- 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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- 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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- 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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- 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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- 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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- 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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- 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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