- Linderapyrone: A Wnt signal inhibitor isolated from Lindera umbellata
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Linderapyrone, a Wnt signal inhibitor was isolated from the methanolic extract of the stems and twigs of Lindera umbellata together with epi-(-)-linderol A. Linderapyrone inhibited TCF/β-catenin transcriptional activity that was evaluated using cell-based TOPFlash luciferase assay system. To evaluate the structure-activity relationship and mechanism, we synthesized linderapyrone and its derivatives from piperitone. As the results of further bioassay for synthesized compounds, we found both of pyrone and monoterpene moieties were necessary for inhibitory effect. cDNA microarray analysis in a linderapyrone derivative treated human colorectal cancer cells showed that this compound downregulates Wnt signaling pathway. Moreover, we successes to synthesize the derivative of linderapyrone that has stronger inhibitory effect than linderapyrone and ICG-001 (positive control).
- Matsumoto, Takahiro,Kitagawa, Takahiro,Imahori, Daisuke,Matsuzaki, Atsushi,Saito, Youhei,Ohta, Tomoe,Yoshida, Tatsusada,Nakayama, Yuji,Ashihara, Eishi,Watanabe, Tetsushi
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Read Online
- Potassium fluoride-barium oxide catalysis in an easy and efficient synthesis of methysticin from piperonal under microwave irradiation
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Condensation of compounds containing active methylene group with aromatic aldehyde (piperonal) in the presence of BaO on KF without a solvent under microwave irradiation is an efficient synthetic approach to methysticin and derivatives of kavalactones (4-methoxy-6-styryl-pyran-2-ones).
- Benferrah,Hammadi,Berthiol
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Read Online
- Regioselective functionalization of pyrones: Facile synthesis of 6-styrylpyrones via KHMDS-mediated aldol condensation
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Herein, we disclose our efforts directed toward the synthesis of the kavalactone-based natural product penstyrylpyrone and other related 4-OMe-2-pyrones possessing diverse substituents at the 3-, 5-, and 7-positions. Further, a facile approach to access 6-styrylpyrones via the KHMDS-mediated regioselective aldol condensation of 2-pyrones is described with moderate substrate scope and good to high yields (58–80%). The utility of this methodology was exemplified by the stereoselective construction of desmethoxyyangonin, asnipyrone A, and asnipyrone B.
- Basu, Manas K.,Mukkanti, K.,Samala, Ramakrishna
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- Synthetic kavalactone analogues with increased potency and selective anthelmintic activity against larvae of haemonchus contortus in vitro
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Kava extract, an aqueous rhizome emulsion of the plant Piper methysticum, has been used for centuries by Pacific Islanders as a ceremonial beverage, and has been sold as an anxiolytic agent for some decades. Kavalactones are a major constituent of kava extract. In a previous investigation, we had identified three kavalactones that inhibit larval development of Haemonchus contortus in an in vitro-bioassay. In the present study, we synthesized two kavalactones, desmethoxyyangonin and yangonin, as well as 17 analogues thereof, and evaluated their anthelmintic activities using the same bioassay as employed previously. Structure activity relationship (SAR) studies showed that a 4-substituent on the pendant aryl ring was required for activity. In particular, compounds with 4-trifluoromethoxy, 4-difluoromethoxy, 4-phenoxy, and 4-N-morpholine substitutions had anthelmintic activities (IC50 values in the range of 1.9 to 8.9 μM) that were greater than either of the parent natural products-desmethoxyyangonin (IC50 of 37.1 μM) and yangonin (IC50 of 15.0 μM). The synthesized analogues did not exhibit toxicity on HepG2 human hepatoma cells in vitro at concentrations of up to 40 μM. These findings confirm the previously-identified kavalactone scaffold as a promising chemotype for new anthelmintics and provide a basis for a detailed SAR investigation focused on developing a novel anthelmintic agent.
- Chang, Bill C. H.,Dilrukshi Herath, H. M. P.,Garcia-Bustos, José,Gasser, Robin B.,Hofmann, Andreas,Jabbar, Abdul,Ma, Guangxu,Nguyen, Nghi,Sleebs, Brad E.,Taki, Aya C.,Wang, Tao
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supporting information
(2020/04/30)
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- Hispidine compound and application thereof
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The invention relates to the technical field of synthetic medicine, in particular to a hispidine compound and pharmaceutical salt thereof, and application to the aspect of treating and preventing obesity and hyperlipemia. The hispidine compound can obviously inhibit the accumulation of triglyceride and total fat in the 3T3-L1 preadipocyte differentiation process; the inhibition effect is superiorto that of a positive control compound of jamaicin; no obvious cytotoxicity exists. In addition, a beta-lactam hispidine compound can also regulate and control the phosphorylation of transcription factors AMPK and ACC of fat metabolism and the SIRT1 expression quantity, and can regulate and control the expression quantity of transcription factors PPAR-gamma, SREBP-1c and FABP4 of the adipocyte differentiation. Therefore the medicine containing the hispidine compound and/or the pharmaceutical salt has good effects of inhibiting the adipocyte differentiation and reducing oil drops and triglyceride in the adipocyte; good development prospects are realized in the aspects of treating or preventing obesity and reducing the blood fat.
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Paragraph 0040; 0043; 0045
(2018/03/25)
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- Toward (-)-Enterocin: An Improved Cuprate Barbier Protocol to Overcome Strain and Sterical Hindrance
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An approach toward (-)-enterocin, an antibiotic isolated from Streptomyces hygroscopicus, is described. Its compact, heavily oxidized protoadamantane core represents a daunting challenge for an efficient synthesis. Convergent assembly of its 2-oxabicyclo[3.3.1]nonane core with a cuprate-mediated Barbier reaction is disclosed. Its functionalization to a suitable substrate for a biomimetic aldol to close the final ring of the natural product is evaluated.
- Rizzo, Antonio,Trauner, Dirk
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supporting information
p. 1841 - 1844
(2018/04/16)
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- Synthesis of 5,6-dehydrokawain and some fluorinated analogues
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An efficient methodology for the synthesis of 6-styrenylpyrone in a four-step sequence is reported. The reactions were performed under catalyst-free conditions with mild and affordable reagents to produce 5,6-dehydrokawain and fluorinated derivatives in good to excellent overall yields (72–86%) on a multigram scale. Two novel difluorinated derivatives are reported here for the first time.
- Obi, Grace,Van Heerden, Fanie R.
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supporting information
p. 1482 - 1486
(2018/05/31)
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- Design, syntheses and lipid accumulation inhibitory activities of novel resveratrol mimics
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Hispidine was initially discovered from Ficus Hispida for cardiovascular protection. In this paper, hispidine derivatives, which contain a novel resveratrol-like scaffold, have been designed, synthesized, and assayed as agents against lipid accumulations in 3T3-L1 pre-adipocytes. Six hispidine derivatives have the activity of reducing TG in 3T3-L1 adipocytes in dosage-dependent manner. The most active compound can reduce the lipid accumulation up to 78.4% at 10 μM qPCR and Western blotting results demonstrate that the two most active compounds inhibit both lipodenesis and adipogenesis in 3T3-L1 cells through (1) increasing the phosphorylations of AMPK and ACC, promoting SIRT1 expression. These three proteins are key regulators for lipogenesis and energy metabolism. (2) Decreasing the expressions of PPARγ, sREBP-1c, and FABP4, which are pivotal regulators for adipogenesis. Overall, this work proves that hispidine derivatives diminish the lipid accumulation in 3T3-L1 cell line by downregulating lipogenic and adipogenic pathways.
- Li, Chanjuan,Cheng, Bao,Fang, Sai,Zhou, Huihao,Gu, Qiong,Xu, Jun
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p. 114 - 122
(2017/11/27)
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- Synthesis of novel 5,6-dehydrokawain analogs as osteogenic inducers and their action mechanisms
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An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synthesized and evaluated series of 5,6-dehydrokawain analogs. Our structure-activity relationships revealed that alkylation of para or meta position of aromatic ring of 1 promote osteogenic activity. Among the potential analogs we synthesized, (E)-6-(4-Ethylstyryl)-4-methoxy-2H-pyran-2-one (14) and (E)-6-(4-Butylstyryl)-4-methoxy-2H-pyran-2-one (21) both significantly up-regulated Runx2 and Osterix mRNA expression at 10?μM. These osteogenic activities could be mediated by bone morphogenetic protein (BMP) and activation of p38 MAPK signaling pathways. Compounds 14 and 21 also inhibited RANKL-induced osteoclast differentiation of RAW264 cells. These results indicated that novel 5,6-dehydrokawain analogs not only increase osteogenic activity but also inhibit osteoclast differentiation, and could be potential lead compounds for the development of anti-osteoporosis agents.
- Kumagai, Momochika,Nishikawa, Keisuke,Mishima, Takashi,Yoshida, Izumi,Ide, Masahiro,Koizumi, Keiko,Nakamura, Munetomo,Morimoto, Yoshiki
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supporting information
p. 2401 - 2406
(2017/05/09)
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- Easy and green synthesis of 6-(arylvinyl)-4-hydroxy-3-(phenylsulfanyl)-2H-pyran-2-ones in aqueous potassium hydroxide
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A convenient green procedure have been proposed for the synthesis of 6-(2-arylvinyl)-4-hydroxy-3-(phenylsulfanyl)-2H-pyran-2-ones by condensation of 6-(arylvinyl)-4-hydroxy-2H-pyran-2-ones with S-phenyl benzenesulfonothioate in aqueous potassium hydroxide at room temperature.
- Benferrah,Hammadi,Berthiol
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p. 2881 - 2886
(2017/03/22)
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- An improved aldol protocol for the preparation of 6-styrenylpyrones
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An improved aldol protocol for the synthesis of 6-styrenylpyrones is reported. The first synthesis of PTP1B inhibitor 1 and 4 has been described.
- Kraus, George A.,Wanninayake, Umayangani K.
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p. 7112 - 7114
(2015/12/01)
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- Heck-matsuda arylation as a strategy to access kavalactones isolated from polygala sabulosa, piper methysticum, and analogues
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Herein, we describe the total syntheses of three bioactive pyrones isolated from Polygala sabulosa (i.e., 1, 4, and 7) and eight isolated from Piper methysticum (i.e., 8-10, 13, 15, and 18-20) using the Heck-Matsuda arylation as the key strategy. The evaluation of this methodology by employing different arenediazonium tetrafluoroborates revealed that the Heck arylation was more efficient when the olefin undergoing arylation possessed the vinyl-2-pyrone structural unit instead of the vinyl dihydro-2-pyrone moiety. The Heck-Matsuda arylation of many of the examined olefins proceeded in a practical manner with total regio- and stereocontrol.
- Soldi, Cristian,Moro, Angelica V.,Pizzolatti, Moacir G.,Correia, Carlos R. D.
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experimental part
p. 3607 - 3616
(2012/07/31)
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- Synthesis and antimalarial and antituberculosis activities of a series of natural and unnatural 4-methoxy-6-styryl-pyran-2-ones, dihydro analogues and photo-dimers
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Previous studies have identified the 3,6-dialkyl-4-hydroxy-pyran-2-one marine microbial metabolites pseudopyronines A and B to be modest growth inhibitors of Mycobacterium tuberculosis and a range of tropical diseases including Plasmodium falciparum and Leishmania donovani. In an effort to expand the structure-activity relationship of this compound class towards infectious diseases, a library of natural product and natural product-like 4-methoxy-6-styryl-pyran-2-ones and a subset of catalytically reduced examples were synthesized. In addition, the photochemical reactivity of several of the 4-methoxy-6-styryl-pyran-2-ones were investigated yielding head-to-head and head-to-tail cyclobutane dimers as well as examples of asymmetric aniba-dimer A-type dimers. All compounds were evaluated for cytotoxicity and activity against M. tuberculosis, P. falciparum, L. donovani, Trypanosoma brucei rhodesiense and Trypanosoma cruzi. Of the styryl-pyranones, natural product 3 and non-natural styrene and naphthalene substituted examples 13, 18, 21, 22 and 23 exhibited antimalarial activity (IC50 10. Δ7 Dihydro analogues were typically less active or lacked selectivity. Head-to-head and head-to-tail photodimers 5 and 34 exhibited moderate IC50s of 2.3 to 17 μM towards several of the parasitic organisms, while the aniba-dimer-type asymmetric dimers 31 and 33 were identified as being moderately active towards P. falciparum (IC50 1.5 and 1.7 μM) with good selectivity (SI ~80). The 4-tert-butyl aniba-dimer A analogue 33 also exhibited activity towards L. donovani (IC50 4.5 μM), suggesting further elaboration of this latter scaffold could lead to the identification of new leads for the dual treatment of malaria and leishmaniasis.
- McCracken, Stephen T.,Kaiser, Marcel,Boshoff, Helena I.,Boyd, Peter D.W.,Copp, Brent R.
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experimental part
p. 1482 - 1493
(2012/04/23)
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- Towards synthesis of kavalactone derivatives
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Kavalactone derivatives were synthesized using a Heck reaction of the 4-methoxy-6-vinyl-5,6-dihydropyran-2-one with aryl iodides. The Suzuki-Miyaura reaction of an aryl boronic acid and (Z)-4-methoxy-6-(2-iodovinyl)-5,6-dihydropyran-2-one has also been successfully used to produce both Z and E isomers of lactones.
- Amaral, Patrícia A.,Gouault, Nicolas,Roch, Myriam Le,Eifler-Lima, Vera L.,David, Michèle
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supporting information; experimental part
p. 6607 - 6609
(2009/04/06)
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- Triacetic acid lactone methyl ether as a natural products synthon
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Deprotonation at the 6-methyl group of 4-methoxy-6-methyl-3-trimethylsilyl-2H-pyran-2-one (ld) resulted in the formation of an extended enolate (le) which was spectroscopically identified. The utility of this enolate towards the synthesis of some natural products of polyketide origin has been described, e.g. the synthesis of 4-methoxy-6-(2-oxopropyl)-2H-pyran-2-one (4) and 4-methoxy-6-phenacyl-2H-pyran-2-one (5), the former having been isolated from Penicillium stipitatum culture, and the synthesis of 5,6-dehydrokawain (6), a natural product extracted from the wood of Aniba firmula and from the seeds of Alpina blepharocalyx. CSIRO 2000.
- Younis, Younis M.,Al-Shihry, Shar S.
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p. 589 - 591
(2007/10/03)
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