Honokiol
From Wikipedia, the free encyclopedia
| Honokiol | |
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| IUPAC name | 2-(4-hydroxy-3-prop-2-enyl-phenyl)- 4-prop-2-enyl-phenol |
| Other names | houpa, hnk |
| Identifiers | |
| CAS number | [35354-74-6] |
| SMILES | C=CCC1=CC(=C(C=C1)O)C2=CC (=C(C=C2)O)CC=C |
| Properties | |
| Molecular formula | C18H18O2 |
| Molar mass | 266.334 g/mol |
| Appearance | White solid |
| Solubility in water | sparingly (25 °C) |
| Related compounds | |
| Related biphenols | diethylstilbestrol, dihydroxyeugenol, resorcinol |
| Related compounds | magnolol |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references |
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Honokiol (C18H18O2) is a biphenolic molecule present in the cones, bark, and leaves of Magnolia grandifloris that has been used in the traditional Japanese medicine Saiboku-to as an anxiolytic, anti-thrombotic, anti-depressant, anti-emetic, and anti-bacterial. While early research on the effective compounds in traditional remedies have simply used whole magnolia bark extracts, known as houpu magnolia, recent work has identified honokiol and its structural isomer magnolol as the active compounds in magnolia bark. In the late 1990's, honokiol saw a revival in western countries as a potent and highly tolerable anti-tumorigenic and neurotrophic compound.
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[edit] Biological Activity
Anti-tumorigenic activities
Honokiol has shown pro-apoptotic effects in melanoma, sarcoma, myeloma, leukemia, bladder, lung, prostate, and colon cancer cell lines1-4. Honokiol inhibits phosphorylation of Akt, p44/42mitogen-activated protein kinase (MAPK), and src. Additionally, honokiol modulates the nuclear factor kappa beta (NfKB) activation pathway, an upstream effector of vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2), and MCL1, 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.
Neurotrophic Activity
Honokiol has been shown to promote neurite outgrowth and have neuroprotective effects in rat cortical neurons. Additionally, honokiol increases free cytoplasmic Ca2+ in rat cortical neurons5.
Anti-thrombolytic
Honokiol inhibits platelet aggregation in rabbits in a dose-dependent manner, and protects cultured RAEC against oxidized low density liproptein injury. Honokiol significantly increases the prostacyclin metabolite 6-keto-PGF1alpha, potentially the key factor in honokiol's anti-thrombotic activity6.
[edit] Purification
Several methods for purifying honokiol have been utilized. As honokiol exists naturally with its structural isomer magnolol, which differs from honokiol only by the position of one hydroxyl group, 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 silica7.
Figure 1
Magnolol and Honokiol are normally inseparable. Honokiol is easily separable from the protected magnolol acetonide
[edit] Synthesis
The synthesis of pure honokiol (Figure 2) involves a Pd-catalyzed Myaura-Suzuki coupling, but this synthesis has afforded only moderate yields8. An older synthetic method involves reaction of quinol-acetates with the Grignard reagent followed by claisen rearrangement9.
Figure 2
Synthetic scheme for total synthesis of honokiol utilizing Pd-catalzyed Suzuki-coupling.
[edit] See also
[edit] References
1. Shigemura K, Arbiser JL, Sun SY, Zayzafoon M, Johnstone PA, Fujisawa M, Gotoh A, Weksler B, Zhau HE, Chung LW. Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer. 2007 Apr 1;109(7):1279-89.
2. Ishitsuka K, Hideshima T, Hamasaki M, Raje N, Kumar S, Hideshima H, Shiraishi N, Yasui H, Roccaro AM, Richardson P, Podar K, Le Gouill S, Chauhan D, Tamura K, Arbiser J, Anderson KC. Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis. Blood. 2005 Sep 1;106(5):1794-800. Epub 2005 May 3.
3. Battle TE, Arbiser J, Frank DA. The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood. 2005 Jul 15;106(2):690-7. Epub 2005 Mar 31.
4. Bai X, Cerimele F, Ushio-Fukai M, Waqas M, Campbell PM, Govindarajan B, Der CJ, Battle T, Frank DA, Ye K, Murad E, Dubiel W, Soff G, Arbiser JL. Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem. 2003 Sep 12;278(37):35501-7. Epub 2003 Jun 19.
5. Fukuyama Y, Nakade K, Minoshima Y, Yokoyama R, Zhai H, Mitsumoto Y. Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons. Bioorg Med Chem Lett. 2002 Apr 22;12(8):1163-6
6. Hu H, Zhang XX, Wang YY, Chen SZ. Honokiol inhibits arterial thrombosis through endothelial cell protection and stimulation of prostacyclin. Acta Pharmacol Sin. 2005 Sep;26(9):1063-8.
7. Amblard F, Delinsky D, Arbiser JL, Schinazi RF. Facile purification of honokiol and its antiviral and cytotoxic properties. J Med Chem. 2006 Jun 1;49(11):3426-7.
8. Esumi T, Makado G, Zhai H, Shimizu Y, Mitsumoto Y, Fukuyama Y. Efficient synthesis and structure-activity relationship of honokiol, a neurotrophic biphenyl-type neolignan. Bioorg Med Chem Lett. 2004 May 17;14(10):2621-5.
9. Takeya, Tetsuya; Okubo, Toru; Tobinaga, Seisho. Showa Coll. Pharm. Sci., Tokyo, Japan. Chemical & Pharmaceutical Bulletin (1986), 34(5), 2066-70.
