- Role of metabolic activation in elemicin-induced cellular toxicity
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Elemicin, an alkenylbenzene constituent of natural oils of several plant species, is widely distributed in food, dietary supplements, and medicinal plants. 1′-Hydroxylation is known to cause metabolic activation of alkenylbenzenes leading to their potential toxicity. The aim of this study was to explore the relationship between elemicin metabolism and its toxicity through comparing the metabolic maps between elemicin and 1′-hydroxyelemicin. Elemicin was transformed into a reactive metabolite of 1′-hydroxyelemicin, which was subsequently conjugated with cysteine (Cys) and N-acetylcysteine (NAC). Administration of NAC could significantly ameliorate the elemicin- A nd 1′-hydroxyelemicin-induced cytotoxicity of HepG2 cells, while depletion of Cys with diethyl maleate (DEM) increased cytotoxicity. Recombinant human CYP screening and CYP inhibition experiments revealed that multiple CYPs, notably CYP1A1, CYP1A2, and CYP3A4, were responsible for the metabolic activation of elemicin. This study revealed that metabolic activation plays a critical role in elemicin cytotoxicity.
- Wang, Yi-Kun,Yang, Xiao-Nan,Zhu, Xu,Xiao, Xue-Rong,Yang, Xiu-Wei,Qin, Hong-Bo,Gonzalez, Frank J.,Li, Fei
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- [Pd]-Catalyzedpara-selective allylation of phenols: access to 4-[(E)-3-aryl/alkylprop-2-enyl]phenols
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4-[(E)-3-Arylprop-2-enyl]phenols are omnipresent scaffolds and constitute natural products and biologically significant compounds. Obtusastyrene and obtustyrene are two such phenolic-based natural products isolated fromDalbergia retusa. The development of strategies based on a site-selective allylation, particularly protecting group-free substrates and non-activated coupling agents, is indispensable in organic synthesis. Herein, we present a highly regioselective [Pd]-catalyzedpara-allylation of phenols using simple, inactivated allylic alcohols as allylating coupling partners. Notably, this strategy is successful in open-air and under mild reaction conditions. Besides, the efficacy of the present protocol was demonstrated by the direct synthesis of obtusastyrene and obtustyrene.
- Chinnabattigalla, Sreenivasulu,Choudhury, Aditya,Gedu, Satyanarayana
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supporting information
p. 8259 - 8263
(2021/10/12)
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- Nickel-Catalyzed Reductive Csp2-Csp3Cross Coupling Using Phosphonium Salts
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A nickel-catalyzed reductive cross coupling with phosphonium salts and allylic C(sp3)-O bond electrophiles, which granted direct construction of the C(sp2)-C(sp3) bond, is successfully developed. The protocol features broad substrate scope, high-functional-group tolerance, and heterocycle compatibility. Notably, the much more challenging reductive cross coupling with heterocyclic thiazolylphosphonium salts has also been accomplished for the first time.
- Liang, Hongze,Lu, Xinyao,Luo, Yunjie,Man, Xi,Mou, Zehuai,Wang, Huifei,Wang, Yuting,Yang, Mengwan
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supporting information
p. 8183 - 8188
(2021/11/13)
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- Design and synthesis of a compound library exploiting 5-methoxyleoligin as potential cholesterol efflux promoter
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5-Methoxyleoligin and leoligin are natural occurring lignans derived from Edelweiss (Leontopodium nivale ssp. alpinum), displaying potent pro-angiogenic and pro-arteriogenic activity. Cholesterol efflux from macrophages is associated with reverse cholesterol transport which inhibits the development of cardiovascular disease. Within this study, we developed a modular and stereoselective total synthesis of 5-methoxyleoligin which can be readily used to prepare a novel compound library of related analogs. The target 5-methoxyleoligin was synthesized exploiting a recently disclosed modular route, which allows also rapid synthesis of analogous compounds. All obtained products were tested towards macrophage cholesterol efflux enhancement and the performance was compared to the parent compound leoligin. It was found that variation on the aryl moiety in 2-position of the furan ring allows optimization of the activity profile, whereas the ester-functionality does not tolerate significant alterations.
- Linder, Thomas,Geyrhofer, Sophie,Papaplioura, Eleni,Wang, Limei,Atanasov, Atanas G.,Stuppner, Hermann,Dirsch, Verena M.,Schnürch, Michael,Mihovilovic, Marko D.
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supporting information
(2020/02/18)
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- Structure-guided design, synthesis, and biological evaluation of (2-(1 H-Indol-3-yl)-1 H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) methanone (ABI-231) analogues targeting the colchicine binding site in Tubulin
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ABI-231 is a potent, orally bioavailable tubulin inhibitor that interacts with the colchicine binding site and is currently undergoing clinical trials for prostate cancer. Guided by the crystal structure of ABI-231 in complex with tubulin, we performed structure-activity relationship studies around the 3-indole moiety that led to the discovery of several potent ABI-231 analogues, most notably 10ab and 10bb. The crystal structures of 10ab and 10bb in complex with tubulin confirmed their improved molecular interactions to the colchicine site. In vitro, biological studies showed that new ABI-231 analogues disrupt tubulin polymerization, promote microtubule fragmentation, and inhibit cancer cell migration. In vivo, analogue 10bb not only significantly inhibits primary tumor growth and decreases tumor metastasis in melanoma xenograft models but also shows a significant ability to overcome paclitaxel resistance in a taxane-resistant PC-3/TxR model. In addition, pharmacological screening suggested that 10bb has a low risk of potential off-target function.
- Wang, Qinghui,Arnst, Kinsie E.,Wang, Yuxi,Kumar, Gyanendra,Ma, Dejian,White, Stephen W.,Miller, Duane D.,Li, Wei,Li, Weimin
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p. 6734 - 6750
(2019/08/20)
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- Cobalt-Catalyzed Asymmetric Hydroboration/Cyclization of 1,6-Enynes with Pinacolborane
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We report a cobalt-catalyzed asymmetric hydroboration/cyclization of 1,6-enynes with catalysts generated from Co(acac)2 and chiral bisphosphine ligands and activated in situ by reaction with pinacolborane (HBpin). A variety of oxygen-, nitrogen
- Yu, Songjie,Wu, Caizhi,Ge, Shaozhong
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supporting information
p. 6526 - 6529
(2017/05/29)
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- Isothiourea-Catalysed Acylative Kinetic Resolution of Aryl–Alkenyl (sp2vs. sp2) Substituted Secondary Alcohols
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The non-enzymatic acylative kinetic resolution of challenging aryl–alkenyl (sp2vs. sp2) substituted secondary alcohols is described, with effective enantiodiscrimination achieved using the isothiourea organocatalyst HyperBTM (1 mol %) and isobutyric anhydride. The kinetic resolution of a wide range of aryl–alkenyl substituted alcohols has been evaluated, with either electron-rich or naphthyl aryl substituents in combination with an unsubstituted vinyl substituent providing the highest selectivity (S=2–1980). The use of this protocol for the gram-scale (2.5 g) kinetic resolution of a model aryl–vinyl (sp2vs. sp2) substituted secondary alcohol is demonstrated, giving access to >1 g of each of the product enantiomers both in 99:1 e.r.
- Musolino, Stefania F.,Ojo, O. Stephen,Westwood, Nicholas J.,Taylor, James E.,Smith, Andrew D.
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supporting information
p. 18916 - 18922
(2016/12/26)
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- The synthesis and analysis of lignin-bound Hibbert ketone structures in technical lignins
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Understanding the structure of technical lignins resulting from acid-catalysed treatment of lignocellulosic biomass is important for their future applications. Here we report an investigation into the fate of lignin under acidic aqueous organosolv conditions. In particular we examine in detail the formation and reactivity of non-native Hibbert ketone structures found in isolated organosolv lignins from both Douglas fir and beech woods. Through the use of model compounds combined with HSQC, HMBC and HSQC-TOCSY NMR experiments we demonstrate that, depending on the lignin source, both S and G lignin-bound Hibbert ketone units can be present. We also show that these units can serve as a source of novel mono-aromatic compounds following an additional lignin depolymerisation reaction.
- Miles-Barrett, Daniel M.,Neal, Andrew R.,Hand, Calum,Montgomery, James R.D.,Panovic, Isabella,Ojo, O. Stephen,Lancefield, Christopher S.,Cordes, David B.,Slawin, Alexandra M.Z.,Lebl, Tomas,Westwood, Nicholas J.
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supporting information
p. 10023 - 10030
(2016/11/06)
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- Expanding the scope of the Babler–Dauben oxidation: 1,3-oxidative transposition of secondary allylic alcohols
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We report the catalytic chromium-mediated oxidation of secondary allylic alcohols to give α,β-unsaturated aldehydes with exclusive (E)-stereoselectivity. This facile procedure employs catalytic PCC (5?mol?%) and periodic acid (H5IO6) as a co-oxidant. This transformation occurs specifically with aromatic substituted allyl alcohols containing both electron withdrawing and electron donating substituents as well as a range of functional groups.
- Killoran, Patrick M.,Rossington, Steven B.,Wilkinson, James A.,Hadfield, John A.
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supporting information
p. 3954 - 3957
(2016/08/09)
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- Titanocene(III) chloride mediated radical induced addition-elimination route to the synthesis of racemic and optically active trisubstituted tetrahydrofurans: Formal synthesis of magnofargesin and 7’-epimagnofargesin
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Titanocene(III) Chloride mediated radical induced synthesis of 4-benzylidene substituted tetrahydrofuran, a typical lignan skeleton, has been accomplished in good yield through addition-elimination route in racemic as well as in optically active forms. The method has been applied to the synthesis of furano lignans, magnofargesin (1) and 7’-epimagnofargesin (2) in optically active forms.
- Chakraborty,Mandal,Roy
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p. 1067 - 1079
(2016/07/19)
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- The first stereoselective total synthesis of a new antitumour and anti-inflammatory neolignan, surinamensinol A
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The stereoselective total synthesis of an antitumour and anti-inflammatory 8-O-4′-neolignan, surinamensinol A has been accomplished starting from two aldehydes, 3,4,5-trimethoxy benzaldehyde and vanillin. The key steps involve an asymmetric reduction using a chiral oxazaborolidine complex, a Sharpless asymmetric dihydroxyllation and a Mitsunobu reaction. This is the first report of the total synthesis of surinamensinol A.
- Reddy, Parigi Raghavendar,Das, Biswanath
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p. 7432 - 7434
(2014/02/14)
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- Titanocene(III) chloride mediated formal synthesis of magnofargesin and 7′-epimagnofargesin
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Formal synthesis of two bioactive lignans, magnofargesin and 7′-epimagnofargesin has been accomplished in both racemic and optically active forms through titanocene(III) chloride (Cp2TiCl) mediated radical induced cyclization reaction. Ti(III)
- Chakraborty, Pushkin,Jana, Samaresh,Saha, Sumit,Roy, Subhas Chandra
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p. 6584 - 6587,4
(2012/12/12)
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- cis-selective single-cleavage skeletal rearrangement of 1,6-enynes reveals the multifaceted character of the intermediates in metal-catalyzed cycloisomerizations
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A skeleton in the closet: The unprecedented title rearrangement of 1,6-enynes has been observed with gold and platinum catalysts (see scheme, [M] = metal catalyst, Z = C(CO2Me)2, R = electron-donating group). This reaction is propose
- Jimenez-Nunez, Eloisa,Claverie, Christelle K.,Bour, Christophe,Cardenas, Diego J.,Echavarren, Antonio M.
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supporting information; experimental part
p. 7892 - 7895
(2009/05/07)
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- Synthesis and biological activity of the tea catechin metabolites, M4 and M6 and their methoxy-derivatives
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Syntheses are reported for metabolites M4 (1) and M6 (2) of the green tea polyphenols epicatechin (EC) and epigallocatechin (EGC) and their gallate derivatives. Several methoxy-derivatives of 1 and 2 were also prepared. Compounds 1 and 2 were evaluated for growth inhibitory activity against a panel of immortalized and malignant human cell lines with 1 being the more active compound. The possible antiinflammatory activity of 1 and its trimethoxy derivative was also evaluated. Neither compound inhibited the release of arachidonic acid, although 1 inhibited NO production by 50% at 20 μM.
- Lambert, Joshua D.,Rice, Joseph E.,Hong, Jungil,Hou, Zhe,Yang, Chung S.
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p. 873 - 876
(2007/10/03)
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- Concise Synthesis of Dihydrochalcones via Palladium-Catalyzed Coupling of Aryl Halides and 1-Aryl-2-propen-1-ols
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An expedient route to substituted dihydrochalcones is reported. The key step is a palladium-assisted arylation of 1-aryl-2-propen-1-ols. This two-step/one-purification process allows the synthesis of a wide range of compounds with original substitution patterns, including polyphenolic derivatives.
- Briot, Anne,Baehr, Corinne,Brouillard, Raymond,Wagner, Alain,Mioskowski, Charles
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p. 1374 - 1377
(2007/10/03)
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