- Conformational analysis of (+)-germacrene A by variable-temperature NMR and NOE spectroscopy
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(+)-Germacrene A, an important intermediate in sesquiterpene biosynthesis, was isolated in pure form from a genetically engineered yeast and was characterized by chromatographic properties (TLC, GC), MS, optical rotation, UV, IR, 1H NMR, and 13C NMR data. Variable-temperature 500 MHz 1H NMR spectra in CDCl3 showed that this flexible cyclodecadiene ring exists as three NMR-distinguishable conformational isomers in a ratio of about 5:3:2 at or below ordinary probe temperature (25 °C). The conformer structures were assigned by 1H NMR data comparisons, NOE experiments, and vicinal couplings as follows: 1a (52%, UU), 1b (29% UD), and 1c (19%, DU).
- Faraldos, Juan A.,Wu, Shuiqin,Chappell, Joe,Coates, Robert M.
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- Pentalenene synthase. Analysis of active site residues by site-directed mutagenesis
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Incubation of farnesyl diphosphate (1) with the W308F or W308F/H309F mutants of pentalenene synthase, an enzyme from Streptomyces UC5319, yielded pentalenene (2), accompanied by varying proportions of (+)-germacrene A (7) with relatively minor changes in kcat and kcat/Km. By contrast, single H309 mutants gave rise to both (+)-germacrene A (7) and protoilludene (8) in addition to pentalenene (2). Mutation to glutamate of each of the three aspartate residues in the Mg2+-binding aspartate-rich domain, 80DDLFD, resulted in reduction in the kcat/Km for farnesyl diphosphate and formation of varying proportions of pentalenene and (+)-germacrene A (7). Formation of (+)-germacrene A (7) by the various pentalenene synthase mutants is the result of a derailment of the natural anti-Markovnikov cyclization reaction, and not simply the consequence of trapping of a normally cryptic, carbocationic intermediate. Both the N219A and N219L mutants of pentalenene synthase were completely inactive, while the corresponding N219D mutant had a kcat/Km which was 3300-fold lower than that of the wild-type synthase, and produced a mixture of pentalenene (2) (91%) and the aberrant cyclization product β-caryophyllene (9) (9%). Finally, the F77Y mutant had a kcat/Km which was reduced by 20-fold compared to that of the wild-type synthase.
- Seemann, Myriam,Zhai, Guangzhi,De Kraker, Jan-Willem,Paschall, Chiana M.,Christianson, David W.,Cane, David E.
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- Sesquiterpenes of the liverwort Scapania undulata
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The essential oil of the liverwort Scapania undulata, collected in the Harz mountains, Northern Germany, was analysed by gas chromatography (GC), GC-mass spectrometry (MS) and several new components were isolated and investigated by various NMR techniques. As new natural compounds the sesquiterpene hydrocarbons (+)-helminthogermacrene (1) [the 4Z-isomer of germacrene A (9)], (-)-cis-β-elemene (2) as a Cope-rearrangement product of 1, (+)-β-isolongibornene (3) and (-)-perfora-1,7-diene (4) could be identified. 1 has an identical mass spectrum and identical GC retention time on a non-polar stationary phase as germacrene A (9) but is considerably more stable than the latter. The Cope-rearrangement of 1 proceeds slowly at 350°C and (-)-cis-β-elemene (2) is formed together with small amounts of other diastereoisomers.
- Adio, Adewale Martins,Paul, Claudia,Kloth, Petra,Koenig, Wilfried A.
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- Synthesis of trans-β-Elemene
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Highly efficient syntheses of the anti-cancer agent trans-β-elemene have been achieved by using the readily available (±)-limonene as starting material. The syntheses were achieved in only nine to eleven steps with good overall yields. The key step in these reaction sequences is a stereoselective radical cyclization, induced by titanocene chloride.
- Benito Iglesias,Herrero Teijón,Rubio González, Rosa,Fernández-Mateos
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p. 4926 - 4932
(2018/09/11)
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- Efficient synthesis of the anticancer β-elemene and other bioactive elemanes from sustainable germacrone
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Highly efficient preparations of anticancer β-elemene and other bioactive elemanes were carried out using the natural product germacrone as a renewable starting material. The syntheses were achieved in only 3-5 steps with excellent overall yields (43-54%). An enantioselective approach to these molecules is also described
- Barrero, Alejandro F.,Herrador, M. Mar,Quilez Del Moral, Jose F.,Arteaga, Pilar,Meine, Niklas,Perez-Morales, M. Carmen,Catalan, Julieta V.
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p. 1118 - 1125
(2011/04/15)
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- A versatile photoactivatable probe designed to label the diphosphate binding site of farnesyl diphosphate utilizing enzymes
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Farnesyl diphosphate (FPP) is a substrate for a diverse number of enzymes found in nature. Photoactive analogues of isoprenoid diphosphates containing either benzophenone, diazotrifluoropropionate or azide groups have been useful for studying both the enzymes that synthesize FPP as well as those that employ FPP as a substrate. Here we describe the synthesis and properties of a new class of FPP analogues that links an unmodified farnesyl group to a diphosphate mimic containing a photoactive benzophenone moiety; thus, importantly, these compounds are photoactive FPP analogues that contain no modifications of the isoprenoid portion of the molecule that may interfere with substrate binding in the active site of an FPP utilizing enzyme. Two isomeric compounds containing meta- and para-substituted benzophenones were prepared. These two analogues inhibit Saccharomyces cerevisiae protein farnesyltransferase (ScPFTase) with IC50 values of 5.8 (meta isomer) and 3.0 μM (para isomer); the more potent analogue, the para isomer, was shown to be a competitive inhibitor of ScPFTase with respect to FPP with a KI of 0.46 μM. Radiolabeled forms of both analogues selectively labeled the β-subunit of ScPFTase. The para isomer was also shown to label Escherichia coli farnesyl diphosphate synthase and Drosophila melanogaster farnesyl diphosphate synthase. Finally, the para isomer was shown to be an alternative substrate for a sesquiterpene synthase from Nostoc sp. strain PCC7120, a cyanobacterial source; the compound also labeled the purified enzyme upon photolysis. Taken together, these results using a number of enzymes demonstrate that this new class of probes should be useful for a plethora of studies of FPP-utilizing enzymes.
- Henry, Olivier,Lopez-Gallego, Fernando,Agger, Sean A.,Schmidt-Dannert, Claudia,Sen, Stephanie,Shintani, David,Cornish, Katrina,Distefano, Mark D.
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experimental part
p. 4797 - 4805
(2009/11/30)
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- Synthesis of beta-elemene, intermediates thereto, analogues and uses thereof
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The present invention provides convergent processes for preparing beta-elemene, and analogues thereof. Also provided are analogues related to beta-elemene and intermediates useful for preparing the same. The present invention further provides novel compositions based on analogues of beta-elemene and methods for the treatment of cancer, such as brain tumor, lung cancer, colorectal cancer, gastric intestional cancer, and stomach cancer.
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Page/Page column 5
(2010/02/15)
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- Isogermacrene A, a proposed intermediate in sesquiterpene biosynthesis
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A sesquiterpene hydrocarbon, isogermacrene A (5), which is structurally related to the gorgonanes and zieranes, was isolated from the essential oil of Saccogyna viticulosa (Hepaticae). This monocyclic compound is proposed as the biogenetic intermediate of some rare sequiterpene skeletons. In the essential oil of the liverwort Saccogyna viticulosa, collected on the island of Madeira, the new sesquiterpene hydrocarbons isogermacrene A (5) and its Cope rearrangement product iso-β-elemene (6) were identified. 5 is proposed to act as the biogenetic precursor of several new sesquiterpenes identified in the volatiles of S. viticulosa. These include iso-α-humulene, α-gorgonene, gorgona-1,4(15),11-triene and gorgon-11-en-4-ol. In addition, the Cope product of zierene, isozierene, allo-aromadendra-4(15),10(14)-diene, aromadendra-4(15),10(14)-dien-1-ol and a prenylguaiane diterpene alcohol, named viticulol, were identified as new natural products.
- Hackl, Thomas,K?nig, Wilfried A.,Muhle, Hermann
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p. 2261 - 2275
(2007/10/03)
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- Absolute configuration of helminthogermacrene
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The absolute configuration of the sesquiterpene hydrocarbon helminthogermacrene is established. Helminthogermacrene is an (E,Z)-configurational isomer of germacrene A and thus undergoes similar transformations forming elemenes via Cope rearrangement and yielding bicyclic systems via acid catalyzed reactions. The reaction products are investigated using enantioselective GC and extensive NMR measurements (1H-; 1H1H-COSY; HSQC; HMBC and NOE-experiments). In addition, NMR data of related compounds isolated during the course of this investigation not yet reported in literature are given.
- Adio, Adewale Martins,Paul, Claudia,Tesso, Hailemichael,Kloth, Petra,Koenig, Wilfried A.
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p. 1631 - 1635
(2007/10/03)
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- Germacrenes from fresh costus roots
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Four germacrenes, previously shown to be intermediates in sesquiterpene lactone biosynthesis, were isolated from fresh costus roots (Saussurea lappa). The structures of (+)-germacrene A, germacra-1(10),4,11(13)-trien-12-ol, germacra-1(10),4,11(13)-trien-12-al, and germacra-1(10),4,11(13)-trien-12-oic acid were deduced by a combination of spectral data and chemical transformations. Heating of these compounds yields (-)-β-elemene, (-)-elema-1,3,11(13)-trien-12-ol, (-)-elema-1,3,11(13)-trien-12-al, and elema-1,3,11(13)-trien12-oic acid respectively, in addition to small amounts of their diastereomers. Acid induced cyclisation of the germacrenes yields selinene, costol, costal, and costic acid respectively. It is highly probable that the elemenes reported in literature for costus root oil are artefacts.
- De Kraker, Jan-Willem,Franssen, Maurice C.R,De Groot, Aede,Shibata, Toshiro,Bouwmeester, Harro J
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p. 481 - 487
(2007/10/03)
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- Stereoselective synthesis of (±)-β-elemene by a doubly diastereodifferentiating internal alkylation: A remarkable difference in the rate of enolization between syn and anti esters
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A total synthesis of the sesquiterpene (±)-β-elemene (1) has been achieved starting from a simple acyclic precursor 4. Key transformations include a 'doubly diastereodifferentiating folding and allylic strain-controlled' intramolecular ester enolate alkylation. In the course of the synthesis, we encountered remarkably different reactivity between syn and anti diastereomeric esters in the enolization step.
- Kim, Deukjoon,Lee, Jongkook,Chang, Jiyoung,Kim, Sanghee
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p. 1247 - 1252
(2007/10/03)
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- Enantioselective total synthesis of β-elemene and fuscol based on enantiocontrolled Ireland-Claisen rearrangement
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The potent antiinflammatory agent precursor (+)-fuscol (2) has been synthesized using the chiral reagent 1 to effect the key step, the completely enantioselective Ireland-Claisen rearrangement of ester 3 to acid 4a. Conversion of 4a to the corresponding aldehyde 4c, cation-olefin cyclization to 5a, and deoxygenation produced (+)-β-elemene (6). (+)-Fuscol (2) was synthesized from 6 via intermediates 7 and 8.
- Corey,Roberts, Bryan E.,Dixon, Brian R.
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p. 193 - 196
(2007/10/02)
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- SYNTHESIS OF HELMINTHOGERMACRENE AND β-ELEMENE
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Helminthogermacrene (1) and β-elemene (3) have been synthesized by a short route starting from geranylacetone.Titanium-induced cyclization of 3-isopropenyl-6-methyl-10-oxo-6E-undecenal (7) was used as the key step.
- McMurry, John E.,Kocovsky, Pavel
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p. 2171 - 2172
(2007/10/02)
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