Effect on Insecticidal Activity of Substituents at the 1,4-Benzodioxanyl Moiety of Haedoxan

The haedoxan analog, (±)-2-(2,6-dimethoxyphenoxy)-1-hydroxy-6-(6-methoxy-l,4-benzodioxan-7-yl)-3,7-dioxabicyclo[3.3.0]octane, and its congeners with 2-alkoxymethyl, 2-hydroxymethyl, 2-chloromethyl and 3-(3,4-methylenedioxyphenyl) substituents on the 1,4-benzodioxanyl group were synthesized from 6-methoxy-l,4-benzodioxan-7-carbaldehyde and its (±)-2- and 3-substituted derivatives, respectively. Some analogs were considerably insecticidal, although much less active than natural haedoxan A. The assay results suggest that 2,3-disubstitution on the 1,4-benzodioxanyl group was necessary to intensify the insecticidal activity.     

Synthesis and Insecticidal Activity of Lignan Analogs (III)

Ten haedoxan analogs with the bond split between 2C and 3C of the 6-methoxy-2-methoxymethyl-3-(3,4-methylenedioxy)phenyl-1,4-benzodioxan-7-yl group of haedoxans were synthesized, and their insecticidal activity was assessed on the housefly. The inactivity of an analog having a 2-methoxy-5-(2-methoxyethoxy)-4-(3,4-methylenedioxybenzyloxy)phenyI instead of the 1,4-benzodioxan-7-yl group made it evident that the benzodioxane framework is essential for the activity of haedoxans.     

Inhibition of Sporulation of Genus Bacillus by Various Microbial Protease Inhibitors

Several analogs modifying the 6-methoxy-2-methoxymethyl-3-(3,4-methyienedioxyphenyl)-1,4-benzodioxan-7-yl group of haedoxans were synthesized and their insecticidal activity was examined. 2-(2,6-Dimethoxyphenoxy)-1-hydroxy-6-(2-methoxy-5-methoxyethoxyphenyl)-3,7-dioxabicyclo-[3.3.0]octane, which lacked the 3-(3,4-methylenedioxybenzyloxy) moiety of the benzodioxanyl group, was not insecticidal, but caused prolonged paralysis of the housefly. A compound replacing the 6-(2-methoxy-5-methoxyethoxyphenyl) by 6-(5-butoxy-2-methoxyphenyl) exhibited insecticidal activity comparable to one thirty-thousandth of that of haedosan A. It became evident that the 1,4-benzodioxane framework charging the 3-(3,4-methylenedioxy)phenyl group is important for the insecticidal activity of haedoxans.     

Identification of a Novel Casbane-Type Diterpene Phytoalexin,ent-10-Oxodepressin,from Rice Leaves

(+)-Haedoxan A, an insecticidal sesquilignan, inhibited the specific binding of the noncompetitive GABA antagonist [³⁵S]t-butylbicyclophosphorothionate (TBPS) to rat brain membranes in concentration-dependent and noncompetitive manners. The data show haedoxan’s interaction with a site coupled to the TBPS-binding site on the GABA_A receptor in rat brain, while the physiological significance of the interaction remains to be discovered.     

Synthesis and stereostructure-activity relationship of three asymmetric center pyrethroids: 2-methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether and cyanohydrin ester

2-Methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether 2 and cyanohydrin ester 3, a couple of pyrethroids with three asymmetric centers, were synthesized. Of each of the four diastereomers of 2 and 3, only the (1R*,2R*,3R*)-2a and 3a showed significant insecticidal activities. Dual sets of enantiomers [(1R,2R,3R)-(-)-2a and (1S,2S,3S)-(+)-2a] and [(1R,2R,3R)-(-)-3a and (1S,2S,3S)-(+)-3a] were synthesized through the asymmetric cyclopropanation using the Aratani catalyst. Significant separations of insecticidal activities were observed between both the enantiomers against the tobacco cutworm (Spodoptera litura) and the common mosquito (Culex pipiens pallens); (1S,2S,3S)-(+)-2a and (+)-3a showed higher activities than their antipodes (1R,2R,3R)(-)-2a and (-)-3a. This result is the second example of such synthetic pyrethroids with three asymmetric centers.     

鸭儿芹的化学成分及对Hep G2细胞毒性

该研究采用大孔树脂(D101)、硅胶、羟丙基葡聚糖凝胶(Sephadex LH-20)和十八烷基硅烷键合硅胶(ODS)等色谱方法,对鸭儿芹的化学成分进行了分离纯化,根据理化性质、质谱和核磁共振波谱数据,并参考相关文献综合分析化合物结构,进而采用噻唑蓝(MTT)法,对鸭儿芹化合物抗Hep G2细胞活性进行筛选。结果表明:共从鸭儿芹中分离鉴定了7个化合物,分别为p-(acetylamino)phenol(1),辛酸甲酯(2),丁酸异戊酯(3),N,N-二甲基-苯并咪唑-2胺(4),5-羟基-1-(4-羟基-3-甲氧苯基)庚3酮(5),3,5二丁基六氢吡咯里嗪(6),(S)-4-(1-hydroxyallyl)phenyl acetate(7)。其中,化合物6对细胞具有抑制作用,抑制率达到89.1%。该研究结果表明化合物1-7均为首次从鸭儿芹中分离得到,其中化合物6对Hep G2细胞的生长具有抑制作用,且具有剂量依赖性。     

Stereoselective Synthesis of the Optically Active Samin Type of Lignan from L-Glutamic Acid

The optically active samin type of lignan, (1R,2S,5R, 6S)-6-(2-methoxy-4,5-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]octan-2-ol, was stereoselectively synthesized from L-glutamic acid via (2R,3R)-2-[(1S and R)- 1-[(tert-butyldimethylsilyl)oxy]-1-(2-methoxy-4,5-methylenedioxyphenyl)methyl]-3-[(tert-butyldiphenylsilyl)oxy]methyl-1,4-butanediol.     

Isolation and structure elucidation of caryophyllane sesquiterpenoids from leaves of Eremophila spathulata

Crude extract of Eremophila spathulata leaves was investigated by semi-preparative scale high-performance liquid chromatography (HPLC), analytical scale HPLC, and hyphenated high-performance liquid chromatography-photodiode array-high-resolution mass spectrometry-nuclear magnetic resonance (HPLC-PDA-HRMS-SPE-NMR), which afforded seven previously unreported caryophyllane sesquiterpenoids. Semi-preparative scale separation of the crude extract afforded (1R*,4R*,9S*,E)-8-formyl-11,11-dimethylbicyclo[7.2.0]undec-7-ene-4-carboxylic acid (5) and analytical-scale HPLC separation afforded (1R*,4S*,7S*,9S*)-7-hydroxy-11,11-dimethyl-8-methylenebicyclo[7.2.0]undecane-4-carboxylic acid (1), (1S*,6R*,9R*,E)-10,10-dimethylbicyclo[7.2.0]undec-2-ene-2,6-dicarboxylic acid (2), (1R*,4S*,9S*)-11,11-dimethyl-8-oxobicyclo[7.2.0]undecane-4-carboxylic acid (3), and (1R*,4R*,9S*)-11,11-dimethyl-8-oxobicyclo[7.2.0]undecane-4-carboxylic acid (4). HPLC-PDA-HRMS-SPE-NMR afforded (1R*,4R*,9S*)-11,11-dimethyl-8-methylenebicyclo[7.2.0]undecane-4-carboxylic acid (6) and (1R*,4S*,9S*)-11,11-dimethyl-8-methylenebicyclo[7.2.0]undecane-4-carboxylic acid (7). The structures of all isolated compounds were established based on HRMS as well as extensive 1D and 2D NMR analysis. Relative configurations were determined by correlations in spectra from rotational Overhauser effect spectroscopy.     

The utility of 1-[18F]fluoro-3-iodopropane for the synthesis of certain dopamine D-1 and benzodiazepine receptor radioligands

No-carrier-added (NCA) R(+)-7-chloro-8-hydroxy-3-(3′-[¹⁸F]fluoropropyl)-1-phenyl-2,3,4,5-tetrahydro-3-benzazepine (2b) (an analog of dopamine D-1 receptor ligand SCH 23390), ethyl 8-fluoro-5,6-dihydro-5-(3′-fluoropropyl)-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (4b) and 3′-[¹⁸F]fluoropropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (6b) (analogs of the benzodiazepine RO 15-1788) were synthesized by alkylation of the corresponding nor-compound with NCA 1-[¹⁸F]fluoro-3-iodopropane in 10–15% yield (EOB) in ~110min and with a mass of 2–3nmol. Compound 2 is less potent (~ 12–14 times) than SCH 23390 in binding to rat striatal membranes in vitro. Compounds 2b, 4b and 6b exhibit no specific anatomical distribution to mouse brain. These results suggest that the substituent at position 3 of SCH 23390, and position 5 and carboxylate group of RO 15-1788 are critical determinants both of affinity and selectivity for receptor binding, and underscores the evaluation necessary when even minor changes (C1 to C3) are made in bioactive compounds.     

Enantioselective σ1 receptor binding and biotransformation of the spirocyclic PET tracer 1′‐benzyl‐3‐(3‐fluoropropyl)‐3H‐spiro[[2]benzofuran‐1,4′‐piperidine]

It was shown that racemic (±)‐ 2 [1′‐benzyl‐3‐(3‐fluoropropyl)‐3H‐spiro[[2]benzofuran‐1,4′‐piperidine], WMS‐1813 ] represents a promising positron emission tomography (PET) tracer for the investigation of centrally located σ₁ receptors. To study the pharmacological activity of the enantiomers of 2 , a preparative HPLC separation of (R)‐2 and (S)‐2 was performed. The absolute configuration of the enantiomers was determined by CD‐spectroscopy together with theoretical calculations of the CD‐spectrum of a model compound. In receptor binding studies with the radioligand [³H]‐(+)‐pentazocine, (S)‐2 was thrice more potent than its (R)‐configured enantiomer (R)‐2 . The metabolic degradation of the more potent (S)‐enantiomer was considerably slower than the metabolism of (R)‐2 . The structures of the main metabolites of both enantiomers were elucidated by determination of the exact mass using an Orbitrap‐LC‐MS system. These experiments showed a stereoselective biotransformation of the enantiomers of 2 . Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Three sesquiterpene hydrocarbons from the roots of Panax ginseng C.A. Meyer (Araliaceae)

The volatile constituents of the roots of Panax ginseng C.A. Meyer have been investigated after hydrodistillation and analysed by means of different analytical methods. Besides several compounds already known three sesquiterpene hydrocarbons have been isolated from the essential oil. Structure elucidation of the bicyclic panaxene as well as of the tricyclic panaginsene and ginsinsene was performed by MS and NMR. They have been identified as (1R*,2S*,5S*)-2-ethenyl-1(1-methylethenyl)-2,6,6-trimethylbicyclo[3.2.0]heptane (panaxene), (1S*,8S*,11R*)-4,7,7,11-tetramethyltricyclo[6.3.0.0(1,5)]undec-4-ene (panaginsene) und (1R*,6R*,7R*)-3,7,10,10-tetramethyltricyclo[4.3.2.0(2,6)]undec-2-ene (ginsinsene).     

Isolation of plasma membrane and binding of the Ca2+ antagonist nimodipine in Chlamydomonas reinhardtii

Chlorophyll-free plasma membranes of the unicellular green alga Chlamydomonas reinhardtii Dangeard were purified from a microsomal fraction using an aqueous polymer two-phase system of 6.5% (w/w) dextran T500, 6·5% (w/w) polyethylene glycol 3350, 60 mM NaCI, 0 33 M sucrose and 5 mM potassium phosphate (pH 7·8). The plasma membrane fraction contained only 2·4% of the microsomal membrane protein. Specific activity of the plasma membrane marker enzyme, K*, Mg²⁺-ATPase (EC 3.6.1.3). was enriched 9-fold over the microsomal fraction, and 22% of total activity was recovered in the upper, polyethylene glycol-rich phase. Contamination from intracellular membranes was minimal. K*, Mg²⁺-ATPase showed a pH optimum at about 6·5, and addition of 0·05% (w/v) Triton X-100 stimulated the activity 3-fold. [³H]-Nimodipinc was employed to characterize 1,4-dihydropyridine-specific membrane receptors. Two apparent binding sites with different affinities to nimodipine were found in the crude microsomal fraction. The separation of plasma membranes from intracellular membranes revealed that one binding site with higher affinity (K_D= 9 nM) was located on the plasma membrane and a second binding site with lower affinity (K_D= 36 nM) on an intracellular membrane The apparent dissociation constants determined from the association and dissociation rate constants in kinetic experiments were comparable to those determined by equilibrium experiments. The maximum number of binding sites of the plasma membrane fraction and the intracellular membrane fraction was B_max= 440 and 470 fmol (mg protein)^-1, respectively. [³H]-Nimodipinc binding was inhibited by (±) verapamil and stimulated by D-cis-diltiazem in both fractions. Moreover, ethyle-neglycol-bis(2-aminoethylcther)-N, N'-tetraacctic acid (EGTA) inhibited [³H]-nimo-dipinc binding in the plasma membrane fraction but not in the intracellular membrane fraction This effect was cancelled by the addition of CaCl₂.     

Lasiolactols A and B Produced by the Grapevine Fungal Pathogen Lasiodiplodia mediterranea

A strain of Lasiodiplodia mediterranea, a fungus associated with grapevine decline in Sicily, produced several metabolites in liquid medium. Two new dimeric γ‐lactols, lasiolactols A and B ( 1 and 2 ), were characterized as (2S*,3S*,4R*,5R*,2′S*,3′S*,4′R*,5′R*)‐ and (2R*,3S*,4R*,5R*,2′R*,3′S*,4′R*,5′R*)‐(5‐(4‐hydroxymethyl‐3,5‐dimethyl‐tetrahydro‐furan‐2‐yloxy)‐2,4‐dimethyl‐tetrahydro‐furan‐3‐yl]‐methanols by IR, 1D‐ and 2D‐NMR, and HR‐ESI‐MS. Other four metabolites were identified as botryosphaeriodiplodin, (5R)‐5‐hydroxylasiodiplodin, (–)‐(1R,2R)‐jasmonic acid, and (–)‐(3S,4R,5R)‐4‐hydroxymethyl‐3,5‐dimethyldihydro‐2‐furanone ( 3  –  6 , resp.). The absolute configuration (R) at hydroxylated secondary C‐atom C(7) was also established for compound 3 . The compounds 1  –  3 , 5, and 6 , tested for their phytotoxic activities to grapevine cv. Inzolia leaves at different concentrations (0.125, 0.25, 0.5, and 1 mg/ml) were phytotoxic and compound 5 showed the highest toxicity. All metabolites did not show in vitro antifungal activity against four plant pathogens.     

Highly oxygenated bisabolenes and an acetylene from Matricaria aurea.

Reinvestigation of the aerial parts of Matricaria aurea led to the isolation of three new bisabolenes and a new acetylene. The structures of the four compounds, namely (1R*,2R*,3R*,6R*,7R*)1,2,3,6,7- pentahydroxy-bisabol-10(11)-ene, (1R*,2R*,3R*,6R*,7R*)1,2,3,6,7-pentahydroxy-1-acetoxy-bisabol-10(1 1)-ene, (1R*,2R*,3R*,6R*,7R*)1,2,3,6,7-pentahydroxy-2-acetoxy-bisabol-10(1 1)-ene and (3S*,4S*,5R*)-(E)-3,4-dihydroxy-2-(hexa-2,4-diynyliden)-1,6- dioxaspiro-(4,5)decane, were deduced from the high field NMR studies.     

Alkyl phenols and derivatives from Tapirira obtusa

From the bark of Tapiria obtusa, six alkyl phenol derivatives were isolated: 1-hydroxy-3-[(Z)-7'-nonadecenyl]-benzene, 1-hydroxy-3-[(Z)-7'-heptadecenyl]-benzene, 1-hydroxy-3-[14'-phenyltetradecyl]-benzene, and 1-hydroxy-3-[16'-phenyltetradecyl]-benzene, and their possible biogenetic precursors, 1-(16'-phenyl-12'Z-hexadecenyl)-4-Z-cyclohexene-(1S*,3S*)-diol and (4S*,6S*)-dihydroxy-6-(14'Z-nonadecenyl)-2-cyclohexenone. The structures of these compounds were elucidated by chemical and spectroscopic analysis, (4S*,6S*)-Dihydroxy-6-(14'Z-nonadecenyl)-2-cyclohexenone showed cytotoxic activity.     

Stereoselective synthesis of the optically active samin type of lignan from L-glutamic acid

The optically active samin type of lignan, (1R,2S,5R, 6S)-6-(2-methoxy-4,5-methylenedioxyphenyl)-3,7-dioxabicyclo[3.3.0]octan-2-ol, was stereoselectively synthesized from L-glutamic acid via (2R,3R)-2-[(1S and R)1-[(tert - butyldimethylsilyl)oxyl-1-(2-methoxy-4,5methylenedioxyphenyl)methyl]-3-[(tert- butyldiphenylsilyl)oxylmethyl-1,4-butanediol.     

Synthesis and pKa determination of new enantiopure dimethyl‐substituted acridino‐crown ethers containing a carboxyl group: Useful candidates for enantiomeric recognition studies

New enantiopure dimethyl‐substituted acridino‐18‐crown‐6 and acridino‐21‐crown‐7 ethers containing a carboxyl group at position 9 of the acridine ring [(S,S )‐ 8 , (S,S )‐ 9 , (R,R )‐ 10 ] were synthesized. The pK _a values of the new crown ethers [(S,S )‐ 8 , (S,S )‐ 9 , (R,R )‐ 10 ] and of an earlier reported macrocycle [(R,R )‐ 2 ] were determined by UV‐pH titrations. Crown ether (S,S )‐ 8 was attached to silica gel by covalent bonds and the enantiomeric separation ability of the newly prepared chiral stationary phase [(S,S )‐CSP‐ 12 ] was studied by high‐performance liquid chromatography (HPLC). Homochiral preference was observed and the best separation was achieved for the enantiomers of 1‐NEA. Ligands (S,S )‐ 9 and (R,R )‐ 10 are precursors of enantioselective sensor and selector molecules for the enantiomers of protonated primary amines, amino acids, and their derivatives.     

Synthesis and Lateral Root-Inducing Activity of Novel N-Substituted-2-Piperidones with a 1,4-Benzodioxan Ring

Novel N-substituted-2-piperidones with a 1,4-benzodioxan ring were prepared and evaluated for their activity to induce lateral roots in lettuce seedlings. Compounds were obtained by aldol condensation of the lithium enolate of N-substituted-2-piperidones with 1,4-benzodioxan-6-carbaldehyde. Of the series compounds tested, N-cinnamyl-3-[1-(1,4-benzodioxan-6-yl)-1-hydroxymethyl]-2-piperidone (2e) had the highest activity. In seedlings treated with 10 ppm of 2e, all of the primary roots formed lateral roots. Only erythro-2e showed lateral root-inducing activity, while threo-2e was inactive.     

Synthesis of (-)-methyl shikimate via enzymatic resolution of (1S*, 4R*, 5R*)-4-hydroxy-6-oxabicyclo[3.2.1]oct-2-en-7-one.

The synthesis of methyl (-)-shikimate [(-)-2] was achieved via lipase-catalyzed optical resolution of (1S*, 4R*, 5R*)-4-hydroxy-6-oxabicyclo[3.2.1]oct-2-en-7-one (3). Transesterification of (+/-)-3 and vinyl acetate with lipase MY and subsequent hydrolysis gave optically pure (-)-3. This compound was converted to (-)-2 in two steps.     

Evaluation of Oligonucleotides Containing Two Novel 2′-O-Methyl Modified Nucleotide Monomers: A 3′-C-Allyl and a 2′-O-3′-C-Linked Bicyclic Derivative

Abstract

The two ribo-configured nucleosides 1-(3-C-allyl-2–0-methyl-β-D-ribo-pentofuranosyl)thymine 3 and (1S,5R,6R,8R)-5-hydroxy-6-(hydroxymethyl)-1-methoxy-8-(thymin-1-yl)-2,7-dioxabicyclo[3.3.0]octane 6 have been transformed into their corresponding phosphoramidites, 5 and 8 respectively, and used as building blocks for the synthesis of modified oligonucleotides. The oligonucleotides were shown to hybridize with decreased binding affinity towards complementary single stranded DNA and RNA.