- Efficient synthesis of neurotrophic honokiol using Suzuki-Miyaura reactions
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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
- Harada, Kenichi,Arioka, Chiharu,Miyakita, Akina,Kubo, Miwa,Fukuyama, Yoshiyasu
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- Concise total synthesis of honokiol via Kumada cross coupling
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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.
- Srinivas, Jada,Singh, Parvinder Pal,Varma, Yogesh Kumar,Hyder, Irfan,Kumar, Halmuthur M. Sampath
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- In vitro metabolism and disposition of honokiol in rat and human livers
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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.
- Boehmdorfer, Michaela,Maier-Salamon, Alexandra,Taferner, Barbara,Reznicek, Gottfried,Thalhammer, Theresia,Hering, Steffen,Huefner, Antje,Schuehly, Wolfgang,Jaeger, Walter
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- Total synthesis of honokiol by selective samarium-mediated allylic benzoate reduction
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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.
- Wright, Alicia M.,O'Neil, Gregory W.
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- A concise synthesis of honokiol
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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
- Chen, Chang-Ming,Liu, Yeuk-Chuen
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- Mechanisms of osteoclastogenesis inhibition by a novel class of biphenyl-type cannabinoid CB2 receptor inverse agonists
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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.
- Schuehly, Wolfgang,Paredes, Juan Manuel Viveros,Kleyer, Jonas,Huefner, Antje,Anavi-Goffer, Sharon,Raduner, Stefan,Altmann, Karl-Heinz,Gertsch, Juerg
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- Transition-Metal-Free C(sp2)–C(sp2) Cross-Coupling of Diazo Quinones with Catechol Boronic Esters
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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.
- Che, Chi-Ming,Wu, Kai,Wu, Liang-Liang,Zhou, Cong-Ying
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supporting information
p. 16202 - 16208
(2020/07/17)
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- Concise and practical approach for the synthesis of honokiol, a neurotrophic agent
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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.
- Khan, P. Rasvan,Mujawar, Taufiqueahmed,Shankar, G.,Shekhar, P.,Subba Reddy, BV.,Subramanyam, Ravi
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supporting information
(2020/08/06)
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- SYNTHESIS OF HONOKIOL
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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.
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- A short and efficient synthesis of honokiol via Claisen rearrangement
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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.
- Subba Reddy,Nageshwar Rao,Siva Senkar Reddy,Somaiah,Yadav,Subramanyam, Ravi
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p. 1049 - 1051
(2014/02/14)
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- A short and efficient synthesis of honokiol via Claisen rearrangement
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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.
- Subba Reddy,Nageshwar Rao,Siva Senkar Reddy,Somaiah,Yadav,Subramanyam, Ravi
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p. 1049 - 1051
(2015/02/19)
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- METHOD OF PRODUCING BIPHENOLIC COMPOUND, NOVEL BIPHENYL COMPOUND AND SYNTHESIS METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION FOR TREATING PARKINSON'S DISEASE
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A method of producing honokiol and analogues thereof, and novel intermediates prepared by virtue thereof are disclosed herein. A pharmaceutical composition for treating Parkinson's disease, which contains honokiol and/or the analogues thereof, is also disclosed herein.
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- An expedient synthesis of honokiol and its analogues as potential neuropreventive agents
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An efficient synthesis of honokiol with Suzuki-Miyaura cross coupling obtained an overall yield of 45%. The proposed approach successfully synthesized several structurally similar alkyl, alkenyl and alkynyl analogues, seven of which showed potential neuropreventive activity against MPP+-induced and CHP/TBHP oxidative stress induced neuroblastoma cell death.
- Tripathi, Subhankar,Chan, Ming-Huan,Chen, Chinpiao
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p. 216 - 221
(2012/02/15)
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- A concise synthesis of honokiol
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Two approaches to the synthesis of the plant-derived biaryl neolignan honokiol are described. The second approach provided the natural product in either four steps with 34% overall yield or five steps and 55% overall yield.
- Denton, Ross M.,Scragg, James T.,Galofré, Adri M.,Gui, Xiechao,Lewis, William
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experimental part
p. 8029 - 8035
(2010/10/20)
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- Efficient synthesis and structure-activity relationship of honokiol, a neurotrophic biphenyl-type neolignan
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Honokiol, a biphenyl-type neolignan, which shows the remarkable neurotrophic effect in primary cultured rat cortical neurons, has been effectively synthesized in 21% yield over 14 steps starting from 5-bromosalicylic acid and p-hydroxybenzoic acid by utilizing Pd-catalyzed Suzuki-Miyaura coupling reaction as a key step. Additionally, the structure-activity relationship between neurite outgrowth-promoting activity and its O-methylated and/or its hydrogenated analogues was examined in the primary cultures of fetal rat cortical neurons, suggesting that 5-allyl and 4′-hydroxyl groups are essential for affecting the neurotrophic activity of honokiol.
- Esumi, Tomoyuki,Makado, Gouki,Zhai, Haifeng,Shimizu, Yasuhiro,Mitsumoto, Yasuhide,Fukuyama, Yoshiyasu
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p. 2621 - 2625
(2007/10/03)
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- NEUROTROPHIC SESQUITERPENE-NEOLIGNANS FROM MAGNOLIA OBOVATA: STRUCTURE AND NEUROTROPHIC ACTIVITY
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Novel sesquiterpene-neolignans, eudesobovatols A (1) and B (2), eudesmagnolol (3), eudeshonokiols A (4) and B (5), clovanemagnolol (6), and caryolanemagnolol (7), have been isolated from the bark of Magnolia obovata.Their structures were elucidated to be sesquiterpenes (eudesmol, 4,4,8-trimethyltricyclo2,5>dodecane-1,9-diol, and clovanediol) combined through ether bond with neolignans such as obovatol, honokiol, and magnolol on the basis of spectral data, degradation, and/or synthesis.Compounds 1, 6, and 7 were found to exhibit interesting neurotrophic activity on a neuronal cell culture system derived from fetal rat hemisphere.
- Fukuyama, Yoshiyasu,Otoshi, Yukio,Miyoshi, Kumi,Nakamura, Kazuhiko,Kodama, Mitsuaki,et al.
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p. 377 - 392
(2007/10/02)
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- Structures of Eudesmagnolol and Eudeshonokiol, Novel Sesquiterpene-Neolignans Isolated from Magnolia obovata
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Eudesmagnolol and eudeshonokiol, isolated from the bark of Magnolia obovata, have been assigned to unprecedented structures linked via an ether bond between sesquiterpene, eudesmol, and neolignans, magnolol and honokiol, respectively.
- Fukuyama, Yoshiyasu,Otoshi, Yukio,Nakamura, Kazuhiko,Kodama, Mitsuaki,Sugawara, Michiharu,Nagaswa, Masakazu
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p. 295 - 296
(2007/10/02)
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