Synthesis and Antimicrobial Activity of Chiral cis-Cycloheximide Isomers

Such (+)- and (?)-cis-cycloheximide isomers as isocyclohcximide (1a, 1b), α-epiisocycloheximide (2a, 2b) and neocycloheximide (3a, 3b) were synthesized by aldol condensation of (?)-(2R, 4R)- and (+)-(2S, 4S)-cis-2,4-dimethyl-1-cyclohexanone (5a, 5b). obtained by microbial resolution, with 4-(2-oxoethyl)-2,6-piperidinedione (7). The absolute configuration of the (?)-cis-ketone 5a was confirmed by chemical correlation with natural (2S, 4S, 6S, αR)-cycloheximide (4). The newly synthesized isomer, (?)-α-epiisocycloheximide (2b), showed strong antimicrobial activity against S. cerevisiae andP. oryzae close to that of natural cycloheximide (4).     

Synthesis of Streptovitacin-C2 Isomers

(2R*,4S*,6S*,αS*)- and (2R,4R,6R,αS)-Streptovitacin-C₂ (STV-C₂) (1a and 1b) were synthesized by an aldol condensation of (2R*,4S*)- or (2R,4R)-2,4-dimethyl-2-trimethylsiloxy-1-cyclohexanone (15a or 15b) with 4-(2-oxoethyl)-2,6-piperidinedione (16), which was followed by desilylation of the products. The stereochemistry of the synthesized STV-C₂ isomers (1a and 1b) was elucidated by NMR. STV-C₂ isomers (1a and 1b) did not show strong antimicrobial activity against Saccharomyces cerevisiae and Pyricularia oryzae.     

Uptake of exogenous metabolites by virus-transformed cells: changes induced by temperature and pH.

Bestatin, [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-(S)-leucine, inhibited aminopeptidase B and leucine aminopeptidase in a competitive manner and their K_i values were calculated to be 6 × 10^?8 and 2 × 10^?8M, respectively. Among all stereoisomers of bestatin synthesized, those which have a (2S)-configuration in the 3-amino-2-hydroxy-4-phenylbutanoyl moiety showed marked inhibition against aminopeptidase B and leucine aminopeptidase compared with the other isomers which have (2R)-configuration. One of the isomers, [(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-(R)-leucine, showed somewhat stronger activity against aminopeptidase B than bestatin. Aminopeptidase B appears to be a metallo-exopeptidase. It is proposed that bestatin and its active isomers are effective due to a mechanism other than a chelating action at the active center.     

Syntheses of all eight stereoisomers of conidendrin

ABSTRACT

All eight stereoisomers of conidendrin were synthesized from (1 R,2 S,3 S)-1-(4-benzyloxy-3-methoxyphenyl)-3-(4-benzyloxy-3-methoxybenzyl)-2- hydroxymethyl-1,4-butanediol ((+)-4) and its enantiomer with high optical purity. The configurations at 4-positions of the conidendrin stereoisomers were constructed by intramolecular Friedel-Crafts reaction of protected 4. After conversion to tetrahydronaphthalene intermediate 7a, the 2- and 3-position of tetrahydronaphthalene structure 7a were converted to 3a- and 9a-position of (+)-α-conidendrin (3a), respectively. By the epimerization process of 2- or 3-position of 7a, the other diastereomers were obtained. All enantiomers were also synthesized from (?)-4.     

Efficient Synthesis of (22R,23R,24S)-22,23-Isopropylidenedioxy-5α-ergost-2-en-6-one,a Key Intermediate in the Preparation of Brassinolide

(22R,23R,24S)-22,23-Isopropylidenedioxy-5α-ergost-2-en-6-one 2b is an important intermediate of brassinolide. We found that the enone 2b can be prepared by transformation of (22R,23R,24S)-3α,5-cyclo-22,23-isopropylidenedioxy-5α-ergostan-6-one 5b with catalytic amount of both p-TsOH and NaBr in DMF under reflux. 5b was prepared from (22R,23R,24S)-3α,5-cyclo-22,23-dihydroxy-6β-methoxy-5α-ergostane 9b or a 6β-benzyloxy compound 9c, which was obtained in a manner similar to Mori’s brassinolide synthesis. The enone 2b was eventually prepared via a benzyl ether 9c from stigmasterol 3a in a 15.5% yield in 11 steps.     

Four cypermethrin isomers induced stereoselective metabolism in H295R cells

Cypermethrin (CP) is widely used for controlling agricultural and indoor vermin. Previous studies have reported the stereoselective difference of CP in biological activities. However, little is known about their potential mechanisms between metabolic phenotypes and endocrine-disrupting effects. Herein, nuclear magnetic resonance (NMR)-based metabolomics combining metabolite identification and pathway analysis were applied to evaluate the stereoselective metabolic cdisorders induced by CP isomers in human adrenocortical carcinoma cells (H295R) culture medium. Then, gene expression levels related to disturbed metabolic pathways were assessed to verify according to metabolic phenotypes. Metabolomics profiles showed that [(S)-cyano(3-phenoxyphenyl)methyl](1R,3R)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate [(1R,3R,αS)-CP] induced the most significant changes in metabolic phenotypes than did the other stereoisomers. There are 10 differential metabolites (isoleucine, valine, leucine, ethanol, alanine, acetate, aspartate, arginine, lactate, and glucose) as well as two significantly disturbed pathways, including “pyruvate metabolism” and “alanine, aspartate, and glutamate metabolism,” that were confirmed in H295R cells culture medium of (1R,3R,αS)-CP compared with other stereoisomers. Polymerase chain reaction (PCR) array also confirmed the results of metabolomics. Our results can help to understand the potential mechanisms between the isomer selectivity in metabolic phenotypes and endocrine-disrupting effects. Data provided here not only lend authenticity to the cautions issued by the scientists and researchers but also offer a solution for the balance between environment and political regulations.     

Asymmetric Hydrolysis of Prochiral Diesters with Pig Liver Esterase. Preparation of Optically Active Intermediates for the Synthesis of (+)-Biotin and (+)-α-Methyl-3,4-dihydroxyphenylalanine

With pig liver esterase, 1,3-dibenzyl-4,5-cis-bis(alkyloxycarbonyl)-2-oxoimidazolidine (1) was asymmetrically hydrolyzed to (4S,5R)-1,3-dibenzyl-5-alkyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (2). This acid 2 was reduced with lithium borohydride to (4S,5R)-1,3-dibenzyl-5-hydroxymethyl-2-oxoimidazolidine-4-carboxylic acid lactone (3), which is known to be converted to (+)-biotin (4). With the same esterase, diethyl 3,4-dimethoxyphenylmethyl-(methyl)malonate (5) was asymmetrically hydrolyzed to (R)-ethyl hydrogen 3,4-dimethoxy-phenylmethyl(methyl)malonate (6), which can be converted to (S)-α-methyl-3,4-dihydroxyphenyl-alanine(l-α-methyldopa) (9).     

A comparison of the enantioselective reduction potential of five strains of Saccharomyces cerevisiae towards a selected ketone

The enantioselectivity potential of five strains of Saccharomyces cerevisiae was studied for the reduction of ethyl N-{2-{4-[(2-oxocyclohexyl)methyl]phenoxy}ethyl} carbamate (1), an insect juvenile hormone bioanalog. The products of the reaction, the cis and trans isomers of ethyl N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (2 and 3), were obtained in 45–49% (w/w) chemical yields and with 79 to > 99% enantiomeric purity values. The absolute configurations of the major products were assigned as ethyl (1S,2S)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (2) and ethyl (1S,2R)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (3). The products 2 and 3 belong to the series of the chiral insect juvenile hormone analogs.     

Biotransformation of zerumbone by <Emphasis Type="Italic">Caragana chamlagu</Emphasis>

Suspension cultured cells of Caragana chamlagu (Leguminosae) converted zerumbone (1) into zerumbone epoxide (2) as the intermediate, (2R,3R,7R)-2,3-epoxy-9-humulen-8-one (3) and (2R,3S,7R)-2,3-epoxy-9-humulen-8-one (4) as new sesquiterpenes in 11%, 36% and 21% yields, respectively.     

Preparation of Optically Pure cis-2,4-Dimethyl-l-cyclohexanones,the Key Intermediates in Cycloheximide Synthesis,Using Microbial Resolution

Asymmetric hydrolysis of acetate (10) of (±)-t-2,t-4-dimethyl-r-l-cyclohexanol with Bacillus subtilis var. niger gave (?)-(lS,2S,4S)-2,4-dimethyl-l-cyclohexanol (6a) and (+)-(1R,2R,4R)-acetate (10b) with high optical purities. Optically pure (?) and (+)-alcohols (6a and 6b) were prepared via corresponding 3,5-dinitrobenzoates. Oxidation of alcohols (6a and 6b) with chromic acid gave optically pure (?)-(2S,4S) and (+)-(2R,4R)-2,4-dimethyl-l-cyclohexanones (2a and 2b), respectively.     

柯拉斯那沉香的生物活性成分研究

为了解柯拉斯那(Aquilaria crassna)的化学成分,从其所产沉香中分离得到10个化合物,经波谱分析分别鉴定为:6,8-羟基-2-(2-苯乙基)色酮(1),6,8-二羟基-2-[2-(4-甲氧基苯)乙基]色酮(2),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-5-(2-phenylethyl)-7H-oxireno[f][1]benzopyran-7-one(3),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-[2-(4-methoxyphenyl)-ethyl]-7H-oxireno[f][1]benzopyran-7-one(4),rel-(1a R,2R,3R,7b S)-1a,2,3,7b-tetrahydro-2,3-dihydroxy-5-[2-(3-hydroxy-4-methoxyphenyl)-ethyl]-7H-oxireno[f][1]benzopyran-7-one(5),oxidoagarochromone B(6),oxidoagarochromone C(7),(5S,6R,7S,8R)-2-[2-(3′-hydroxy-4′-methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone(8),6,7-cis-dihydroxy-2-(2-phenylethyl)-5,6,7,8-tetrahydrochromone(9),N-trans-feruloyltyramine(10)。化合物3~5和8~10为首次从柯拉斯那沉香中分离得到。化合物1,3,6,7,9和10对乙酰胆碱酯酶具有一定的抑制活性,化合物4对人慢性髓原白血病细胞株K-562和人胃癌细胞株SGC-7901均具有较小的抑制作用,化合物1和3对人肝癌细胞株BEL-7402也有抑制活性。     

New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities

Chemical investigation of the ethanol extract of the branch and leaves of Illicium majus resulted in the isolation of four new phenylpropanoid glycosides ( 1 – 4 ) and one new phenolic glycoside ( 9 ), along with 13 known ones. Spectroscopic techniques were used to elucidate the structures of the new isolates such as 3-[(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-yl]propyl β-D-glucopyranoside ( 1 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-glucopyranoside ( 2 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-xylopyranoside ( 3 ), 3-[(2R,3S)-3-({[2-O-(4-O-acetyl-α-L-rhamnopyranosyl)-β-D-xylopyranosyl]oxy}methyl)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro-1-benzofuran-5-yl]propyl acetate ( 4 ), and 4-(2-hydroxyethyl)phenyl 3-O-β-D-glucopyranosyl-β-D-glucopyranoside ( 9 ). Free radical scavenging activities of the isolates were elucidated through the DPPH assay method. The most active compounds, 1-O-caffeoyl-β-D-glucopyranose ( 17 ) and soulieana acid 1 ( 18 ), exhibited moderate radical scavenging activities (IC₅₀=37.7±4.4 μM and IC₅₀=97.2±3.4 μM, respectively). The antibacterial activities of the isolates against Staphylococcus aureus and Escherichia coli were also assessed, and no activity was shown at the measured concentration (<32 μg/mL).     

Compounds with neuroprotective activity from the medicinal plant Machilus thunbergii

The dichloromethane fraction of the bark of Machilus thunbergii Sieb. et Zucc. (Lauraceae) significantly protected primary cultures of rat cortical cells exposed to the excitotoxic amino acid, L-glutamate. Through the activity-guided isolation from the CH₂Cl₂ fraction, (+)-9′-hydroxygalbelgin (1), isogalcatin B (2), (7S,8S,8′R)-3′,4′-dimethoxy-3,4,-methylenedioxylignan-7-ol (3), 1-hydroxy-7-hydroxymethyl-6-methoxyxanthone (4), 5,7-dimethoxy-3′,4′-methylenedioxyflavan-3-ol (5), (+)-(3S,4S,6R)-3,6-dihydroxypiperitone (6), protocatechuic acid methyl ester (7) and tyrosol (8) were obtained. All of them had significant neuroprotective activities against glutamate-induced neurotoxicity in primary cultures of rat cortical cells at concentrations ranging from 0.1 μM to 10.0 μM and were comparable to MK-801, a well-known inhibitor of glutamate receptor.     

Constituents of Limonia acidissima inhibit LPS-induced nitric oxide production in BV-2 microglia

The ethyl acetate (EtOAc) soluble fraction of the 85% ethanol (EtOH) extract of the dried bark of Limonia acidissima potently inhibited nitric oxide (NO) production in lipopolysaccharide (LPS) activated BV-2 cells, a microglial cell line. Bioassay-guided column chromatography separation afforded a new stereoisomer of neolignan, (7’E)-(7R,8S)-4-hydroxy-3,5’-dimethoxy-4’,7-epoxy-8,3’-neolig-7’-en-9,9’-diyil diacetate (1), together with two known lignans, (+)-yangambin (2) and (+)-syringaresinol (3), three known triterpenoids, hederatriol (4), basic acid methyl ester (5), and 3β-hydroxyolean-12-en-11-one (6), and four known fatty acid derivatives, cascarillic acid (7), (+)-α-dimorphecolic acid (8), 8(R)-hydroxylinoleic acid (9), and (6Z,9Z,12Z)-pentadecatrienoic acid (10). The structure of the new compound 1 was elucidated by detailed analysis of spectroscopic data and circular dichroism (CD) spectroscopy. Compounds 1, 3-6, and 8-10 isolated from L. acidissima significantly reduced NO production in LPS-stimulated BV-2 microglia cells.     

Discovery of stereospecific cytotoxicity of (8R,8′R)-trans-arctigenin against insect cells and structure-activity relationship on aromatic ring

One of the arctigenin stereoisomers, (8R,8′R)-trans-form 1, showed stereospecific cytotoxicity against insect cells, Sf9 and NIAS-AeAl-2 cells. By the comparison with other stereoisomers, the most importance of the 8′R stereochemistry for the higher activities was clarified. On the other hand, the wider range of activity level among stereoisomers against cancer cells, HL-60, was not observed. The structure-activity relationship research using derivatives bearing (8R,8′R)-trans-form was performed to show the same level of activities of 3-iodo, 4-iodo, and 3,4-methylenedioxy derivatives 28, 29, and 36 as (8R,8′R)-trans-arctigenin 1. In the examination of thiono derivatives, 4-iodo thiono and 3,4-methylenedioxy thiono derivatives 66, 67 showed similar level of activities to that of (8R,8′R)-trans-arctigenin 1. The expression of ribosomal 28S rRNA gene of Sf9 cells was increased by (8R,8′R)-trans-arctigenin 1, whereas a degradation of DNA was not observed.     

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 of Ceramides from Tagetes patula L. Yellow Flowers and Nematicidal Activity of the Fractions and Pure Compounds against Cyst Nematode,Heterodera zeae

Investigation of yellow flower extract of Tagetes patula L. led to the identification of an aggregate of five phytoceramides. Among them, (2R)‐2‐hydroxy‐N‐[(2S,3S,4R,8E)‐1,3,4‐trihydroxyicos‐8‐en‐2‐yl]icosanamide, (2R)‐2‐hydroxy‐N‐[(2S,3S,4R,8E)‐1,3,4‐trihydroxyicos‐8‐en‐2‐yl]heneicosanamide, (2R)‐2‐hydroxy‐N‐[(2S,3S,4R,8E)‐1,3,4‐trihydroxyicos‐8‐en‐2‐yl]docosanamide, and (2R)‐2‐hydroxy‐N‐[(2S,3S,4R,8E)‐1,3,4‐trihydroxyicos‐8‐en‐2‐yl]tricosanamide were identified as new compounds and termed as tagetceramides, whereas (2R)‐2‐hydroxy‐N‐[(2S,3S,4R,8E)‐1,3,4‐trihydroxyicos‐8‐en‐2‐yl]tetracosanamide was a known ceramide. A steroid (β‐sitosterol glucoside) was also isolated from the subsequent fraction. The structures of these compounds were determined on the basis of spectroscopic analyses, as well as chemical method. Several other compounds were also identified by GC/MS analysis. The fractions and some commercial products, a ceramide HFA, β‐sitosterol, and stigmasterol were evaluated against an economically important cyst nematode, Heterodera zeae. Ceramide HFA showed 100 % mortality, whereas, β‐sitosterol and stigmasterol were 40–50 % active, at 1 % concentration after 24 h of exposure time, while β‐sitosterol glucoside revealed no activity against the nematode.     

Synthesis of a Base-Protected α-L-LNA Guanine Nucleoside

Abstract

Synthesis of (1R,3R,4S,7R)-7-hydroxy-1-hydroxymethyl-3-(2-N-isobutyroylguanin-9-yl)-2,5-dioxabicyclo[2.2.1]heptane (12), a protected α-L-LNA guanine nucleoside, has been accomplished using a convergent synthetic strategy starting from 1,2-di-O-acetylfuranose 4.     

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine,and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B₁₆F₁₀, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

The Synthesis of Enantiomerically Pure Pyrazolo[4,3-c]pyridine Carbarzbo C-Nucleoside

Abstract

The synthesis of (-)-3-[(1S,2S,3R,4R)-2,3-dihydroxy-4-(hydroxmethyl) cyclopentan-1-yl]-1H-pyrazolo[4,3-c]pyridme-4,6(5H,7H)-dione 3 was accomplished via enantiomerically pure carbocyclic 5-(β-D-ribofuranosyl)tetrazole 4.