- Cyclization mechanism of amorpha-4,11-diene synthase, a key enzyme in artemisinin biosynthesis
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Cyclization of farnesyl diphosphate into amorpha-4,11-diene by amorpha-4,11-diene synthase (ADS) initiates biosynthesis of artemisinin, a clinically important antimalarial drug precursor. Three possible ring-closure mechanisms, two involving a bisabolyl carbocation intermediate followed by either a 1,3-hydride shift or two successive 1,2-shifts, and one involving a germacrenyl carbocation, were proposed and tested by analyzing the fate of farnesyl diphosphate H-1 hydrogen atoms through 1H and 2H NMR spectroscopy. Migration of one deuterium atom of [1,1-2H 2]farnesyl diphosphate to H-10 of amorpha-4,11-diene singled out the bisabolyl carbocation mechanism with a 1,3-hydride shift. Further confirmation was obtained through enzyme reactions with (1R)- and (1S)-[1- 2H]farnesyl diphosphate. Results showed that deuterium of the 1R compound remained at H-6, whereas that of the 1S compound migrated to H-10 of amorpha-4,11-diene. Incorporation of one deuterium into amorphadiene in the cyclization process was observed when the reaction was performed in 2H2O, as evidenced by an increase of 1 amu in the mass of the molecular ion.
- Kim, Soon-Hee,Heo, Keon,Chang, Yung-Jin,Park, Si-Hyung,Rhee, Sang-Ki,Kim, Soo-Un
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Read Online
- Marine Terpenoid Diacylguanidines: Structure, Synthesis, and Biological Evaluation of Naturally Occurring Actinofide and Synthetic Analogues
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A new diacylguanidine, actinofide (1), has been isolated from the marine mollusk Actinocyclus papillatus. The structure, exhibiting a guanidine moiety acylated by two terpenoid acid units, has been established by spectroscopic methods and secured by synthesis. Following this, a series of structural analogues have been synthesized using the same procedure. All of the compounds have been evaluated in vitro for the growth inhibitory activity against a variety of cancer cell lines.
- Carbone, Marianna,Letizia Ciavatta,Mathieu, Véronique,Ingels, Aude,Kiss, Robert,Pascale, Paola,Mollo, Ernesto,Ungur, Nicon,Guo, Yue-Wei,Gavagnin, Margherita
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- Schizostatin, a novel squalene synthase inhibitor produced by the mushroom, Schizophyllum commune. II. Structure elucidation and total synthesis
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Schizostatin (1) has been isolated as a potent and selective inhibitor of squalene synthase. Its structure has been determined using spectroscopic methods: the compound is shown to be a diterpenoid which has a trans-dicarboxylic acid moiety. Total synthesis of schizostatin (1) was achieved by the highly regio- and stereoselective coupling reaction of an allylic bromide with a barium reagent. The Z-isomer 16 was also prepared using the stereoselective syn-addition of an organocopper reagent to acetylenedicarboxylate.
- Kogen, Hiroshi,Tago, Keiko,Kaneko, Satoru,Hamano, Kiyoshi,Onodera, Kaori,Haruyama, Hideyuki,Minagawa, Katsuhiro,Kinoshita, Takeshi,Ishikawa, Tomio,Tanimoto, Tatsuo,Tsujita, Yoshio
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- Formal [3 + 3] Cycloaddition Approach to Chromenes and Chromanes. Concise Total Syntheses of (±)-Rhododaurichromanic Acids A and B and Methyl (±)-Daurichromenic Ester
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(Matrix presented) Total syntheses of (±)-rhododaurichromanic acids A and B and methyl (±)-daurichromenic ester are described here. Despite the complex appearances of these compounds, their syntheses are completed in six steps with a 15% overall yield as
- Kurdyumov, Aleksey V.,Hsung, Richard P.,Ihlen, Kirsten,Wang, Jiashi
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Read Online
- METHOD FOR SYNTHESISING VITAMIN A
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A method for preparing dehydro-cyclofarnesal from dehydro-farnesal by cyclization in the presence of an acid may include the dehydro-farnesal being obtained from the farnesal by dehydrogenation and may further includes the cyclization being carried out in the presence of an acid selected from Lewis acids, Bronstedt acids, and zeolites. The synthesis of vitamin A using this method further includes the conversion of dehydro-cyclofarnesal into vitamin A.
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Paragraph 0048-0050
(2021/10/11)
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- Highly Selective and Catalytic Generation of Acyclic Quaternary Carbon Stereocenters via Functionalization of 1,3-Dienes with CO2
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The catalytic asymmetric functionalization of readily available 1,3-dienes is highly important, but current examples are mostly limited to the construction of tertiary chiral centers. The asymmetric generation of acyclic products containing all-carbon quaternary stereocenters from substituted 1,3-dienes represents a more challenging, but highly desirable, synthetic process for which there are very few examples. Herein, we report the highly selective copper-catalyzed generation of chiral all-carbon acyclic quaternary stereocenters via functionalization of 1,3-dienes with CO2. A variety of readily available 1,1-disubstituted 1,3-dienes, as well as a 1,3,5-triene, undergo reductive hydroxymethylation with high chemo-, regio-, E/Z-, and enantioselectivities. The reported method features good functional group tolerance, is readily scaled up to at least 5 mmol of starting diene, and generates chiral products that are useful building blocks for further derivatization. Systemic mechanistic investigations using density functional theory calculations were performed and provided the first theoretical investigation for an asymmetric transformation involving CO2. These computational results indicate that the 1,2-hydrocupration of 1,3-diene proceeds with high π-facial selectivity to generate an (S)-allylcopper intermediate, which further induces the chirality of the quaternary carbon center in the final product. The 1,4-addition of an internal allylcopper complex, which differs from previous reports involving terminal allylmetallic intermediates, to CO2 kinetically determines the E/Z- and regioselectivity. The rapid reduction of a copper carboxylate intermediate to the corresponding silyl-ether in the presence of Me(MeO)2SiH provides the exergonic impetus and leads to chemoselective hydroxymethylation rather than carboxylation. These results provide new insights for guiding further development of asymmetric C-C bond formations with CO2
- Chen, Xiao-Wang,Zhu, Lei,Gui, Yong-Yuan,Jing, Ke,Jiang, Yuan-Xu,Bo, Zhi-Yu,Lan, Yu,Li, Jing,Yu, Da-Gang
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p. 18825 - 18835
(2019/11/28)
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- Bicatalytic Multistep Reactions En Route to the One-Pot Total Synthesis of Complex Molecules: Easy Access to Chromene and 1,2-Dihydroquinoline Derivatives from Simple Substrates
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By combining nanocatalysis with base catalysis, a novel one-pot multistep process was found for the synthesis of substituted heterocycles of biological relevance from simple substrates. The process is based on the initial Au/O2 oxidation of allylic alcohols, which is followed by base-catalyzed tandem hetero-Michael/aldolization/crotonization with ortho-hydroxy- or ortho-aminobenzaldehydes. The flexibility of the reaction even allowed the benzaldehyde partner to be prepared in situ in an example of a one-pot/five-step process.
- Giorgi, Pascal D.,Miedziak, Peter J.,Edwards, Jennifer K.,Hutchings, Graham J.,Antoniotti, Sylvain
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- PRODUCTION OF FARNESOL
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The present invention relates to an improved way for the production of farnesol.
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Page/Page column 10
(2017/04/11)
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- Selective Oxidation of Activated Alcohols by Supported Gold Nanoparticles under an Atmospheric Pressure of O2: Batch and Continuous-Flow Studies
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In the hunt for a simple, mild, and scalable protocol for gold nanoparticle-catalyzed oxidation of benzylic and allylic alcohols under O2, we have used commercially available gold nanoparticles supported on alumina to selectively oxidize a large range of activated alcohols to the corresponding carbonyl compounds in good yields (68–99 %) and with excellent selectivity (ca. 100 %). The true heterogeneous nature of the catalysis by gold was demonstrated, allowing us to further adapt this protocol to continuous-flow reactors by using the tube-in-tube technology, in which higher yields were obtained thanks to an improved oxygenation of the reaction medium.
- Giorgi, Pascal D.,Elizarov, Nelli,Antoniotti, Sylvain
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p. 1830 - 1836
(2017/05/29)
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- Bis (acetylacetonate) Dioxothiazolidine molybdenum (VI) using the method of manufacturing a [...]
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PROBLEM TO BE SOLVED: To provide a method for producing farnesal useful as an intermediate for the production of a medicine, an agrochemical and perfume.SOLUTION: A method for producing farnesal represented by formula (2) includes reacting (E)-nerolidol represented by formula (1) with an oxidizing agent in the presence of bis(acetylacetonato)dioxomolybdenum(VI).
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Paragraph 0037-0045
(2018/06/30)
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- Bis (acetylacetonate) oxocarboxylic vanadium (IV) [...] manufacturing method using the same
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PROBLEM TO BE SOLVED: To provide a method for producing farnesal useful as an intermediate for the production of a medicine, an agrochemical and perfume.SOLUTION: A method for producing farnesal represented by formula (2) includes reacting (E)-nerolidol represented by formula (1) with an oxidizing agent in the presence of a piperidin-1-oxyl compound and/or a sulfoxide using bis(acetylacetonato)oxovanadium(IV) and an oxidizing agent.
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Paragraph 0039-0046
(2018/09/02)
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- Convenient synthesis of deuterium labelled sesquiterpenes
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Sesquiterpenes are an important class of molecules, with roles ranging from pollination and signalling to defense mechanisms. Despite their apparent importance, the limited number of commercial standards has hindered their study and precise quantification. Herein, we report the syntheses of fourteen labelled sesquiterpenes with a high level of deuterium incorporation (>95%) for applications in MS-based studies.
- Duhamel, Nina,Martin, Damian,Larcher, Roberto,Fedrizzi, Bruno,Barker, David
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supporting information
p. 4496 - 4499
(2016/09/14)
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- (2E, 6E) enriching [...] -
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PROBLEM TO BE SOLVED: To provide a method for producing (2E, 6E)-farnesal useful as an intermediate for the production of a polyisoprenoid derivative useful as an anticancer agent.SOLUTION: The method for producing (2E, 6E)-farnesal includes heating (2Z, 6E)-farnesal in the presence of a piperidin-1-oxyl compound represented by formula (1) [wherein Ris a hydrogen atom; Ris a hydrogen atom, cyano, carboxy, isothiocyanato, maleimide, phosphate group, -OR' group or -NHR group (wherein R' is a hydrogen atom, 1-4C alkyl, acyl or 1-4C alkanesulfonyl; R is a hydrogen atom, acetyl or haloacetyl); or Rand Rtogether form an oxo group].
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Paragraph 0046
(2018/09/25)
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- Method for preparing french Nepal aldehydeaccompanies the Swiss Uygur A and method for the preparation of acid
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The invention provides a preparation method for Fanny aldehyde. The method comprises the step of performing an oxidizing reaction on farnesol under the effects of a catalyst and an oxidizing agent in an organic solvent to obtain the Fanny aldehyde, wherein the catalyst is Cu (copper) or a cupric compound. The invention further provides a preparation method for peretinoin. By the method disclosed by the invention, the metallic copper or the cupric compound are used as the catalyst to catalyze farnesol into the Fanny aldehyde, so that not only is the catalytic efficiency higher and the reaction conditions are mild, but also the purity and the yield of the prepared Fanny aldehyde are higher, and the Fanny aldehyde can be directly used for subsequently preparing the peretinoin without being purified. In addition, the preparation method for the Fanny aldehyde disclosed by the invention is green and pollution-free, and the industrial production can be realized. Experiment results prove that the yield of the Fanny aldehyde prepared by the method provided by the invention is more than 85%, and the purity is more than 95%; experiment results prove that the purity of a crude product of the peretinoin prepared by the method provided by the invention is more than 98%, and the purity is more than 99% after the crude product is recrystallized and refined.
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Paragraph 0078; 0079
(2017/04/05)
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- Method of preparation of stereospecific quinone derivatives
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A novel process for the regio- and stereospecific synthesis of polyprenylated quinone derivatives, such as Vitamin K1, K2 and Ubiquinone, has been achieved exploiting dithioacetal-, especially 1,3-dithiane-, mediated Umpolung chemistry which works along a new concept "Inhibiting resonance delocalization (IRD)" to overcome isomerization generated due to delocalization of allylic carbanions on the π-electron cloud of an allylic system. The present novel synthesis of all-trans Vitamins K1, K2 and Ubiquinone is achieved by coupling of a quinone group with a polyprenyl side chain where either of the two moieties may have 1,3-dithiane as a terminal group while undergoing umpolung chemistry. Similarly while coupling two polyprenyl fragments to each other in building of the all-trans side chain. A stereospecific synthesis of vitamin K1 was also achieved along the same synthetic outline using a chiral hexahydrofarnesyl derivative retaining optical and geometrical isomeric properties equivalent to those of the natural K1.
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Paragraph 0072-0073
(2015/05/19)
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- METHOD OF PREPARATION OF STEREOSPECIFIC QUINONE DERIVATIVES
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The description provides processes for the regio and stereospecific synthesis of polyprenylatedquinone derivatives, such as Vitamin K1, K2 and Ubiquinone, exploiting dithioacetals, especially 1,3-dithiane, mediated Umpolung chemistry which works along a new concept “Inhibiting resonance delocalization (IRD)” to overcome isomerization generated due to delocalization of allyliccarbanion on the π-electron cloud of an allylic systems by the conventional synthesis.
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Paragraph 0169-0170
(2015/05/13)
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- METHOD FOR PRODUCING FARNESAL USING VANADIUM COMPLEX
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The present invention provides a method for producing farnesal that is useful as a production intermediate of pharmaceuticals, agricultural chemicals and perfumes. More specifically, the present invention provides a method for producing farnesal (3), comp
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Paragraph 0102
(2014/11/13)
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- FENDILINE DERIVATIVES AND METHODS OF USE THEREOF
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Disclosed herein are novel derivatives of fendiline, including compounds of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising these derivative compounds. Methods and intermediates useful for making the derivatives, and methods of using the derivatives, for example, for the inhibition of K-Ras plasma membrane localization, and compositions thereof, including for the treatment of cancer, are also provided.
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Page/Page column 80; 81
(2014/03/25)
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- Iron-catalyzed aerobic oxidation of allylic alcohols: The issue of C=C bond isomerization
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An aerobic oxidation of allylic alcohols using Fe(NO3) 3·9H2O/TEMPO/NaCl as catalysts under atmospheric pressure of oxygen at room temperature was developed. This eco-friendly and mild protocol provides a convenient pathway to the synthesis of stereodefined α,β-unsaturated enals or enones with the retention of the C-C double-bond configuration.
- Liu, Jinxian,Ma, Shengming
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supporting information
p. 5150 - 5153
(2013/11/06)
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- Naphthyl groups in chiral recognition: Structures of salts and esters of 2-methoxy-2-naphthylpropanoic acids
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The crystal structures of salt 8, which was prepared from (R)-2-methoxy-2-(2-naphthyl)propanoic acid ((R)-MβNP acid, (R)-2) and (R)-1-phenylethylamine ((R)-PEA, (R)-6), and salt 9, which was prepared from (R)-2-methoxy-2-(1-naphthyl)propanoic acid ((R)-MαNP acid, (R)-1) and (R)-1-(p-tolyl)ethylamine ((R)-TEA, (R)-7), were determined by X-ray crystallography. The MβNP and MαNP anions formed ion-pairs with the PEA and TEA cations, respectively, through a methoxy-group-assisted salt bridge and aromatic CH...π interactions. The networks of salt bridges formed 21 columns in both salts. Finally, (S)-(2E,6E)-(1-2H 1)farnesol ((S)-13) was prepared from the reaction of (2E,6E)-farnesal (11) with deuterated (R)-BINAL-H (i.e., (R)-BINAL-D). The enantiomeric excess of compound (S)-13 was determined by NMR analysis of (S)-MαNP ester 14. The solution-state structures of MαNP esters that were prepared from primary alcohols were also elucidated. Princess and the PEA: The crystal structures of the MαNP and MβNP salts were determined by X-ray crystallography. The 1-naphthyl group of the MαNP anion and the 2-naphthyl group of the MβNP anion acted as a C-H donor and -acceptor, respectively. Copyright
- Ichikawa, Akio,Ono, Hiroshi,Mikata, Yuji
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p. 2294 - 2304,11
(2020/08/24)
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- Synthetic studies towards stachybotrin C
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The preparation of racemic des-hydroxy stachybotrin C is described. Different approaches have been studied. Observations made in the course of the synthesis show the efficiency of the intermolecular cyclization between the diethyl acetal 19 and phenol 12 leading to the benzopyran moiety 17. Georg Thieme Verlag KG · Stuttgart · New York.
- Tumma, Naresh,Jacolot, Maiwenn,Jean, Mickael,Chandrasekhar, Srivari,Van De Weghe, Pierre
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supporting information
p. 2919 - 2922
(2013/02/22)
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- Roles of rat and human aldo-keto reductases in metabolism of farnesol and geranylgeraniol
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Farnesol (FOH) and geranylgeraniol (GGOH) with multiple biological actions are produced from the mevalonate pathway, and catabolized into farnesoic acid and geranylgeranoic acid, respectively, via the aldehyde intermediates (farnesal and geranylgeranial). We investigated the intracellular distribution, sequences and properties of the oxidoreductases responsible for the metabolic steps in rat tissues. The oxidation of FOH and GGOH into their aldehyde intermediates were mainly mediated by alcohol dehydrogenases 1 (in the liver and colon) and 7 (in the stomach and lung), and the subsequent step into the carboxylic acids was catalyzed by a microsomal aldehyde dehydrogenase. In addition, high reductase activity catalyzing the aldehyde intermediates into FOH (or GGOH) was detected in the cytosols of the extra-hepatic tissues, where the major reductase was identified as aldo-keto reductase (AKR) 1C15. Human reductases with similar specificity were identified as AKR1B10 and AKR1C3, which most efficiently reduced farnesal and geranylgeranial among seven enzymes in the AKR1A-1C subfamilies. The overall metabolism from FOH to farnesoic acid in cultured cells was significantly decreased by overexpression of AKR1C15, and increased by addition of AKR1C3 inhibitors, tolfenamic acid and R-flurbiprofen. Thus, AKRs (1C15 in rats, and 1B10 and 1C3 in humans) may play an important role in controlling the bioavailability of FOH and GGOH.
- Endo, Satoshi,Matsunaga, Toshiyuki,Ohta, Chisato,Soda, Midori,Kanamori, Ayano,Kitade, Yukio,Ohno, Satoshi,Tajima, Kazuo,El-Kabbani, Ossama,Hara, Akira
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experimental part
p. 261 - 268
(2012/04/11)
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- Synthesis of (sulfonyl)methylphosphonate analogs of prenyl diphosphates
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Syntheses of several (sulfonyl)methylphosphonate analogs of geranyl, neryl, and farnesyl diphosphates are described. Key steps include utilization of an (E)-selective Horner-Wadsworth-Emmons olefination which couples an aldehyde to the sulfone phosphonate moiety, and a selective reduction of the resulting dienyl sulfone phosphonate substrates.
- Lodewyk, Michael W.,Lui, Victor G.,Tantillo, Dean J.
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supporting information; experimental part
p. 170 - 173
(2010/03/04)
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- Synthetic studies toward the PPAP natural products, prolifenones A and B and hyperforin: An Effenberger cyclization approach
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A synthetic approach toward the geranylated PPAP natural products, prolifenones A and B, employing Effenberger cyclization as the key step, is delineated. The efficacy of this approach is further expanded through access to an advanced precursor of hyperfo
- Mehta, Goverdhan,Dhanbal, Thangavel,Bera, Mrinal K.
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scheme or table
p. 5302 - 5305
(2010/11/03)
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- Ti-catalyzed Barbier-type allylations and related reactions
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Titanocene(III) complexes, easily generated in situ from commercial Ti IV precursors, catalyze Barbiertype allylations, intramolecular crotylations (cyclizations), and prenylations of a wide range of aldehydes and ketones. The reaction displays surprising and unprecedented mechanistic subtleties. In cyclizations a fast and irreversible addition of an allyl radical to a TiIII-coordinated carbonyl group seems to occur. Intermolecular additions to conjugated aldehydes proceed through a coupling of a Ti IV-bound ketyl radical with an allyl radical. Reactions of ketones with allylic halides take place by the classical addition of an allylic organometallic reagent. The radical coupling processes enable transformations such as the highly regioselective α-prenylation that are otherwise difficult to achieve. The mild reaction conditions and the possibility to employ titanocene complexes in only catalytic quantities are highly attractive features of our protocol. These unusual properties have been taken advantage of for the straightforward synthesis of the natural products rosiridol, shikalkin, and 12-hydroxysqualene.
- Estevez, Rosa E.,Justicia, Jose,Bazdi, Btissam,Fuentes, Noelia,Paradas, Miguel,Choquesillo-Lazarte, Duane,Garcia-Ruiz, Juan M.,Robles, Rafael,Gansaeuer, Andreas,Cuerva, Juan M.,Oltra, J. Enrique
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experimental part
p. 2774 - 2791
(2009/12/03)
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- Influence of heterocyclic and oxime-containing farnesol analogs on quorum sensing and pathogenicity in Candida albicans
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A series of synthetic molecules combining a geranyl backbone with a heterocyclic or oxime head group are quorum-sensing molecules that block the yeast to mycelium transition in the dimorphic fungus Candida albicans. A number of the analogs have an IC50 ≤ 10 μM, a level of potency essentially identical to the natural quorum sensing signal, the sesquiterpene farnesol. Two of the most potent analogs, neither toxic toward healthy mice, display remarkably different effects when co-administered with C. albicans. While neither offers protection from candidiasis, one analog mimics farnesol in acting as a virulence factor, whereas the other has no effect. The results offer the first example of highly potent synthetic fungal quorum-sensing molecules, and provide the first evidence for the ability to decouple quorum sensing and virulence.
- Shchepin, Roman,Navarathna, Dhammika H.M.L.P.,Dumitru, Raluca,Lippold, Shane,Nickerson, Kenneth W.,Dussault, Patrick H.
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p. 1842 - 1848
(2008/09/20)
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- Large-scale synthesis of immunoactivating natural product, pristane, by continuous microfluidic dehydration as the key step
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(Figure Presented) An efficient protocol of dehydration was developed under microfluidic conditions. The method was applied to a multikilogram synthesis of pristane, a biologically important natural product, which is now widely used as an adjuvant for monoclonal antibody production.
- Tanaka, Katsunori,Motomatsu, Shinya,Koyama, Koichi,Tanaka, Shin-Ichi,Fukase, Koichi
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p. 299 - 302
(2007/10/03)
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- Substituted Cyclohexadienals - Syntheses and Applications
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The present invention is generally directed to the use of L-proline and certain derivatives thereof to catalyze the asymmetric self-condensation of α,β-unsaturated aldehydes to form homodimer and heterodimer cyclohexadienals. Reaction conditions are mild
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Page/Page column 17
(2010/11/28)
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- Phosphonates useful as modulators of t γ(g)9γ(d)2 lymphocyte activity
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The invention concerns novel phosphonate derivatives, preparation method, use thereof as ligands modulating T γ9δ2 lymphocyte activity and pharmaceutical compositions comprising them.
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Page/Page column 7-8
(2010/11/24)
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- Conjugated nitro alkene anticancer agents based on isoprenoid metabolism
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Conjugated nitro alkene compounds hamper or prevent proliferation of cancer cells in cell culture and in cancer patients, which can result in a decrease in tumor size and/or disappearance of the cancer. The compounds may act by interference with cancer cell biochemistry, in which isoprenoid groups such as farnesyl and geranylgeranyl become bonded to various oncogenic proteins such as Ras, RhoA, RhoB, or some other growth-related cellular protein(s).
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Page/Page column 12
(2008/06/13)
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- A modular and concise total synthesis of (±)-daurichromenic acid and analogues
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A modular and concise total synthesis of (±)-daurichromenic acid has been accomplished in four steps from ethyl acetoacetate, ethyl crotonate, and trans,trans-farnesal. A series of analogues of this natural product, which has potent anti-HIV activity, were also prepared from ethyl or methyl acetoacetate and a series of readily available α,β-unsaturated esters and aldehydes.
- Hu, Hongjuan,Harrison, Tyler J.,Wilson, Peter D.
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p. 3782 - 3786
(2007/10/03)
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- Synthesis, characterization and transfection activity of new saturated and unsaturated cationic lipids
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We synthesized new cationic lipids, analogue to N-[1-(2,3-dioleoyloxy) propyl]-N,N,N-trimethylammonium chloride (DOTMA) and 1,2-dimyristyloxypropyl-3- dimethyl-hydroxyethylammonium bromide (DMRIE), in order to compare those containing a dodecyl chain with those having a relatively long chain with two or five double bonds, such as squalenyl and dihydrofarnesyl derivatives, or complex saturated structures, such as squalane derivatives. The fusogenic helper lipid dioleoylphosphatidylethanolamine (DOPE) was added to cationic lipids to form a stable complex. Liposomes composed of 50:50 w/w cationic lipid/DOPE were prepared and incubated with plasmidic DNA at various charge ratios and the diameter and zeta potential of the complexes were measured. The surface charge of the DNA/lipid complexes can be controlled by adjusting the cationic lipid/DNA ratio. Finally, we tested the in vitro transfection efficiency of the cationic lipid/DNA complexes using different cell lines. The transfection efficiency was highest for the dodecyloxy derivative containing a single hydroxyethyl group in the head, followed by the dodecyloxy and the farnesyloxy trimethylammonium derivatives. Instead the C27 squalenyl and C27 squalanyl derivatives resulted inactive.
- Arpicco, Silvia,Canevari, Silvana,Ceruti, Maurizio,Galmozzi, Enrico,Rocco, Flavio,Cattel, Luigi
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p. 869 - 878
(2007/10/03)
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- Synthesis of prenyl pyrophosphonates as new potent phosphoantigens inducing selective activation of human Vγ9Vδ2 T lymphocytes
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γ9δ2T cells represent the most abundant population of human blood γδT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus- containing antigens in the family of prenyl pyrophosphates and their related biosynthetic precursors such as isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are naturally occurring metabolites in mycobacteria and several other microbial pathogens. The broad specificity in the recognition of these molecules by the T-lymphocyte population expressing a Vγ9Vδ2 cell receptor might facilitate their manipulation by designing small potent synthetic agonist ligands. In this paper, we describe the synthesis and the biological evaluation of new pyrophosphonate compounds as new isosteric analogues of natural prenyl pyrophosphates. Several prenyl and alkenyl pyrophosphonate with different chain lengths and degrees of insaturation (24-28, 48-50, and 64-66) were tested as well as the alkoxymethylpyrophosphonic analogue of IPP (compound 76) as its closest isostere. Several of them appeared to be better activators of Vγ9Vδ2 T cell proliferation than IPP. These results open the perspective of a potential use of isoprenoides pyrophosphonates as specific immunoregulatory molecules.
- Zgani, Ibrahim,Menut, Chantal,Seman, Michel,Gallois, Valerie,Laffont, Virginie,Liautard, Jeanine,Liautard, Jean-Pierre,Criton, Marc,Montero, Jean-Louis
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p. 4600 - 4612
(2007/10/03)
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- Niaviolides, new macrocyclic sesquiterpenes secreted by males of the African butterfly Amauris niavius
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The abdominal androconial organs ("hairpencils") of the African butterfly Amauris niavius (Danainae) emit a complex scent bouquet consisting of previously described aromatic compounds, terpenoids, fatty acids, and hydrocarbons. This work reports the identification of two major sesquiterpenes, each possessing a unique 13-membered macrolide ring, originating from an α,ω-oxidation pattern of the sesquiterpene backbone. To the best of our knowledge, sesquiterpene macrolides have not been found before in nature. The structure elucidation of the two compounds, which we propose to call niaviolide (3) and epoxyniaviolide (4), by NMR and GC/MS experiments is presented, together with their subsequent synthesis. Finally, the absolute configuration of natural 4 was determined to be (S,S) by stereoselective synthesis and chiral gas chromatography. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Stritzke, Katja,Schulz, Stefan,Boppre, Michael
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p. 1337 - 1342
(2007/10/03)
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- Total Synthesis of the Highly Potent Anti-HIV Natural Product Daurichromenic Acid along with Its Two Chromane Derivatives, Rhododaurichromanic Acids A and B
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(Equation presented) The highly potent anti-HIV natural product daurichromenic acid was successfully synthesized in only five steps with 49% overall yield. The key step in the synthetic strategy involves a microwave-assisted tandem condensation and intramolecular SN2′- type cyclization to form the 2H-benzopyran core structure.
- Kang, Ying,Mei, Yan,Du, Yuguo,Jin, Zhendong
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p. 4481 - 4484
(2007/10/03)
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- Insect toxins from spruce endophytes
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Extracts of fermentation cultures of a fungal endophyte (DAOM 221611) from spruce needles have afforded the known macrocyclic antibiotic vermiculin (1), 7α,8β,11-trihydroxydrimane (2), and eight novel 13-carbon γ-lactones, namely trans-3-methyldodec-cis-6-en-4-olide (3), trans-8-hydroxy-3-methyldodec-cis-6-en-4-olide (4), trans-8-acetoxy-3-methyldodec-cis-6-en-4-olide (5), trans-9-hydroxy-3-methyl-8-oxo-dodec-trans-6-en-4-olide (6), trans-8,9-dihydroxy-3-methyldodec-cis-6-en-4-olide (7), trans-9-hydroxy-8-oxo-3-methyldodecan-4-olide (8), trans-7,9-dihydroxy-3-methyl-8-oxo-dodecan-4-olide (9), and trans-6-hydroxymethyl-3-methyl-7-oxo-undecan-4-olide (10). A known JH III metabolism product, 10,11-dihydroxyfarnesenic acid (11), was also isolated and synthesized from farnesol. Other endophyte cultures from black spruce and white spruce afforded the novel 6,7-dihydroxy-2-propyl-2,4-octadien-4-olide (16), 5,6,8-trihydroxy-4-(1′-hydroxyethyl) isocoumarin (17) plus the known sescandelin (18), sescandelin B (19), and 4-hydroxy-2-methoxyacetanilide (20). Several of the γ-lactones showed toxicity to spruce budworm (Choristoneura fumiferana Clem.) larvae and vermiculin 1 and compound 16 were toxic to spruce budworm cells.
- Findlay, John A.,Li, Guoqiang,Miller, J. David,Womiloju, Taiwo O.
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p. 284 - 292
(2007/10/03)
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- Method for oxidation of allyl alcohol
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Allyl alcohols are converted into corresponding aldehydes or ketones in a high yield under a mild condition by using an inexpensive aluminum alkoxide as an Oppenauer oxidation catalyst and a hydride acceptor. Thus, there is provided an industrially useful method for converting allyl alcohols to corresponding aldehydes or ketones.
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- Enantio- and diastereoselective stepwise cyclization of polyprenoids induced by chiral and achiral LBAs. A new entry to (-)-ambrox, (+)-podocarpa-8,11,13-triene diterpenoids, and (-)-tetracyclic polyprenoid of sedimentary origin
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An enantio- and diastereoselective stepwise cyclization of polyprenoids induced by Lewis acid-assisted chiral Bronsted acids (chiral LBAs) and achiral LBAs is described. In particular, the absolute stereocontrol in the initial cyclization of polyprenoids to form an A-ring induced by chiral LBAs and the importance of the nucleophilicity of the internal terminator in polyprenoids for the relative stereocontrol in subsequent cyclization are demonstrated. (-)-Ambrox was synthesized via the enantioselective cyclization of (E,E)-homofarnesyl triethyrsily ether with triethylsilyl ether with tin(IV) chloride-coordinated (R)-2-(o-fluorobenzyloxy)-2′-hydroxy-1,1′-binaphthyl ((R)-BINOL-o-FBn) and subsequent diastereoselective cyclization with CF3CO2H·SnCl4 as key steps. Protection of (E,E)-homofarnesol by a triethylsilyl group increased the enantioselectivity of chiral LBA-induced cyclization and both the chemical yield and diastereoselectivity in the subsequent cyclization. The enantioselective cyclization of homo(polyprenyl)arenes possessing an aryl group was also induced by (R)-BINOL-o-FBn·SnCl4. Several optically active podocarpa-8,11,13-triene diterpenoids and (-)-tetracyclic polyprenoid of sedimentary origin were synthesized (75-80% ee) by the enantioselective cyclization of homo(polyprenyl)benzene derivatives induced by (R)-BINOL-o-FBn·SnCl4 and subsequent diastereoselective cyclization induced by BF3-Et2O/EtNO2 or CF3CO2H·SnCl4.
- Ishihara, Kazuaki,Ishibashi, Hideaki,Yamamoto, Hisashi
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p. 3647 - 3655
(2007/10/03)
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- Evaluation of morphogenic regulatory activity of farnesoic acid and its derivatives against Candida albicans dimorphism
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A series of farnesoic acid derivatives was prepared and their morphogenic regulatory activities were evaluated. Their inhibitory activities against yeast cell growth and yeast-to-hypha transition examined in Candida albicans cells are dependent upon the chain length as well as the substitution patterns on the isoprenoid template. The preliminary structure-activity relationship of these compounds is described to elucidate the essential structural requirements.
- Kim, Sanghee,Kim, Eunkyung,Shin, Dong-Sun,Kang, Heonjoong,Oh, Ki-Bong
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p. 895 - 898
(2007/10/03)
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- Synthesis of vinyl pyrophosphonate analogues of farnesyl pyrophosphate: New potential inhibitors of farnesyl protein transferase
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The synthesis of new bioisosteric analogues of farnesyl pyrophosphate where a vinyl pyrophosphonate replaced the pyrophosphate moiety is described. These compounds have been prepared using a Horner-Wadsworth-Emmons procedure and a modified Michelson react
- Zgani, Ibrahim,Menut, Chantal,Monte,ro, Jean Louis
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p. 654 - 661
(2007/10/03)
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- The first total synthesis of preverecynarmin
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Preverecynaimin, isolated from a pennatulatean coral, has been synthesized from E,E-farnesol.
- Lan, Jiong,Liu, Zuosheng,Cen, Wen,Xing, Yacheng,Li, Yulin
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p. 1963 - 1966
(2007/10/03)
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- The first total synthesis of preverecynarmin
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Preverecynarmin, isolated from a pennatulacean coral, has been synthesized from E,E-famesol. The key steps are alkylation of the cyanohydrin trimethylsilyl ether 5 with the halide 6, the regioselective epoxidation of the siloxyl ether 9, and the intramolecular macrocyclization of the siloxyl ether 12 induced by Ti(0).
- Lan, Jiong,Liu, Zuosheng,Li, Yulin,Cen, Wen,Xing, Yacheng
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p. 941 - 946
(2007/10/03)
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- Synthesis and enzymatic cyclization of (3S)-14-fluoro-2,3-oxidosqualene
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A convergent asymmetric synthesis led to (3S)-14-fluoro-2,3- oxidosqualene (14-FOS, 16), which was cyclized by bacterial squalene:hopane cyclase to a monocarbocyclic product with a bridged ether and a 2:3 mixture of bicyclic alcohols. 14-FOS was neither a
- Robustell, Brian J.,Abe, Ikuro,Prestwicht, Glenn D.
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p. 9385 - 9388
(2007/10/03)
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- Inhibitors of farnesyl protein transferase
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Inhibition of farnesyl transferase, which is an enzyme involved in ras oncogene expression, and inhibition of cholesterol biosynthesis, are effected by compounds of the formula STR1 their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs, and solvates, wherein: x is --ONR1 C(O)--, --N(OR1)C(O)--, --NR1 C(O)--, --C(O)NR1 --, --NR1 S(O2)--, --C(O)O--, --OC(O)--, --C(O)--, --O--, --NR1 -- or --(S)q --; Y is --CO2 R2, --SO3 R2 or --P(O) (OR2) (R3); R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenylene or aryl; R3 is --(O)t R4 ; R1, R2 and R4 are each independently hydrogen, alkyl, aryl or aralkyl; m and n are each independently 0 or an integer from 1 to 5; p and t are each independently 0 or 1; and q is an integer from 1 to 2.
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- Farnesyl Diphosphate-Based Inhibitors of Ras Farnesyl Protein Transferase
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The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described.Compound 3, wherein a β-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 μM) and mevalonate kinase (I50(MK) = >200 μM).A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken.Both the carboxylic and phosphonic acid groups of the β-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 μM).The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 μM), substitution by a dodecyl fragment (14, I50 = 9 μM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 μM).Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 μM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM).FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.
- Patel, Dinesh V.,Schmidt, Robert J.,Biller, Scott A.,Gordon, Eric M.,Robinson, Simon S.,Manne, Veeraswamy
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p. 2906 - 2921
(2007/10/02)
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- Determination of the regiochemistry of insect epoxide hydrolase catalyzed epoxide hydration of juvenile hormone by 18O-labeling studies
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The regiochemistry of Trichoplusia ni epoxide hydrolase catalyzed epoxide hydration of insect juvenile hormone (JH) III has been determined by GC/MS studies of 18O-label incorporation. Nucleophilic addition occurs at C10 of the C10,11 epoxide of JH III. The identification of isotopically labeled and unlabeled diol from the enzyme catalyzed hydration reaction in H218O implies that a covalently bound ester intermediate may be involved in the mechanism of the reaction.
- Linderman, Russell J.,Walker, Elizabeth A.,Haney, Carol,Roe, R. Michael
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p. 10845 - 10856
(2007/10/02)
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- Methods of using α-phosphonosulfonate squalene synthetase inhibitors including the treatment of atherosclerosis and hypercholesterolemia
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α-Phosphonosulfonate compounds are provided which inhibit the enzyme squalene synthetase and thereby inhibit cholesterol biosynthesis. These compounds have the formula STR1 wherein R2 is OR5 or R5a ; R3 and R5 are independently H, alkyl, arylalkyl, aryl or cycloalkyl; R5a is H, alkyl, arylalkyl or aryl; R4 is H, alkyl, aryl, arylalkyl, or cycloalkyl;, Z is H, halogen, lower alkyl or lower alkenyl; and R1 is a lipophilic group which contains at least 7 carbons and is alkyl, alkenyl, alkynyl, mixed alkenyl-alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl; as further defined above; including pharmaceutically acceptable salts and or prodrug esters of the phosphonic (phosphinic) and/or sulfonic acids.
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- Z-selective formation of trisubstituted α,β-unsaturated nitrile by the Horner-Emmons reaction
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Conditions which allow the Horner-Emmons reaction of phosphononitrile to proceed Z-selectively were clarified. The generality and usefulness of the procedure were demonstrated by an application to a stereoselective synthesis of plaunotol (9).
- Takayanagi, Hisao
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p. 1581 - 1584
(2007/10/02)
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- Macrocyclisations using Allylic Radical Intermediates. A New Synthetic Approach to Natural 14-Membered Cembranoids
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A range of alternative radical macrocyclisation approaches to cembranoids have been evaluated.Radical macrocyclisations involving the allylic radicals 11 generated from the corresponding allylic iodides, 15b and 20b, in the presence of Bu3SnH-AIBN, are shown to lead to 14-membered trienones, viz 10, via selective 14-endo-trig processes.Both 10a and 10b can then be elaborated to the natural marine cembranoids 8 (mukulol) and 9 respectively, by straightforward functional group interconversions.Concise syntheses of the α,ω-dial 28, the terminal acetylenic aldehyde 27 and the allylic iodide enal 37 were developed, but neither was found to undergo radical mediated cyclisation to the corresponding 14-membered carbocycles 29, 30 and 38 respectively.Instead, only the products of reduction, e.g. 39, or intermolecular pinacolisation, e.g. 34 were produced.
- Cox, Nicolas J. G.,Mills, Stuart D.,Pattenden, Gerald
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p. 1313 - 1322
(2007/10/02)
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