Docking based design of diastereoisomeric MTCA as GPIIb/IIIa receptor inhibitor

In GPIIb/IIIa mediated arterial thrombosis platelet activation plays a central role. To discover platelet activation inhibitor the pharmacophores of GPIIb/IIIa receptor inhibitors and anti-thrombotic agents were analyzed. This led to the design of (1R,3S)- and (1S,3S)-1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acids as GPIIb/IIIa inhibitors. Comparing to (1S,3S)-isomer (1R,3S)-isomer had lower cdocker interaction energy. AFM image showed that the minimal effective concentration of (1S,3S)-isomer and (1R,3S)-isomer inhibiting platelet activation were 10^?5?M and 10^?6?M, respectively. In vivo 1?μmol/kg of oral (1S,3S)-isomer effectively inhibited the rats to form arterial thrombus and down regulated GPIIb/IIIa expression, but the activities were significantly lower than those of 1?μmol/kg of oral (1R,3S)-isomer. Both (1S,3S)-isomer and (1R,3S)-isomer can be safely used for structural modifications, but (1R,3S)-isomer should be superior to (1S,3S)-isomer.     

Cloning and Expression of the Bacillus subtilis No. 313 γ-Cyclodextrin Forming CGTase Gene in Escherichia coli

All four stereoisomers of pyriculol were synthesized to assist in forming a correlation between their chemical structure and biological activity. The (R,E)-2-hydroxy-3-pentenal derivative was coupled with a lithium acetylide derivative to give a diastereomeric mixture of the acetylenic alcohol, which led to the antipode of pyriculol and its 3′-epimer. Similarly obtained were the natural pyriculol and its 3′-epimer from the (S)-isomer of this aldehyde.     

Biological activities of juvenile hormone III skipped bisepoxide in last instar nymphs and adults of a stink bug, Plautia stali

Juvenile hormone III skipped bisepoxide (JHSB₃), methyl (2R,3S,10R)-2,3;10,11-bisepoxyfarnesoate was recently determined as a novel juvenile hormone (JH) in a stink bug, Plautia stali. To further confirm the biological function of JHSB₃ in this insect, its juvenilizing, reproduction-stimulating and diapause-terminating activities and the presence in the hemolymph were examined. Topical application of JHSB₃ to last instar nymphs inhibited their metamorphosis in a dose-dependent fashion. In allatectomized and diapausing adults, JHSB₃ application exerted stimulatory effects on the development of ovaries and ectadenia in females and males, respectively. JHSB₃ was detected from the hemolymph of reproductively active females by gas chromatography-mass spectrometry analysis while its titer in the hemolymph collected from diapausing adults was too low to be detected. These results demonstrated that JHSB₃ has biological function as a JH in P. stali. Topical application of JHSB₃, its stereoisomers and 10R-JH III also indicated that compounds with the 2R,3S-configuration were more potent than those with the 2S,3R-configuration and 2,3-double bond.     

Constitutional Studies on the Mucilage of “Yamanoimo,” Dioscorea batatas Decne,forma Tsukune

All four stereoisomers of 10,14-dimethyloctadec-1-ene, a sex pheromone component of the apple leafminer (Lyonetia prunifoliella: Lepidoptera), were synthesized starting from (R)- and (S)-propylene oxide by applying stereospecific inversion of chiral secondary tosylates as a key step. Field evaluation showed that male moths of the Japanese population were selectively attracted by the (10S,14S)-isomer and that the activity was not inhibited by the enantiomer.     

An Improved Method for Determining Lipolytic Acyl-hydrolase Activity

The effects of 2-phthalimidooxyalkanoic acid derivatives on the germination and root-growth of cress were examined. Since 2-phthalimidooxypropionates were most effective, the optically active ethyl esters were prepared. As the result of biological testing, the (S)-(-)-isomer exhibited stronger activity than the (R)-(+)-isomer. This result is contrary to those from commercial herbicides with similar structures, phenoxy- and oxyphenoxy-propionate-type compounds, where the (R)-isomers are generally known to be the active principles.     

Composition and stereochemistry of ephedrine alkaloids accumulation in Ephedra sinica Stapf

Ephedra sinica Stapf (Ephedraceae) is a widely used Chinese medicinal plant (Chinese name: Ma Huang). The main active constituents of E. sinica are the unique and taxonomically restricted adrenergic agonists phenylpropylamino alkaloids, also known as ephedrine alkaloids: (1R,2S)-norephedrine (1S,2S)-norpseudoephedrine, (1R,2S)-ephedrine, (1S,2S)-pseudoephedrine, (1R,2S)-N-methylephedrine and (1S,2S)-N-methylpseudoephedrine. GC–MS analysis of freshly picked young E. sinica stems enabled the detection of 1-phenylpropane-1,2-dione and (S)-cathinone, the first two putative committed biosynthetic precursors to the ephedrine alkaloids. These metabolites are only present in young E. sinica stems and not in mature stems or roots. The related Ephedra foemina and Ephedra foliata also lack ephedrine alkaloids and their metabolic precursors in their aerial parts. A marked diversity in the ephedrine alkaloids content and stereochemical composition in 16 different E. sinica accessions growing under the same environmental conditions was revealed, indicating genetic control of these traits. The accessions can be classified into two groups according to the stereochemistry of the products accumulated: a group that displayed only 1R stereoisomers, and a group that displayed both 1S and 1R stereoisomers. (S)-cathinone reductase activities were detected in E. sinica stems capable of reducing (S)-cathinone to (1R,2S)-norephedrine and (1S,2S)-norpseudoephedrine in the presence of NADH. The proportion of the diastereoisomers formed varied according to the accession tested. A (1R,2S)-norephedrine N-methyltransferase capable of converting (1R,2S)-norephedrine to (1R,2S)-ephedrine in the presence of S-adenosylmethionine (SAM) was also detected in E. sinica stems. Our studies further support the notion that 1-phenylpropane-1,2-dione and (S)-cathinone are biosynthetic precursors of the ephedrine alkaloids in E. sinica stems and that the activity of (S)-cathinone reductases directs and determines the stereochemical branching of the pathway. Further methylations are likely due to N-methyltransferase activities.     

Evaluation of the Suppressive Effect on Bitter Taste of Gluconate

Improved conditions for the production and characterization of 1-arylpropane-1, 2-diols and related compounds were developed. Experimental conditions providing highly enhanced activity of pyruvate decarboxylase in bakers’ yeast in the presence of pyruvate, thiamine pyrophosphate, and magnesium(II) salt were applied to the preparation of (R)-1-hydroxy-1-phenyl-2-propanone from benzaldehyde. Subsequent reduction with bakers’ yeast efficiently afforded 1-phenyl-1, 2-propanediol (35%). The composition of its stereoisomers was precisely determined, and the major (1R, 2S)-isomer (89% of the total mixture) could be isolated by recrystallizing the corresponding benzoate. The analytical method for identifying the stereoisomeric composition was also effective for the determination of 5-phenyl-4-pentene-2, 3-diol, the biotransformation product from cinnamaldehyde, the vinylogous substrate of benzaldehyde. Furthermore, the structural characterization of 1-(2-furyl)propane-1, 2-diol, which was obtained from furfural (28%) by the action of brewers’ yeast Saccharomyces cerevisiae (carlsbergensis), is described. The major (1S, 2S)-isomer could be isolated by recrystallizing the crude product.     

Nogo-B promotes invasion and metastasis of nasopharyngeal carcinoma via RhoA-SRF-MRTFA pathway

Distant metastasis remains the major cause for treatment failure in patients with nasopharyngeal carcinoma (NPC). Thus, it is necessary to investigate the underlying regulation mechanisms and potential biomarkers for NPC metastasis. Nogo-B (neurite outgrowth inhibitor B), encoded by reticulon-4, has been shown to be associated with the progression and advanced stage of several cancer types. However, the relationship between Nogo-B and NPC remains unknown. In this study, we found that higher expression of Nogo-B was detected in NPC cells and tissues. Higher expression of Nogo-B was statistically relevant to N stage, M stage, and poor prognosis in NPC patients. Further functional investigations indicated that Nogo-B overexpression could increase the migration, invasion, and metastasis ability of NPC cells in vitro and in vivo. Mechanistically, Nogo-B promoted epithelial-mesenchymal transition (EMT) and enhanced the invasive potency by interacting directly with its receptor NgR3 in NPC. Additionally, overexpression of Nogo-B could upregulate the protein levels of p-RhoA, SRF, and MRTFA. A positive relationship was found between the expression of Nogo-B and the p-RhoA in NPC patients as well as in mouse lung xenografts. Nogo-B^high p-RhoA^high expression was significantly associated with N stage, M stage, and poor prognosis in NPC patients. Notably, CCG-1423, an inhibitor of the RhoA-SRF-MRTFA pathway, could reverse the invasive potency of Nogo-B and NgR3 in NPC cell lines, and decrease the expression of N-Cadherin, indicating that CCG-1423 may be a potential target drug of NPC. Taken together, our findings reveal that Nogo-B enhances the migration and invasion potency of NPC cells via EMT by binding to its receptor NgR3 to regulate the RhoA-SRF-MRTFA pathway. These findings could provide a novel insight into understanding the metastasis mechanism and targeted therapy of advanced NPC.Subject terms: Head and neck cancer, Drug discovery     

Absolute configuration of norcoronatine

Norcoronamic acid was established as having the absolute stereochemistry (1S,2S)-2-methyl-1-aminocyclopropane-1-carboxylic acid by comparison of its properties with synthetic preparations of the (1R,2R), (1R,2S) and (1S,2R) stereoisomers.     

Syntheses of 6-(2-hydroxy-6-phenylhexyl)-5,6-dihydro-2H-pyran-2-one derivatives and their cytotoxicities

The cytotoxicities against cancer cells (HL-60, HeLa) and insect cells (Sf9) of four stereoisomers of 6-(2-hydroxy-6-phenylhexyl)− 5,6-dihydro-2H-pyran-2-one (1) were evaluated, and then their structure-activity relationships examined. The 2′-dehydroxy derivative 5 of (6 R,2′R)- and (6 R,2′S)-1 showed the highest activity against HeLa cells (IC₅₀ = 1.4 μM). To evaluate the effect of the 2′-hydroxy group of 1, 6R-and 6S-oxetane derivatives were also synthesized and their activities examined. Against HeLa and HL-60 cells, the activities of the less potent stereoisomers were enhanced 3–4-fold by the introduction of the oxetane moieties at the 2′-position. Against the insect cell line (Sf9), phenyl derivative 7 showed the highest activity with an IC₅₀ value of 8.0 μM.     

4-Hydroxyisoleucine from seed of Trigonella foenum-graecum

The principal free amino acid present in seed of Trigonella foenum-graecum has been isolated and identified as (2S, 3R, 4R)-4-hydroxyisoleucine. This compound has not been reported previously as a constituent of higher plants, but it is a component of the toxic peptide, γ-amanitin, produced by Amanita phalloides. The (2S, 3R, 4R)-isomer lactonizes readily under acidic conditions, whilst strong acid causes partial epimerization. The (2R, 3R, 4R)-isomer forms a minor component of Trigonella seed. The 4-hydroxyisoleucine content of fenugreek increases during the growth of seedlings and plants, and ¹⁴C-isoIeucine was used effectively as a biosynthetic precursor.     

R-(−)-mandelic acid production from racemic mandelic acids by Pseudomonas polycolor with asymmetric degrading activity

The microbial asymmetric degradation of S-(+)-mandelic acid was investigated in order to develop a practical process for R-(−)-mandelic acid production from racemic mandelic acids. Among the 790 culture strains tested, microorganisms belonging to the Brevibacterium, Pseudomonas, Rhodococcus, Rhodotorula, Rhodosporidium, Sporobolomyces and Gibberella genera exhibited high S-(+)-mandelic acid degrading activity. Pseudomonas polycolor IFO 3918 was determined to be the best strain and used as a biocatalyst for eliminating the S-(+)-isomer. The maximum rate of S-(+)-isomer degradation was obtained at 30°C and pH 7.0. Under these optimal conditions, the S-(+)-isomer in a racemic mandelic acid 45 g/l mixture was completely degraded within 24 h, with 20 g of R-(−)-mandelic acid per liter remaining in the reaction mixture. Crystalline R-(−)-mandelic acid with a chemical purity greater than 99% and optical purity of 99.9% enantiomeric excess was obtained at a yield of 35% by acidification of the reaction mixture, extraction with ethyl acetate and subsequent concentration.     

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.     

Geographic variation in the field response of male European pine sawflies, Neodiprion sertifer, to different pheromone stereoisomers and esters

The European pine sawfly, Neodiprion sertifer (Geoffroy) (Hymenoptera: Diprionidae), is a widespread and economically important forest insect. The sex pheromone communication system of this species has been previously investigated in North America, Japan and Europe, with the acetate or propionate of the alcohol (2S,3S,7S)-3,7-dimethyl-2-pentadecanol (diprionol) shown to be the main pheromone component. In some locations, male attraction either increased or decreased by the addition of the (2S,3R,7R)-diprionyl acetate isomer. However, these studies were made with different batches of synthetic pheromones, with different types of traps and according to different procedures, so the observed differences might not reflect true geographic variation. Here we investigate the geographic pattern of male sawfly response by using identical chemicals, traps and experimental procedures at eight field sites ranging from Japan in the east to Canada in the west. We found an increased inhibitory effect of the (2S,3R,7R)-isomer from Japan and Siberia to Europe. At the eastern sites, increasing amounts of the (2S,3R,7R)-isomer up to and equal to the amount of the (2S,3S,7S )-isomer, did not influence the trap catch, whereas at sites in Europe, as little as 1% of the (2S,3R,7R)-isomer almost completely inhibited the attraction. The response of the North American population was intermediate. The only site in which the (2S,3R,7R)-isomer was essential for the attraction of males was in Siberia. A similar pattern was found for the (2S,3R,7S)-isomer. Both the acetate and the propionate form of the (2S,3S,7S)-isomer were attractive by themselves in Japan, Europe and North America, and neither the (2S,3R,7S)-isomer nor the (2S,3R,7R)-isomer alone were attractive, in the acetate or propionate form. We discuss the significance of our findings for the development of more efficient monitoring schemes and for the causes of population divergence and speciation in the European pine sawfly.     

Synthesis,chromatographic resolution and chiroptical properties of carboxyibuprofen stereoisomers: Major metabolites of ibuprofen in man

The chromatographic resolution of the four stereoisomers of carboxyibuprofen, a major metabolite of ibuprofen in man, was achieved using a Chiralpak AD chiral stationary phase (CSP) (J.T. Baker, Milton, Keynes, UK). The elution order of the stereoisomers was determined to be 2′S,2R; 2′R,2R; 2′R,2S; 2′S,2S by a combination of stereoselective synthesis of diastereoisomeric mixtures and analysis of the two diastereoisomers isolated from human urine following the administration of (S)-ibuprofen. The individual stereoisomers were isolated by semipreparative chiral phase chromatography and characterized by circular dichroism spectroscopy. Chirality 9:75–87, 1997. © 1997 Wiley-Liss, Inc.     

Structure–cytotoxic activity relationship of sesquilignan,morinol A

The cytotoxic activities of sesquilignans, (7S,8S,7′R,8′R)- and (7R,8R,7′S,8′S)-morinol A and (7S,8S,7′S,8′S)- and (7R,8R,7′R,8′R)-morinol B were compared, showing no significant difference between stereoisomers (IC₅₀ = 24–35 μM). As a next stage, the effect of substituents at 7, 7′, and 7″-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18 (IC₅₀ = 6–7 μM). In the research on the structure–activity relationship of 7″-position of (7S,8S,7′R,8′R)-7,7′,7″-phenyl derivative 18, the most potent compounds were 7,7′,7″-phenyl derivative 18 (IC₅₀ = 6 μM) against HeLa cells. Against HL-60 cells, 7″-(4-nitrophenyl)-7,7′-phenyl derivative 33 and 7″-hexyl-7,7′-phenyl derivative 37 (IC₅₀ = 5 μM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7′R,8′R)-morinol A. It was also confirmed that the 7′-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity.     

Soybeans and radish leaves contain only one of the sulfonium diastereoisomers of S-adenosylmethionine

Using a liquid chromatography method that separates the two sulfonium diastereoisomers of adenosylmethionine, we have found that immature soybeans, soybean callus culture, radish leaves, yeast and rat liver contain only the (S)-sulfonium form of S-adenosylmethionine. Our findings contradict the suggestion by Stolowitz and Minch that 10–20% of naturally-occurring adenosylmethionine may have the (R)-configuration at the sulfonium pole. Absence of the (R)-sulfonium isomer of adenosylmethionine in biological materials indicates that the (R)-sulfonium form of adenosylmethionine present in commercial adenosylmethionine samples is an artifact of the isolation procedure. Our method of measuring the isomers of adenosylmethionine enabled us to readily determine the rate of racemization and hydrolysis of adenosylmethionine. Our rate constants for racemization (K_r) and hydrolysis (K_h) were 2.4 × 10^?6 sec^?1 and 12.3 × 10-^?6 sec^?1, respectively; values which are noticeably different from those of Wu and co-workers which were obtained with a more complicated method (K_r = 8 × 10^?1 sec^?1; K_h = 6 × 10^?6 sec^?1). We believe the absence of the (R)-isomer in vivo is best explained by stabilization of the (S)-isomer as suggested by Wu et al. Although the tissues we have analysed contained the (S)-sulfonium form of adenosylmethionine exclusively, when ethionine-resistant soybean cell lines were given ethionine, they accumulated both sulfonium diastereoisomers of adenosylethionine.