- Synthesis and in vitro antitumor evaluation of honokiol derivatives
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Honokiol is a natural bioactive neolignan and has been widely researched and structural modified as an anticancer agent. In this paper, 18 honokiol derivatives were synthesized and investigated for their antitumor activity. Among these, the promising compound 5a exhibited much higher anti-proliferative activity with IC50 value of 10.41 μM. Transwell assays showed that 5a could significantly inhibit the invasion and migration of I-10 cells at 2.5 μM, which was further confirmed by the western blotting experiments with down-regulation of the HIF-1α and its associated downstream proteins MMP-2 and MMP-9. Overall, these results provided useful suggestion for further structural optimization of honokiol derivatives.
- Zhu, Meilin,Li, Bohan,Ma, Hui,Huang, Xuenan,Wang, Haotian,Dai, Yiqun,Li, Yu,Li, Hong-Mei,Wu, Cheng-Zhu
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- Nitrogenated honokiol derivatives allosterically modulate GABAA receptors and act as strong partial agonists
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In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignan honokiol together with its isomer magnolol are the main constituents of Magnolia bark extracts. We have previously identified a nitrogen-containing honokiol derivative (3-acetylamino-4′-O-methylhonokiol, AMH) as a high efficient modulator of GABAA receptors. Here we further elucidate the structure-activity relation of a series of nitrogenated biphenyl-neolignan derivatives by analysing allosteric modulation and agonistic effects on α1β2γ2S GABAA receptors. The strongest IGABA enhancement was induced by compound 5 (3-acetamido-4′-ethoxy-3′,5-dipropylbiphenyl-2-ol, Emax: 123.4 ± 9.4% of IGABA-max) and 6 (5′-amino-2-ethoxy-3′,5-dipropylbiphenyl-4′-ol, Emax: 117.7 ± 13.5% of IGABA-max). Compound 5 displayed, however, a significantly higher potency (EC50 = 1.8 ± 1.1 μM) than compound 6 (EC50 = 20.4 ± 4.3 μM). Honokiol, AMH and four of the derivatives induced significant inward currents in the absence of GABA. Strong partial agonists were honokiol (inducing 78 ± 6% of IGABA-max), AMH (63 ± 6%), 5′-amino-2-O-methylhonokiol (1) (59 ± 1%) and 2-methoxy-5′-nitro-3′,5-dipropylbiphenyl-4′-ol (3) (52 ± 1%). 3-N-Acetylamino-4′-ethoxy-3′,5-dipropyl-biphenyl-4′-ol (5) and 3-amino-4′-ethoxy-3′,5-dipropyl-biphenyl-4′-ol (7) were less efficacious but even more potent (5: EC50 = 6.9 ± 1.0 μM; 7: EC50 = 33.2 ± 5.1 μM) than the full agonist GABA.
- Bernaskova, Marketa,Schoeffmann, Angela,Schuehly, Wolfgang,Hufner, Antje,Baburin, Igor,Hering, Steffen
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- Anticancer Effects of Honokiol via Mitochondrial Dysfunction Are Strongly Enhanced by the Mitochondria-Targeting Carrier Berberine
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Mitochondrion is a favorable therapeutic target in cancer, given its regulation of bioenergetics and cell death. Honokiol exhibits antiproliferative effects through mitochondria-mediated death signaling. To enhance its anticancer potential and selectivity, we conjugated honokiol to berberine, a mitochondria-targeting carrier. All designed derivatives displayed 1 order of magnitude increased cytotoxicity compared with the parent compounds, especially with massive cytoplasmic vacuoles. Biological evaluation demonstrated the representative compound 6b localized within the mitochondria, and mitochondrial dilation resulted in vacuolization. 6b induced vacuolation-associated cell death and apoptosis with obvious mitochondrial dysfunction, as demonstrated by booming reactive oxygen species generation, opening mitochondrial permeability transition pore, and reducing mitochondrial membrane potential. The targeting property also conferred 6b with selectivity for tumor cells compared to normal cells. 6b inhibited cancer cell proliferation in the zebrafish xenograft model. These results demonstrate that berberine-linked honokiol derivatives open up a direction for novel mitochondrial-targeting antitumor agents.
- Shi, Xiaojia,Zhang, Tao,Lou, Hongxiang,Song, Huina,Li, Changhao,Fan, Peihong
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- Synthesis of Either C2- or C4′-Alkylated Derivatives of Honokiol and Their Biological Evaluation for Anti-inflammatory Activity
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Honokiol, a biphenolic neolignan isolated from Magnolia officinalis, was reported to have a promising anti-inflammatory activity for the treatment of various diseases. There are many efforts on the synthesis and structure-activity relationship of honokiol derivatives. However, regioselective O-alkylation of honokiol remains a challenge and serves as a tool to provide not only some derivatives but also chemical probes for target identification and mode of action. In this study, we examined the reaction condition for regioselective O-alkylation, in which C2 and C4′-alkylated analogs of honokiol were synthesized and evaluated for inhibitory activity on nitric oxide production and cyclooxygenase-2 expression. Furthermore, we successfully synthesized a potential photoaffinity probe consisting of biotin and benzophenone based on a C4′-alkylated derivative.
- Lee, San-Ha,Fei, Xiang,Lee, Chaelin,Do, Hien Thi Thu,Rhee, Inmoo,Seo, Seung-Yong
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- Method for Synthesizing 4-O-Methylhonokiol
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The present invention refers to a the active compounds useful 4-O-methylhonokiol-chemical method synthesis of relates to a preparation. Of the existing method according to the present invention extracted from natural 4-O the method obtaining-methylhonokiol produce highly pure crude high yield by a unidirectional photocoupler the product may be-methylhonokiol 4-O unit is off.
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- In vitro growth inhibition of human cancer cells by novel honokiol analogs
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Honokiol possesses many pharmacological activities including anti-cancer properties. Here in, we designed and synthesized honokiol analogs that block major honokiol metabolic pathway which may enhance their effectiveness. We studied their cytotoxicity in human cancer cells and evaluated possible mechanism of cell cycle arrest. Two analogs, namely 2 and 4, showed much higher growth inhibitory activity in A549 human lung cancer cells and significant increase of cell population in the G0-G1 phase. Further elucidation of the inhibition mechanism on cell cycle showed that analogs 2 and 4 inhibit both CDK1 and cyclin B1 protien levels in A549 cells.
- Lin, Jyh Ming,Prakasha Gowda,Sharma, Arun K.,Amin, Shantu
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p. 3202 - 3211
(2012/07/28)
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- Expedient synthesis of 4-O-methylhonokiol via Suzuki-Miyaura cross-coupling
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Concise and practical synthesis of 4-O-methylhonokiol was achieved in 34% overall yield. The key features of our synthesis include chemoselective ortho-mono bromination of phenol as well as biaryl formation via Suzuki-Miyaura cross-coupling, in which bromophenol was reacted with potassium aryltrifluoroborate using Pd(OAc)2 and RuPhos under microwave conditions.
- Kwak, Jae-Hwan,Cho, Young Ae,Jang, Jae-Yong,Seo, Seung-Yong,Lee, Heesoon,Hong, Jin Tae,Han, Sang-Bae,Lee, Kiho,Kwak, Young-Shin,Jung, Jae-Kyung
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p. 9401 - 9404
(2011/12/14)
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- Structural modification of honokiol, a biphenyl occurring in magnolia officinalis: The evaluation of honokiol analogues as inhibitors of angiogenesis and for their cytotoxicity and structure-activity relationship
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Honokiol, widely known as an antitumor agent, has been used as an antiangiogenesis drug lead. In this paper, 47 honokiol analogues and derivatives were investigated for their antiangiogenic activity by application of the transgenic zebrafish screening model, antiproliferative and cytotoxic activity against HUVECs, and three tumor cell lines by MTT assay. 3′,5-Diallyl-2, 4′-dihydroxy-[1,1′-biphen-yl]-3,5′-dicarbaldehyde (8c) was found to suppress the newly grown segmental vessels from the dorsal aorta of zebrafish and prevent inappropriate vascularization as well as exhibit more potent inhibitory effects on the proliferation of HUVECs, A549, HepG2, and LL/2 cells (IC50 = 15.1, 30.2, 10.7, and 21.7 μM, respectively) than honokiol (IC50 = 52.6, 35.0, 16.5, and 65.4 μM, respectively). Analogue 8c also effectively inhibited the migration and capillary-like tube formation of HUVECs in vitro. The antiangiogenic effect and antiproliferative activity of these structurally modified honokiol analogues and derivatives have led to the establishment of a structure-activity relationship.
- Ma, Liang,Chen, Jinying,Wang, Xuewei,Liang, Xiaolin,Luo, Youfu,Zhu, Wei,Wang, Tianen,Peng, Ming,Li, Shucai,Jie, Shi,Peng, Aihua,Wei, Yuquan,Chen, Lijuan
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experimental part
p. 6469 - 6481
(2011/12/01)
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- A concise synthesis of 4′-O-methyl honokiol
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A concise and protecting group free synthesis of the naturally occurring neolignan 4′-O-methyl honokiol is developed. The key biaryl bond is constructed by 1,2-addition of an aryl Grignard reagent to a dienone followed by rearrangement.
- Denton, Ross M.,Scragg, James T.,Saska, Jan
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p. 2554 - 2556
(2011/06/21)
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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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