector of vascular endothelial growth factor (VEGF), MCL1, and cyclooxygenase 2 (COX-2), all significant pro-angiogenic and survival factors. Honokiol induces caspase-dependent apoptosis in a TRAIL-mediated manner, and potentiates the pro-apoptotic effects of doxorubicin and other etoposides. So potent is honokiol's pro-apoptotic effects that it overcomes even notoriously drug resistant neoplasms such as multiple myeloma and chronic B-cell leukemia. Honokiol also acts on the PI3K/mTOR pathway in tumor cells while maintaining pathway activity in T cells.[17]

Neurotrophic activity

Honokiol has been shown to promote neurite outgrowth and have neuroprotective effects in rat cortical neurons. Additionally, honokiol increases free cytoplasmic reforforason Ca2+ in rat cortical neurons.[10] Honokiol is a weak CB2 receptor ligand but the naturally occurring derivative 4-O-methylhonokiol was shown to be a potent and selective cannabinoid CB2 receptor inverse agonist and to possess antiosteoclastic effects.[18]

Antithrombotic activity

Honokiol inhibits platelet aggregation in rabbits in a dose-dependent manner, and protects cultured RAEC against oxidized low density lipoprotein injury. Honokiol significantly increases the prostacyclin metabolite 6-keto-PGF1alpha, potentially the key factor in honokiol's antithrombotic activity.[19]

Anti-inflammatory activity

Studies examining honokiol as a protective therapy against focal cerebral ischemia-reperfusion injury have identified a number of anti-inflammatory pathways. Neutrophil infiltration of injured tissues can cause further damage and issues with healing. In in vitro studies, honokiol reduced fMLP (N-formyl-methionyl-leucyl-phenylalanine) and PMA (phorbol-12-myristate-13-acetate) induced neutrophil firm adhesion which is an integral step for infiltration.[1][20] Honokiol inhibits ROS production in neutrophils.[20] Honokiol also blocks inflammatory factor production in glial cells through the inhibition on NF-κB activation.[21][22] This mechanism is believed to suppress production of NO, tumor necrosis factor-α (TNF-α), and RANTES/CCL5.[21]

Antioxidant activity

Honokiol has also been proposed as an antioxidant. The compound protects against lipid peroxidation by interfering with ROS production and migration.[20] Accumulation of ROS extracellularly causes macromolecular damage while intracellular accumulation may induce cytokine activation.

Cytotoxicity inhibition

One way that honokiol acts as a neuroprotective is through cellular regulation and subsequent inhibition of cytotoxicity. Two mechanisms used to achieve this inhibition are GABAA Modulation and Ca2+ Inhibition. Cytotoxicity inhibition may be the neuroprotective mechanism of honokiol. Honokiol has also been shown to inhibit repetitive firing by blocking glutamate.[23]

GABAA modulation
GABAA receptor binding sites

It is believed that honokiol acts on GABAA receptors similarly to benzodiazepines and Z-drugs. However, honokiol has been shown to achieve anxiolysis with fewer motor or cognitive side effects than GABAA receptor agonists such as flurazepam and diazepam. It has been shown that honokiol likely has a higher selectivity for different GABAA receptor subtypes and both magnolol and honokiol showed higher efficacy when acting on receptors containing δ subunits.[1] GABAA receptors control ligand-gated Cl− channels that can help increase seizure thresholds through the influx of chloride anions. Honokiol may also affect the synthesis of GABA. In a study where mice received seven daily injections of honokiol, researchers observed a mild increase in hippocampal levels of glutamate decarboxylase (GAD67) an enzyme that catalyzes the synthesis of GABA. However, the increase was within the margin of error for the method used to quantify the protein.[24]

Ca2+ inhibition

A high concentration of Ca2+ induces excitotoxicity which is believed to be the main mechanism behind movement disorders such as ALS, Parkinson's disease, and convulsive disorders like epilepsy. Honokiol disrupts the interfaces post synaptic density protein (PSD95) and neuronal nitric oxide synthase (nNOS).[1] PSD95 and nNOS coupling to the NMDA receptor causes a conformational change responsible for the intracellular influx of Ca2+ which could in turn be a pathway for neurotoxicity. Calcium overloading can also cause damage by over-activation of calcium-stimulated enzymes. Honokiol can reduce calcium influx through inhibition of the fMLP, AlF4−, and thapsigargin G-protein pathways.[20]

Antiviral activity

Honokiol has been shown to inhibit hepatitis C virus (HCV) infection in vitro.[25] It has weak in vitro activity against human immunodeficiency virus (HIV-1).[4]

Metabolic activity

Honokiol was shown to normalize blood glucose levels and prevent body weight gain in diabetic mice by acting as agonist of PPARgamma.[26]

Pharmacokinetics

The pharmacokinetics of honokiol have been explored in rats and mice; however, further research must be done in humans.[27] Intravenous delivery of 5–10 mg/kg in rodent models has shown a plasma half-life of around 40–60 minutes while intraperitoneal injections of 250 mg/kg had a plasma half-life around 4–6 hours with maximum plasma concentration occurring between 20 and 30 minutes.[1][28]

Delivery methods

Honokiol is most commonly taken orally. There are a number of supplements available containing honokiol. Magnolia tea made from the bark of the tree is also a common delivery method of honokiol.[citation needed] Both Native Americans and Japanese medicine use tea gargles to treat toothaches and sore throats.[29] Because honokiol is highly hydrophobic it must be dissolved in a lipid for many delivery methods. In many current animal studies the compound is dissolved in a lipid emollient and delivered through intraperitoneal injection. There is ongoing[when?] work developing liposomal emulsions for IV delivery.[27]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 Woodbury, Anna; Yu, Shan Ping; Wei, Ling; García, Paul (2013). "Neuro-Modulating Effects of Honokiol: A Review". Frontiers in Neurology 265 (7): 4111–5. doi:10.3389/fneur.2013.00130. PMID 2406271. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Lee, Young-Jung; Lee, Yoot Mo; Lee, Chong-Kil; Jung, Jae Kyung; Han, Sang Bae; Hong, Jin Tae (2011). "Therapeutic applications of compounds in the Magnolia family". Pharmacology & Therapeutics 130 (2): 157–76. doi:10.1016/j.pharmthera.2011.01.010. PMID 21277893. 
  3. ↑ Wang, Xianhuo; Duan, Xingmei; Yang, Guangli; Zhang, Hao; Deng, Chongyang; Wen, Jiaolin; Wang, Ning; Peng, Cheng et al. (2011). "Honokiol Crosses BBB and BCSFB, and Inhibits Brain Tumor Growth in Rat 9L Intracerebral Gliosarcoma Model and Human U251 Xenograft Glioma Model". PLOS ONE 6 (4): e18490. doi:10.1371/journal.pone.0018490. PMID 21559510. Bibcode: 2011PLoSO...618490W. 
  4. ↑ 4.0 4.1 Amblard, Franck; Delinsky, David; Arbiser, Jack L.; Schinazi, Raymond F. (2006). "Facile Purification of Honokiol and Its Antiviral and Cytotoxic Properties". Journal of Medicinal Chemistry 49 (11): 3426–7. doi:10.1021/jm060268m. PMID 16722664. 
  5. ↑ Chen, Lijuan; Zhang, Qiang; Yang, Guangli; Fan, Linyu; Tang, James; Garrard, Ian; Ignatova, Svetlana; Fisher, Derek et al. (2007). "Rapid purification and scale-up of honokiol and magnolol using high-capacity high-speed counter-current chromatography". Journal of Chromatography A 1142 (2): 115–22. doi:10.1016/j.chroma.2006.09.098. PMID 17222860. 
  6. ↑ 6.0 6.1 Sarris, Jerome; McIntyre, Erica; Camfield, David A. (2013). "Plant-Based Medicines for Anxiety Disorders, Part 1". CNS Drugs 27 (3): 207–19. doi:10.1007/s40263-013-0044-3. PMID 23436255. 
  7. ↑ Maruyama, Yuji; Kuribara, H.; Morita, M.; Yuzurihara, M.; Weintraub, S. (1998). "Identification of Magnolol and Honokiol as Anxiolytic Agents in Extracts of Saiboku-to, an Oriental Herbal Medicine". Journal of Natural Products 61 (1): 135–138. doi:10.1021/np9702446. PMID 9461663. 
  8. ↑ Fried, Levi E.; Arbiser, Jack L. (2009). "Honokiol, a Multifunctional Antiangiogenic and Antitumor Agent". Antioxidants & Redox Signaling 11 (5): 1139–48. doi:10.1089/ars.2009.2440. PMID 19203212. 
  9. ↑ Guerra-Araiza, Christian; Álvarez-Mejía, Ana Laura; Sánchez-Torres, Stephanie; Farfan-García, Eunice; Mondragón-Lozano, Rodrigo; Pinto-Almazán, Rodolfo; Salgado-Ceballos, Hermelinda (2013). "Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases". Free Radical Research 47 (6–7): 451–62. doi:10.3109/10715762.2013.795649. PMID 23594291. 
  10. ↑ 10.0 10.1 Fukuyama, Yoshiyasu; Nakade, Kousuke; Minoshima, Yuka; Yokoyama, Ritsuko; Zhai, Haifeng; Mitsumoto, Yasuhide (2002). "Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons". Bioorganic & Medicinal Chemistry Letters 12 (8): 1163–1166. doi:10.1016/S0960-894X(02)00112-9. PMID 11934579. 
  11. ↑ Chen, Xi-rui; Lu, Rui; Dan, Hong-xia; Liao, Ga; Zhou, Min; Li, Xiao-yu; Ji, Ning (2011). "Honokiol: A promising small molecular weight natural agent for the growth inhibition of oral squamous cell carcinoma cells". International Journal of Oral Science 3 (1): 34–42. doi:10.4248/IJOS11014. PMID 21449214. 
  12. ↑ Chang, K. H.; Yan, M. D. (Nov 2013). "Honokiol-induced apoptosis and autophagy in glioblastoma multiforme cells.". Oncology Letters 6 (5): 1435–1438. doi:10.3892/ol.2013.1548. PMID 24179537. 
  13. ↑ Shigemura, Katsumi; Arbiser, Jack L.; Sun, Shi-Yong; Zayzafoon, Majd; Johnstone, Peter A.S.; Fujisawa, Masato; Gotoh, Akinobu; Weksler, Babette et al. (2007). "Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells". Cancer 109 (7): 1279–89. doi:10.1002/cncr.22551. PMID 17326044. 
  14. ↑ Ishitsuka, K.; Hideshima, T; Hamasaki, M; Raje, N; Kumar, S; Hideshima, H; Shiraishi, N; Yasui, H et al. (2005). "Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis". Blood 106 (5): 1794–800. doi:10.1182/blood-2005-01-0346. PMID 15870175. 
  15. ↑ Battle, T. E.; Arbiser, J; Frank, DA (2005). "The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells". Blood 106 (2): 690–7. doi:10.1182/blood-2004-11-4273. PMID 15802533. 
  16. ↑ Bai, X.; Cerimele, F; Ushio-Fukai, M; Waqas, M; Campbell, PM; Govindarajan, B; Der, CJ; Battle, T et al. (2003). "Honokiol, a Small Molecular Weight Natural Product, Inhibits Angiogenesis in Vitro and Tumor Growth in Vivo". Journal of Biological Chemistry 278 (37): 35501–7. doi:10.1074/jbc.M302967200. PMID 12816951. 
  17. ↑ Crane, Courtney; Panner, Amith; Pieper, Russell; Arbiser, Jack; Parsa, Andrew (2009). "Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function.". Journal of Immunotherapy 32 (6): 585–592. doi:10.1097/CJI.0b013e3181a8efe6. PMID 19483651. 
  18. ↑ Schuehly, Wolfgang; Paredes, Juan Manuel Viveros; Kleyer, Jonas; Huefner, Antje; Anavi-Goffer, Sharon; Raduner, Stefan; Altmann, Karl-Heinz; Gertsch, Jürg (2011). "Mechanisms of Osteoclastogenesis Inhibition by a Novel Class of Biphenyl-Type Cannabinoid CB2 Receptor Inverse Agonists". Chemistry & Biology 18 (8): 1053–64. doi:10.1016/j.chembiol.2011.05.012. PMID 21867920. 
  19. ↑ Hu, He; Zhang, Xiao-xue; Wang, Yin-ye; Chen, Shi-Zhong (2005). "Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin". Acta Pharmacologica Sinica 26 (9): 1063–8. doi:10.1111/j.1745-7254.2005.00164.x. PMID 16115372. 
  20. ↑ 20.0 20.1 20.2 20.3 Liou, Kuo-Tong; Shen, Yuh-Chiang; Chen, Chieh-Fu; Tsao, Cheng-Ming; Tsai, Shen-Kou (2003). "Honokiol protects rat brain from focal cerebral ischemia-reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production". Brain Research 992 (2): 159–166. doi:10.1016/j.brainres.2003.08.026. PMID 14625055. http://ntur.lib.ntu.edu.tw/bitstream/246246/2006111501222259/1/6130.pdf. 
  21. ↑ 21.0 21.1 Zhang, Peng; Liu, Xiaoyan; Zhu, Yanjun; Chen, Shizhong; Zhou, Demin; Wang, Yinye (2012). "Honokiol inhibits the inflammatory reaction during cerebral ischemia reperfusion by suppressing NF-κB activation and cytokine production of glial cells.". Neuroscience Letters 534: 123–7. doi:10.1016/j.neulet.2012.11.052. PMID 23262090. 
  22. ↑ Chao, Louis Kuoping; Liao, Pei-Chun; Ho, Chen-Lung; Wang, Eugene I-Chen; Chuang, Chao-Chin; Chiu, Huan-Wen; Hung, Lang-Bang; Hua, Kuo-Feng (2010). "Anti-Inflammatory Bioactives of Honokiol through Inhibition of Protein Kinase C, Mitogen-Activated Protein Kinase, and the NF-κB Pathway To Reduce LPS-Induced TNFα and NO Expression". Journal of Agricultural and Food Chemistry 58 (6): 3472–8. doi:10.1021/jf904207m. PMID 20192217. 
  23. ↑ Lin, Yi-Ruu; Chen, Hwei-Hsien; Ko, Chien-Hsin; Chan, Ming-Huan (2006). "Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage". European Journal of Pharmacology 537 (1–3): 64–9. doi:10.1016/j.ejphar.2006.03.035. PMID 16631734. 
  24. ↑ Ku, Tien-Hsiung; Lee, Yih-Jing; Wang, Su-Jane; Fan, Chen-Hua; Tien, Lu-Tai (2011). "Effect of honokiol on activity of GAD(65) and GAD(67) in the cortex and hippocampus of mice.". Phytomedicine 18 (13): 1126–9. doi:10.1016/j.phymed.2011.03.007. PMID 21561750. 
  25. ↑ Lan, KH; Wang, Ying-Wen; Lee, Wei-Ping; Lan, Keng-Li; Tseng, Szu-Han; Hung, Li-Rong; Yen, Sang-Hue; Lin, Han-Chieh et al. (2012). "Multiple effects of Honokiol on the life cycle of hepatitis C virus". Liver International 32 (6): 989–97. doi:10.1111/j.1478-3231.2011.02621.x. PMID 22098176. 
  26. ↑ Atanasov, Atanas G.; Wang, Jian N.; Gu, Shi P.; Bu, Jing; Kramer, Matthias P.; Baumgartner, Lisa; Fakhrudin, Nanang; Ladurner, Angela et al. (2013). "Honokiol: A non-adipogenic PPARγ agonist from nature". Biochimica et Biophysica Acta (BBA) - General Subjects 1830 (10): 4813–4819. doi:10.1016/j.bbagen.2013.06.021. PMID 23811337. 
  27. ↑ 27.0 27.1 Zheng, J; Tang, Y; Sun, M; Zhao, Y; Li, Q; Zhou, J; Wang, Y (2013). "Characterization, pharmacokinetics, tissue distribution and antitumor activity of honokiol submicron lipid emulsions in tumor-burdened mice". Die Pharmazie 68 (1): 41–6. PMID 23444779. 
  28. ↑ Tsai, Tung-Hu; Chou, Cheng-Jen; Cheng, Fu-Chou; Chen, Chieh-Fu (1994). "Pharmacokinetics of honokiol after intravenous administration in rats assessed using high performance liquid chromatography". Journal of Chromatography B 655 (1): 41–5. doi:10.1016/0378-4347(94)00031-x. PMID 8061832. 
  29. ↑ Shimer, Porter (2004). Healing Secrets of the Native Americans: Herbs, Remedies, and Practices That Rebuild the Spirit. Black Dog & Leventhal Publishers, Incorporated. pp. 83–4. ISBN 978-1-57912-392-5. https://archive.org/details/healingsecretsof00shim_0/page/83. 

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