- 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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- Iterative polyketide synthesis via a consecutive carbonyl-protecting strategy
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To address the difficulty in protecting a β-polycarbonyl compound, a method for the sequential protection of elongating carbonyl groups was demonstrated. The iterative chain elongation of a carboxylic acid with malonic acid half thioester followed by the protection of the resulting β-ketothioester was performed via the stepwise formation of an isoxazole ring using an O-protected oxime functionality. Yangonin and isosakuranetin were synthesized according to this procedure.
- Akagawa, Kengo,Kudo, Kazuaki
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p. 4279 - 4285
(2018/04/14)
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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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- BONE METABOLISM IMPROVER
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PROBLEM TO BE SOLVED: To provide an agent and food/drink having osteoclast differentiation inhibitory action and osteoblast differentiation promoting action and useful against osteoporosis. SOLUTION: The present invention provides an osteoblast differentiation promoter or osteoclast differentiation inhibitor containing a kawalactone derivative compound as an active ingredient, and an agent for preventing or improving osteoporosis or rheumatoid arthritis that contains the same. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0055
(2018/09/26)
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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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- 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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- The Chemical Basis of Fungal Bioluminescence
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Many species of fungi naturally produce light, a phenomenon known as bioluminescence, however, the fungal substrates used in the chemical reactions that produce light have not been reported. We identified the fungal compound luciferin 3-hydroxyhispidin, which is biosynthesized by oxidation of the precursor hispidin, a known fungal and plant secondary metabolite. The fungal luciferin does not share structural similarity with the other eight known luciferins. Furthermore, it was shown that 3-hydroxyhispidin leads to bioluminescence in extracts from four diverse genera of luminous fungi, thus suggesting a common biochemical mechanism for fungal bioluminescence.
- Purtov, Konstantin V.,Petushkov, Valentin N.,Baranov, Mikhail S.,Mineev, Konstantin S.,Rodionova, Natalja S.,Kaskova, Zinaida M.,Tsarkova, Aleksandra S.,Petunin, Alexei I.,Bondar, Vladimir S.,Rodicheva, Emma K.,Medvedeva, Svetlana E.,Oba, Yuichi,Oba, Yumiko,Arseniev, Alexander S.,Lukyanov, Sergey,Gitelson, Josef I.,Yampolsky, Ilia V.
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supporting information
p. 8124 - 8128
(2015/07/07)
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- A rapid and diverse construction of 6-substituted-5,6-dihydro-4-hydroxy-2- pyrones through double Reformatsky reaction
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A rapid and diverse synthesis of biologically important 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through a double Reformatsky reaction of aldehydes to δ-hydroxy-β-ketoesters followed by lactonization is described. Due to the high functional group tolerance and reaction site discrimination between aldehyde, nitrile, and ester groups in the substrate, the protocol can provide the dihydropyrones with bromo, nitro, carboxylic acid, and β-ketoester groups, which are suitable for the further derivatizations. Furthermore, the protocol has been successfully applied to the rapid total synthesis of naturally occurring Yangonin.
- Mineno, Masahiro,Sawai, Yasuhiro,Kanno, Kazuaki,Sawada, Naotaka,Mizufune, Hideya
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p. 10921 - 10926
(2014/01/06)
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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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p. 3607 - 3616
(2012/07/31)
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- Composition for Topical Use
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The use, as a dermatological or cosmetic medicament, of compounds capable of transiently interacting with the AhR receptor (aryl hydrocarbon receptor) as agents for modulating skin functions such as sebaceous function, skin healing, skin atrophy termed “dermatoporosis”, estrogen deprivation and defense against infection, without inducing other toxic effects of the TCDD type. The compounds that interact with the AhR receptor are chosen in that they have a metabolism favorable to the dissociation of these effects, in particular by virtue of in situ production from a precursor and/or metabolization modulated in situ.
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- Highly regio- and stereoselective Heck reaction of allylic esters with arenediazonium salts: Application to the synthesis of kavalactones
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Image Presented A highly efficient palladium-catalyzed Heck reaction of allylic esters with arenediazonium salts is described. The reaction proceeds under mild conditions, with excellent to total regio- and stereochemical control and with retention of the traditional leaving group. Furthermore, the generality of the present methodology is illustrated by the short total synthesis of the natural kavalactones, yangonine, (±)-methysticin, and (±)-dihydromethysticin.
- Moro, Angelica Venturini,Cardoso, Flavio Sega Pereira,Correia, Carlos Roque Duarte
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supporting information; experimental part
p. 3642 - 3645
(2011/02/25)
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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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- Wood preservative
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A wood preservative that comprises as an active ingredient a Piper methysticum, plant or a processed product thereof or a compound represented by Formula (I): wherein R1, R2, R3, R4 and R16 are same or different and each denotes a hydrogen atom, hydroxy or a C1-4 alkoxy, or R1 and R2 are taken together to form a group represented by —O—(CH2)n—O— wherein n is an integer of 1 to 3, R5 is a C1-4 alkoxy and X is —CH=CH—, —CH2—CH2— or epoxyethylene, and the bond: denotes a single bond or a double bond can prevent the attacking wood by an insect harmful to the wood and also prevents the appearance and the growth of a wood-rotting fungus or a wood- staining fungus while being highly safe to humans and animals without exerting no adverse effect on the environment.
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- N-Acyl-2-methylaziridines: Synthesis and utility in the C-acylation of β-ketoester derived dianions
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A 'one pot' method for the preparation of N-acyl-2-methylaziridines is described, and the utility of these compounds in the C-acylation of dianions derived from β-ketoesters investigated. Application of the methodology to the synthesis of the polyketide natural product yangonin is also described.
- Lygo, Barry
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p. 12859 - 12868
(2007/10/02)
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- Functionalization at C-5 and at the C-6 Methyl Group of 4-Methoxy-6-methyl-2-pyrone
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A new entry to C-5 substituted 4-hydroxy-6-methyl-2-pyrones has been achieved.The best conditions to prepare the monobromo and the dibromo derivatives at C-3 and the C-6 methyl group of the title pyrone have been defined.The synthetic applicability of the phosphonium salts at CH3-C-6 of both 4-methoxy-6-methyl-2-pyrone, 5, and dehydroacetic acid, 2, has also been evaluated.
- Bacardit, R.,Moreno-Manas, M.,Pleixats, R.
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p. 157 - 160
(2007/10/02)
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