- Synthesis of small combinatorial libraries of natural products: Identification and quantification of new long-chain 3-methyl-2-alkanones from the root essential oil of Inula helenium L. (Asteraceae)
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Introduction Recently, a potent anti-staphylococcal activity of Inula helenium L. (Asteraceae) root essential oil was reported. Also, bioassay guided fractionation of the oil pointed to eudesmane sesquiterpene lactones and a series of unidentified constituents as the main carriers of the observed activity. Objective To identify nine new constituents (long-chain 3-methyl-2-alkanones) from a fraction of this root essential oil with a low minimum inhibitory concentration value (0.8 μg/mL) by employing a synthetic methodology that leads to the formation of a small combinatorial library of these compounds. Methods The identity of these constituents was inferred from mass spectral fragmentation patterns and GC retention data. A library of 3-methyl-2-alkanones (C11-C19 homologous series) was synthesised in three steps starting from methyl acetoacetate and the corresponding alkyl halides. The synthetic library was also screened for in vitro anti-microbial activity. Results Gas chromatographic analyses of I. helenium essential oil samples with spiked compounds from the synthesised library corroborated the tentative identifications of the long-chain 3-methyl-2-alkanones. The availability of these anti-microbial compounds from this library made it possible to construct GC/FID calibration curves and determine their content in the plant material: 0.08 - 24.2 mg/100 g of dry roots. Conclusion The small combinatorial library approach enabled the first unequivocal identification of long-chain 3-methyl-2-alkanones as plant secondary metabolites, and, also, allowed determination of not only a single compound and biological properties, but those of a group of structurally related compounds. Copyright
- Radulovic?, Niko S.,Denic?, Marija S.,Stojanovic?-Radic?, Zorica Z.
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- Excitatory amino acid receptor ligands. Synthesis and biological activity of 3-isoxazolol amino acids structurally related to homoibotenic acid
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The 3-isoxazolol amino acid (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4- yl)propionic acid (AMPA, 2) and the isomeric compound (RS)-2-amino-3-(3- hydroxy-4-methylisoxazol-5-yl)propionic acid (4-methylhomoibotenic acid, 4a) are potent agonists at the AMPA subtype of central excitatory amino acid receptors. Using 4a as a lead structure, the amino acids 4c-e, in which the 4-methyl group of 4a is replaced by substituents of different size and polarity, were synthesized. Attempts to synthesize 4- (bromomethyl)homoibotenic acid (4f), a potential receptor alkylating agent, were unsuccessful. 4-Butylhomoibotenic acid (4c) and 4-(2- hydroxyethyl)homoibotenic acid (4e) were equipotent as inhibitors of [3H]AMPA binding (IC50 = 2 μM) and showed similar excitatory activity in the rat cortical slice preparation. 4d did not show significant affinity for AMPA receptor sites, but turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist. However, like 4c,e, 4d did not significantly affect the binding of the competitive NMDA antagonist, [3H]CPP, or the noncompetitive NMDA antagonist, [3H]MK-801. None of the amino acids 4c-e showed detectable affinity for [3H]kainic acid binding sites. Like the parent compound 4a (IC50 = 0.18 μM), 4c (IC50 = 0.18 μM), 4e (IC50 = 0.14 μM), and in particular 4d (IC50 = 0.02 μM) were effective inhibitors of calcium chloride-dependent [3H]glutamic acid binding, whereas AMPA is inactive (IC50 > 100 μM) in this binding assay. Thus, 4d is an effective and highly selective inhibitor of calcium chloride-dependent [3H]glutamic acid binding and may be a useful tool for studies of the physiological relevance and pharmacological importance of this binding affinity.
- Christensen,Ebert,Madsen,Nielsen,Brehm,Krogsgaard-Larsen
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p. 3512 - 3519
(2007/10/02)
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- COBALT(II) ACETATE PROMOTED ADDITION OF ACETOACETATE TO TERMINAL OLEFINS: A HIGHLY STEREOSELECTIVE SYNTHESIS OF 5-ALKYL-2-HYDROXY-2-METHYL-3-METHOXYCARBONYL TETRAHYDROFURANS
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Methylacetoacetate and terminal olefins react in presence of Cobalt(II) acetate and Oxygen to give the title compound(2) in a highly stereoselective manner and the structure of this compound is elucidated by 1H NMR simulation studies.
- Iqbal, Javed,Kumar, T. K. Praveen,Manogaran, S.
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p. 4701 - 4702
(2007/10/02)
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