Preparation of alkyl (R)-(-)-3-hydroxybutyrate by acidic alcoholysis of poly-(R)-(-)-3-hydroxybutyrate

An efficient method for the preparation of optically active alkyl (R)-(-)-3-hydroxybutyrates by chemical depolymerization of biopolymer, poly-(R)-(-)-(3-hydroxybutyrate), was established. This method consists of simple recovery of poly-(R)-(-)-(3-hydroxybutyrate) from bacterial cells followed by acidic alcoholysis. When poly-(R)-(-)-(3-hydroxybutyrate) was purified by a simple digestion method that used 0.2 N sodium hydroxide, alkyl (R)-(-)-hydroxybutyrates were most efficiently produced by alcoholysis with anhydrous hydrochloric acid.     

Facile entry to (-)-(R)- and (+)-(S)-mexiletine

The title compounds, 1a and 1b, have been synthesized in a three-step sequence starting from (-)-(S) and (+)-(R)-propylene oxide, respectively, in acceptable overall yields. The enantiomeric excess values for 1a and 1b were 96% and 93% respectively, as assessed by HPLC analysis on a chiral stationary phase of the corresponding N-acetyl derivatives. The synthetic route herein presented may represent a facile entry to highly enriched mexiletine enantiomers, alternative to those previously reported in the literature.     

天然型与非天然型脱落酸的生物活性比较

采用新方法精制脱落酸（ＡＢＡ）异构体试样,提高了（Ｓ）－（＋）－ＡＢＡ与（Ｒ）－（－）－ＡＢＡ两对映体纯度。抑制生长试验和残留量分析以及气孔闭合试验表明：天然型（Ｓ）－（＋）－ＡＢＡ活性显著高于非天然型（Ｒ）－（－）－ＡＢＡ或（ＳＲ）－（±）－ＡＢＡ。抑制莴苣种子发芽５０％的活性强度,（Ｓ）－（＋）－ＡＢＡ约是（Ｒ）－（－）－ＡＢＡ的５倍,（ＳＲ）－（±）－ＡＢＡ介于两者之间。抑制萝卜下胚轴生长试验,最显著有效期为２～６ｄ,生理作用期约为一周,（Ｓ）－（＋）－ＡＢＡ活性是（Ｒ）－（一）－ＡＢＡ的３．５倍。鸭跖革气孔闭合试验,（Ｓ）－（＋）－ＡＢＡ活性比（Ｒ）－（－）－ＡＢＡ高１倍。     

2(S)-(Cycloalk-1-enecarbonyl)-1-(4-phenyl-butanoyl)pyrrolidines and 2(S)-(aroyl)-1-(4-phenylbutanoyl)pyrrolidines as prolyl oligopeptidase inhibitors

In order to replace the P2-P1 amide group, different 1-cycloalkenyls and 2-aryls were studied in the place of the P1 pyrrolidine group of a 4-phenylbutanoyl-L-Pro-pyrrolidine structure, which is a well-known prolyl oligopeptidase inhibitor SUAM-1221. The 1-cyclopentenyl and the 2-thienyl groups gave novel compounds, which were equipotent with the corresponding pyrrolidine-analog SUAM-1221. It was shown that the P2-P1 amide group of POP inhibitors can be replaced by an alpha,beta-unsaturated carbonyl group or the aryl conjugated carbonyl group.     

Synthesis of (R)- and (S)- muscone

(R)-(-)-Muscone (3-methylcyclopentadecanone, 1) the key perfumery component isolated from the male musk deer, Moschus moschiferus,* was synthesized from the easily available chiral building block, (R)-3-tert-butoxycarbonyl-2-methylpropanoic acid (2), by employing ring-closing olefin metathesis (RCM). Antipode (+)-1 was also synthesized in a similar manner from tert-butyl (S)-3-methoxycarbonylbutanoate (10). *(a) Walbaum, H. J. J. Prakt. Chem., 73, 488 (1906); (b) Ruzicka, L., Further considerations on the constitution of muscone. Helv. Chim. Acta, 9, 715, 1008-1017 (1926).     

Synthesis of 2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3-((dimethylamino)methyl)camphor organocatalysts

In a stereo-divergent synthesis, three novel camphor-derived bifunctional thiourea organocatalysts 7-9 have been prepared in five steps starting from (+)-camphor. In addition, borneol-derived bifunctional thiourea organocatalysts 19/19' have been prepared in three steps from (1S)-(+)-camphorquinone. Novel organocatalysts 7-9, 19/19' have been evaluated in a model reaction of Michael addition of dimethyl malonate to trans-β-nitrostyrene with low to moderate enantioselectivities (20%-60% ee). Configuration of all novel compounds has been meticulously determined using nuclear magnetic resonance (NMR) techniques.     

Absolute configuration of (-)-2,6-dimethyl-10-(p-tolyl)-2,6(E)-undecadiene from Cistus monspeliensis

(-)-2,6-Dimethyl-10-(p-tolyl)-2,6(E)-undecadiene (1) is a major constituent in the essential oil of Cistus monspeliensis, an aromatic shrub common in Mediterranian countries. 1 was isolated by column chromatography, subjected to ozonolyses, and the absolute configuration was determined by enantioselective gas chromatographic correlation with the ozonolysis product of the sesquiterpene hydrocarbon ar-curcumene with known absolute configuration.     

Synthesis and Biological Properties of (+) and (-)-(E)-5-(2-bronovinyl)-21 -deoxy-11 a-Carbauridine

Abstract

Carbocyclic (+)- and (-)-(E)-5- (2-bromovinyl)-2′-deoxyuridlne have been prepared from (+)- and (-)-endo-norborn-5-en-2-y1 butyrate. In cell cultures both (+)- and (-)-C-BVDU showed activity against herpes simplex virus types 1 and 2, (+)-C-BVDU being only slightly less active than BVDU itself. (-)-C-BVDU gave a smaller but still significant antiviral effect. A nomenclature for carbocyclic nucleosides is proposed.     

The Synthesis and Antiviral Activity of (E)-5-(2-Nitrovinyl)uridine and (E)-5-(2-Nitrovinyl)-2′-deoxyuridine

Abstract

The protection of the sugar moiety of a 5-formyluracil nucleoside with acid-labile protecting groups allows for the deprotection of the sugar of a subsequently formed nucleoside possessing a 5-nitrovinyl side-chain. The synthesis and antiviral activity of (E) -5-(2-nitrovinyl)-uridine and (E)-5-(2-nitrovinyl)-2′-deoxyuridine are reported.     

Comparative toxicity of (+)-(R)- and (−)-(S)-1,2-dibromo-3-chloropropane

The haloalkane 1,2-dibromo-3-chloropropane (DBCP), an environmental pollutant that was widely used as a soil fumigant, is a carcinogen and a mutagen and displays target-organ toxicity to the testes and the kidneys. Because little is known about effects of stereochemistry on the metabolism and toxicity of halogenated alkyl compounds and because DBCP, which has a chiral center at C-2, may show enantioselectivity in its metabolism and/or toxicities, the optically pure enantiomers of DBCP were tested in vivo in rats for organ toxicity as well as for bacterial mutagenicity. Organ toxicity studies showed that (S)-DBCP was slightly more renal toxic than (R)-DBCP but was not significantly more toxic than the racemate, and that no significant differences were observed in the extents of testicular necrosis and atrophy caused by either enantiomer or the racemate. In contrast, (R)-DBCP was more mutagenic than either (S)-DBCP or the racemate to Salmonella typhimurium (S. typhimurium) strains TA 100 and TA104. However, there was little or no enantioselectivity in glutathione S-transferase (GST)-catalyzed conjugation reactions of glutathione with DBCP based on the lack of selectivity in the rates of disappearance of the enantiomers of DBCP in the presence of glutathione (GSH) and GSTs as monitored by chiral gas chromatography (GC). © 1995 Wiley-Liss, Inc.     

Biomonitoring of environmental tobacco smoke (ETS)-related exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

The exposure of non-smokers to the tobacco-specific N-nitrosamine 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a rodent lung carcinogen, was determined in the air of various indoor environments as well as by biomonitoring of non-smokers exposed to environmental tobacco smoke (ETS) under real-life conditions using the urinary NNK metabolites 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and [4-(N-methylnitrosamino)-1-(3-pyridyl)but-1-yl]-beta-O-D-glucosiduronic acid (NNAL-Gluc). NNK was not detectable (<0.5 ng m^-3) in 11 rooms in which smoking did not occur. The mean NNK concentration in 19 rooms in which smoking took place was 17.5 (2.4-50.0) ng m^-3. The NNK levels significantly correlated with the nicotine levels (r=0.856; p< 0.0001). Of the 29 non-smokers investigated, 12 exhibited no detectable NNAL and NNAL-Gluc excretion (<3 pmol day) in their urine. The mean urinary excretion of NNAL and NNAL-Gluc of the 17 remaining non-smokers was 20.3 (<3-63.2) and 22.9 (<3-90.0) pmol day^-1, respectively. Total NNAL excretion (NNAL+NNAL-Gluc) in all non-smokers investigated significantly correlated with the amount of nicotine on personal samplers worn during the week prior to urine collection (r=0.88; <0.0001) and with the urinary cotinine levels (r=0.40; p=0.038). No correlation was found between NNAL excretion and the reported extent of ETS exposure. Average total NNAL excretion in the non-smokers with detectable NNAL levels was 74 times less than in 20 smokers who were also investigated. The cotinine/total NNAL ratios in urine of smokers (9900) and non-smokers (9300) were similar. This appears to be at variance with the ratios of the corresponding precursors (nicotine/NNK) in mainstream smoke (16400) and ETS (1000). Possible reasons for this discrepancy are discussed. The possible role of NNK as a lung carcinogen in non-smokers is unclear, especially since NNK exposure in non-smokers is several orders of magnitude lower than the ordinary exposure to exogenous and endogenous N-nitrosamines and the role of NNK as a human lung carcinogen is not fully understood.     

Kinetic mechanism of dopamine transporter interaction with 1-(2-(bis-(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine (GBR 12909)

Interaction of piperazine-based dopamine transporter inhibitor GBR12909 with rat dopamine transporters has been studied by means of competition kinetics analysis, employing [(3)H]PE2I as the reporter ligand. It has been found that GBR12909 is capable of inducing so-called "slow isomerization step" upon binding to DAT, probably consisting of a conformational change in the transporter protein. The mechanism exhibited by GBR12909 appears to be similar to the mechanism of PE2I that has been reported earlier and also confirms previous observations for GBR12783 made by Do-Rego and co-workers using dopamine uptake data. It appears that the isomerization phenomenon previously described for PE2I is not limited to tropane-based DAT inhibitors, but is, in fact, a general property of dopamine transporter protein, similar to "isomerization" process reported previously for G-protein coupled receptors. The rapid first step of association of the GBR 12909 is characterized by the equilibrium constant K(L)=34+/-11nM and the second slow step by k(i)=0.033+/-0.005s(-1).     

1-N-methyl-(6E)-(2-methylpropylidene)-(3Z)-3-(phenylmethylene)-2,5-piperazinedione,a metabolite from Streptomyces albus

The structure and stereochemistry of a new piperazinedione, isolated from the cells of Streptomyces albus, are assigned on the basis of spectroscopic data, including comparison with related 2,5-piperazinediones.     

Antioxidant activity and low toxicity of (E)-1-(1-(methylthio)-1-(selenopheny) hept-1-en-2-yl) pyrrolidin-2-one

The aim of the present study was to evaluate the potential pharmacological and toxicological properties of (E)-1-(1-(methylthio)-1-(selenopheny) hept-1-en-2-yl) pyrrolidin-2-one (compound 1), an organoselenium compound. In vitro experiments showed that compound 1 presented a reduction in the lipid peroxidation induced by Fe2? in thiobarbituric acid-reactive species (TBARS) production, and in the generation of reactive species caused by Fe2?/malonate in DCFH-DA oxidation. The high dose (500 mg/kg) induced an increase on ALT but not on AST activity. Hepatic, but not cerebral, δ-ALA-D activity from mice treated with 500 mg/kg presented a significant inhibition. Brain catalase activity was significantly inhibited by 100 mg/kg whereas hepatic catalase activity showed a significant increase at all doses. Hepatic lipid peroxidation was diminished only at lowest dose (100 mg/kg) whereas for brain tissue, all doses induced a significant reduction in TBARS levels. Brain and liver ascorbic acid contents were increased only at highest dose of compound 1. Urea and creatinine levels were not significantly altered by treatments. This is a promising compound with antioxidant activity and low toxicity, suggesting the potential beneficial activity of compound 1 against oxidative damage in many parameters studied in rats and mice.     

Salicylate poly(vinyl chloride) membrane electrode based on (2-[(E)-2-(4-nitrophenyl) hydrazono]-1-phenyl-2-(2-quinolyl)-1-ethanone) Cu(II)

A new salicylate-selective electrode based on the complex of (2-[(E)-2-(4-nitrophenyl)hydrazono]-1-phenyl-2-(2-quinolyl)-1-ethanone) Cu(II) as the membrane carrier was developed. The electrode exhibited a good Nernstian slope of -59.6+/-1.0 mV/decade and a linear range of 1.0 x 10(-6) to 1.0M for salicylate. The limit of detection was 5.0 x 10(-7) M. The electrode had a fast response time of 10 s and can be used for more than 3 months. The selective coefficients were determined by the fixed interference method and could be used in the pH range of 4.0 to 10.5. The electrode was employed as an indicator electrode for direct determination of salicylate in pharmaceutical and biological samples.     

Efficient chemoenzymatic synthesis of (S)- and (R)-5-(1-aminoethyl)-2-(cyclohexylmethoxy)benzamide: key intermediate for Src-SH2 inhibitor

A facile chemoenzymatic synthesis of both the S and R forms of 5-(1-aminoethyl)-2-(cyclohexylmethoxy)benzamide a key intermediate of non-peptidic Src SH2 inhibitors is described. Both the enantiomers were synthesized in high optical purity (>99% ee) by reduction followed by lipase-mediated acylation of the precursor 6 in one-pot. Immobilized Pseudomonas cepacia lipase offered high degree of enantioselectivity with spontaneity.     

Solution conformation of asparagine-linked oligosaccharides: alpha(1-2)-, alpha(1-3)-, beta(1-2)-, and beta(1-4)-linked units

The solution conformation is presented for representatives of each of the major classes of asparaginyl oligosaccharides. In this report the conformation of alpha(1-3)-, alpha(1-2)-, beta(1-2)-, and beta(1-4)-linked units is described. The conformational properties of these glycopeptides were determined by high-resolution 1H nuclear magnetic resonance in conjunction with potential energy calculations. The NMR parameters that were used in this analysis were chemical shifts and nuclear Overhauser enhancements. Potential energy calculations were used to evaluate the preferred conformers available for the different linkages in glycopeptides and to draw conclusions about the behavior in solution of these molecules. It was found that the linkage conformation of the Man alpha 1-3 residues was not affected by substitution either at the 2-position by alpha Man or beta GlcNAc or at the 4-position by beta GlcNAc or by the presence of a bisecting GlcNAc on the adjacent beta Man residue.     

Enantiospecific synthesis of carbocyclic (+)-(E)-5-(2-bromovinyl)-2'-deoxyuridine

(+)-1-[(1R, 3S, 4R)-3-hydroxy-4-hydroxymethylcyclopentyl]-5-[(E)-2- bromovinyl]-1H,3H-pyrimidin-2,4-dione 10 was synthesized starting from (+)-endo-5-norbornen-2-yl acetate. This chiral educt was obtained by enzymatic hydrolysis of racemic esters of endo-5-norbornen-2-ol.     

NMR structural characterization of cecropin A(1-8) - magainin 2(1-12) and cecropin A (1-8) - melittin (1-12) hybrid peptides.

In order to elucidate the structure-antibiotic activity relationships of the peptides, the three-dimensional structures of two hybrid peptides, CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) in trifluoroethanol-containing aqueous solution were investigated by NMR spectroscopy. Both CA(1-8) - MA(1-12) and CA(1-8) - ME(1-12) have strong antibacterial activity but only CA(1-8) - ME(1-12) has hemolytic activity against human erythrocytes. CA(1-8) - MA(1-12) has a hydrophobic 310-helix of only two turns combined with one short helix in the N-terminus with a flexible hinge section in between. CA(1-8) - MA(1-12) has a severely bent structure in the middle of the peptide. These structural features as well as the low hydrophobicity of CA(1-8) - MA(1-12) seem to be crucial for the selective lysis against the membrane of prokaryotic cells. CA(1-8) - ME(1-12) has an alpha-helical structure of about three turns in the melittin domain and a flexible structure with one turn in the cecropin domain connected with a flexible hinge section in between, and these might be the structural features required for membrane disruption against prokaryotic and eukaryotic cells. The central hinge region (Gly9-Ile10-Gly11) in an amphipathic antibacterial peptide is considered to play an important role in providing the conformational flexibility required for ion channel formation of the C-terminal hydrophobic alpha-helix on cell membrane.     

(E)-2-(2-Hydroxyethylidene)-6-methyl-5-heptenal (alpha-acariolal) and (E)-2-(2-hydroxyethyl)-6-methyl-2,5-heptadienal (beta-acariolal), two new types of isomeric monoterpenes from Caloglyphus polyphyllae (Acari: Acaridae)

The opisthonotal gland secretion of the acarid mite, Caloglyphus polyphyllae, contained two new monoterpenes, (E)-2-(2-hydroxyethylidene)-6-methyl-5-heptenal (1) and (E)-2-(2-hydroxyethyl)-6-methyl-2,5-heptadienal (2), to which we have given the trivial names alpha- and beta-acariolal in relation to alpha- and beta-acaridial (3 and 4), respectively. Elucidation of the structure of 1 was established mainly from 1H-NMR and GC/MS spectral data after partial purification, together with the fact that 1 was recovered in the more-polar fraction from a silica gel column than alpha- and beta-acaridial (3 and 4) present in the secretion. Compound 2 was obtained in the same fraction as a mixture with 1. Based on the facts that 2 had the same molecular weight by GC/MS and the same polarity as that of 1, compound 2 was assumed to be a structural analog of 1. The structures of compounds 1 and 2 were confirmed by their synthesis in nine and ten respective steps starting from alpha-bromo-gamma-butyrolactone.