Synthesis of 1,2-cis- and 1,2-trans-glycosides of 2-acetamido-4,6-O-benzylidene-2-deoxy-d-glucopyranose by anomeric O-alkylation

The reaction of a partially protected 1-hydroxy derivative of N-acetyl-d-glucosamine with benzyl bromide under conditions of anomeric O-alkylation was studied. It was found that the stereoselectivity of the reaction depended on the nature of the alkali metal cation constituent of a transient ion pair. The substitution of the Li⁺ cation for K⁺ or complexation with a crown ether allowed the steric outcome to be shifted from β- to α-selectivity.     

Effect of the position of the phenolic group in morphinans on their affinity for opiate receptor binding

Homologous series of N-methyl, N-allyl and N-cyclopropylmethylmorphinans, differing only in the position of the plenolic hydroxy group, were examined with respect to their binding affinities for the opiate receptor. IC₅₀'s were determined for competition with ³H-naltrexone in the presence and absence of 100 mM NaCl. While the compounds with the hydroxy in the 3-position had, as expected, by far the highest affinity, the corresponding molecules with the hydroxy in the 2- or 4- position had significant binding affinity ranging from 30 nM in the cyclopropyl- methyl series to 400 nM for the 2-hydroxy N-methyl morphinan. The sodium indices were also very similar to those of the corresponding 3-hydroxy compounds. The only 1-hydroxy derivative available was about 5-fold weaker than the corresponding 2- and 4-hydroxy compounds. Covering or removing the hydroxy group greatly weakened the binding but did not totally destroy it. There was good correlation between binding affinity and pharmacological potency for all except the methoxy compounds. Their high potency is consonant with $\text{in vivo}$ hydrolysis of the methyl ether.     

Microbial hydroxylation of chiral bicyclic enones by Chaetomium sp.1 and Didymosphaeria igniaria cultures

The biotransformations of (R)-(?)-methyloctalone and (S)-(+)-methyloctalone were investigated using Chaetomium sp.1 KCH 6651 and Didymosphaeria igniaria KCH 6670 as biocatalysts, yielding mostly 6β- and 7β-hydroxy derivatives. During the incubation of (R)-methyloctalone with the Chaetomium sp.1 culture, three products were obtained: the trans-7β-hydroxy derivative in 50% yield, trans-6β-hydroxy derivative in 30% yield and cis-8α-hydroxy derivative in 6% yield. The (S)-enone was hydroxylated mainly in the 6α-position (with 60% yield). 6β- and 7β-hydroxy derivatives are new compounds, not previously described in the literature. The biotransformation of the two enantiomers of methyloctalone with D. igniaria also afforded monohydroxy derivatives. In both cases the main product of transformation was the allylic hydroxy derivative (27–35% yield). D. igniaria transformed the (R)-methyloctalone more rapidly whereas Chaetomium sp. 1 preferred the (S)-methyloctalone.     

Initial Steps in the Degradation of Methoxychlor by the White Rot Fungus Phanerochaete chrysosporium

The white rot fungus Phanerochaete chrysosporium mineralized [ring-(sup14)C]methoxychlor [1,1,1-trichloro-2,2-bis(4-methoxyphenyl)ethane] and metabolized it to a variety of products. The three most prominent of these were identified as the 1-dechloro derivative 1,1-dichloro-2,2-bis(4-methoxyphenyl)ethane, the 2-hydroxy derivative 2,2,2-trichloro-1,1-bis(4-methoxyphenyl)ethanol, and the 1-dechloro-2-hydroxy derivative 2,2-dichloro-1,1-bis(4-methoxyphenyl)ethanol by comparison of the derivatives with authentic standards in chromatographic and mass spectrometric experiments. In addition, the 1-dechloro-2-hydroxy derivative was identified from its (sup1)H nuclear magnetic resonance spectrum. The 1-dechloro and 2-hydroxy derivatives were both converted to the 1-dechloro-2-hydroxy derivative by the fungus; i.e., there was no requirement that dechlorination precede hydroxylation or vice versa. All three metabolites were mineralized and are therefore likely intermediates in the degradation of methoxychlor by P. chrysosporium.     

Synthesis of the amino acid conjugates of <Emphasis Type="Italic">epi</Emphasis>-jasmonic acid

The TES ether of the C6-hydroxy derivative of naturally occurring epi-jasmonic acid (epi-JA) was designed as epimerization-free equivalent of epi-JA. The TES ether was synthesized from (1R,4S)-4-hydroxycyclopent-2-enyl acetate in 13 steps. The acid part of the ether was activated with ClCO₂Bu ⁱ and subjected to condensation with l-amino acid at room temperature for 48 h. The TES group in the condensation product was removed in HCO₂H (0°C, 30 min) and the resulting hydroxyl group was oxidized with Jones reagent (acetone, 0°C, 30 min) to furnish the amino acid conjugate of epi-JA. The amino acids examined are l-isoleucine, l-leucine, l-alanine, l-valine, and d-allo-isoleucine, which afforded the conjugates in 48–68% yields with 89–96% diastereomeric purity over the trans isomers. Similarly, the possible three stereoisomers of epi-JA were condensed with l-isoleucine successfully, producing the corresponding stereoisomers in good yields.     

Hydroxylation of thiacloprid by bacterium Stenotrophomonas maltophilia CGMCC1.1788

Chloropyridinyl neonicotinoid insecticides play a major role in crop protection and flea control on cats and dogs. Imidacloprid, thiacloprid and acetamiprid have in common the 6-chloro-3-pyridinylmethyl group but differ in the nitroguanidine or cyanoamidine substituent on an acyclic or cyclic moiety. Our previous study found that Stenotrophomonas maltophilia CGMCC 1.1788 could hydroxylate imidacloprid to 5-hydroxy imidacloprid, and 5-hydroxy imidacloprid was easily converted to 10–19 times higher insecticidal olefin imidacloprid against aphid or whitefly. Acetamiprid could be transformed by S. maltophilia to form N-demethylation product(IM 2-1). In this paper, we examined S. maltophilia CGMCC 1.1788’s ability of transformation of thiacloprid. S. maltophilia CGMCC 1.1788 can hydroxylate thiacloprid to 4-hydroxy thiacloprid characterized by HPLC-MS/MS and NMR analysis, however 4-hydroxy thiacloprid could not be converted to olefin thiacloprid under acid conditions like imidacloprid, whereas oxidized and decyonated simultaneously to form 4-ketone thiacloprid imine in alkaline solution. Bioassays indicated that 4-hydroxy thiacloprid had 156 times lower insecticidal activity than thiacloprid, and the ketone-imine derivative almost had no toxicity towards aphid. Though both imidacloprid and thiacloprid are hydroxylated by S. maltophilia CGMCC 1.1788 at the same carbon atom position, however the structural difference between in imidacloprid and thiacloprid, originate the entire discrepancy in bioefficacy of metabolite and its further degrading pathway. These results explain that why thiacloprid is classified as not relevant grade for soil and seed applications, whereas imidacloprid is recommended and acetamiprid is limited.     

Nucleosides VIII: 1 Synthesis of 2′, 3′-Dideoxy- and 2′, 3′-Didehydro-2′, 3′-Di Deoxyisoguanosine as Potential Antiretroviral Agents

Abstract

2′, 3′-Didehydro-2′, 3′-dideoxyisoguanosine (2) and 2′, 3′- dideoxyisoguanosine (3) have been synthesized by utilizing the Corey-Winter approach starting from isoguanosine. The 6-amino and 5′-hydroxy biprotected isoguanosine derivative was converted to the corresponding 2′, 3′- thionocarbonate, which was heated with triethyl phosphite to afford the 2′,3′- olefinic product. Either a tert-butyldimethylsilyl or a 4, 4′-dimethoxytrityl group was used in the protection of 5′-hydroxy function. Compounds 2 and 3 were found inactive against human immunodeficiency virus (HIV), human cytomegalovirus (HCMV), and herpes simplex virus type 1 (HSV-1).

     

Diastereoselective hydroxylation and reduction of derivatised tetrahydrofurans by Beauveria bassiana

The filamentous fungus, Beauveria bassiana ATCC 7159, catalyses the regio- and diastereoselective biohydroxylation of trans-2-methyl-5-benzyloxymethyl-tetrahydrofuran to the cis-3-hydroxy derivative. When incubated with cis-2-methyl-3-keto-5-benzyloxymethyltetrahydrofuran, the same fungus performs a reduction to give the cis- and trans-alcohols in a 4:1 ratio.     

A novel method for the measurement of in vitro fatty acid 2-hydroxylase activity by gas chromatography-mass spectrometry

Fatty acid 2-hydroxylase (FA2H), encoded by the FA2H gene, is an enzyme responsible for the de novo synthesis of sphingolipids containing 2-hydroxy fatty acids. 2-Hydroxy sphingolipids are highly abundant in the brain, as major myelin galactolipids (galactosylceramide and sulfatide) contain a uniquely high proportion ( approximately 50%) of 2-hydroxy fatty acids. Other tissues, such as epidermis, epithelia of the digestive tract, and certain cancers, also contain 2-hydroxy sphingolipids. The physiological significance of the 2-hydroxylation on N-acyl chains of subsets of sphingolipids is poorly understood. To study the roles of FA2H and 2-hydroxy sphingolipids in various tissues, we developed a highly sensitive in vitro FA2H assay. FA2H-dependent fatty acid 2-hydroxylation requires an electron transfer system, which was reconstituted in vitro with an NADPH regeneration system and purified NADPH:cytochrome P-450 reductase. A substrate [3,3,5,5-D(4)]tetracosanoic acid was solubilized in alpha-cyclodextrin solution, and the 2-hydroxylated product was quantified by gas chromatography-mass spectrometry after conversion to a trimethylsilyl ether derivative. When the microsomes of FA2H-transfected COS7 cells were incubated with the electron transfer system and deuterated tetracosanoic acid, deuterated 2-hydroxy tetracosanoic acid was formed in a time- and protein-dependent manner. With this method, FA2H activities were reproducibly measured in murine brains and tissue culture cell lines.     

Synthesis of 1,2-cis- and 1,2-trans-glycosides of 2-acetamido-4,6-O-benzylidene-2-deoxy-D-glucopyranose by anomeric O-alkylation

The reaction of a partially protected 1-hydroxy derivative of N-acetyl-D-glucosamine with benzyl bromide under conditions of anomeric O-alkylation was studied. It was found that the stereoselectivity of the reaction depended on the nature of the alkali metal cation constituent of a transient ion pair. The substitution of the Li(+) cation for K(+) or complexation with a crown ether allowed the steric outcome to be shifted from β- to α-selectivity.     

1β,7β-Dihydroxydehydroabietic acid,a new biotransformation product of dehydroabietic acid by Aspergillus niger

Microbial transformation of dehydroabietic acid by Aspergillus niger afforded the new derivative 1β,7β-dihydroxydehydroabietic acid and the known 1β-hydroxy and 7β-hydroxy derivatives. The structures were elucidated by spectroscopic methods. The compounds were assessed towards Gram (+) and Gram (−) bacteria and showed a weak antimicrobial effect. This revised version was published online in August 2006 with corrections to the Cover Date.     

Determination of the ß-blocker carteolol in human plasma by a sensitive gas chromatographic—negative-ion chemical ionization high-resolution mass spectrometric method

A specific and sensitive gas chromatographic-high-resolution mass spectrometric method for the determination of 5-(3-tert.-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril (carteolol), which is a ß-blocker giving depression of intraocular pressure, was developed to elucidate the pharmacokinetics of its ophthalmic application. Carteolol has been determined by high-performance liquid chromatography but with less satisfactory sensitivity. Carteolol was derivatized with pentafluorobenzoyl (PFB) amide followed by dimethylethylsilyl (DMES) ether, resulting in a high negative-ion current. The PFB-DMES derivative of carteolol was determined by the gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) using selected-ion monitoring at low and high mass spectrometric resolution. The detection limit was less than 100 fg when the fragment ion was monitored at m/z 552.2067 in the NICI mode using methane as a reagent gas. The quantification limit of carteolol in human plasma with this method was less than 30 pg/ml. The proposed GC-MS method is considered to have sufficient specificity and sensitivity to study the pharmacokinetics of carteolol used as an ophthalmic solution.     

Synthesis of quinolinomorphinan-4-ol derivatives as δ opioid receptor agonists

The previously reported morphinan derivative SN-28 showed high selectivity and agonist activity for the δ opioid receptor. In the course of examining the structure-activity relationship of SN-28 derivatives, the derivatives with the 4-hydroxy group (SN-24, 26, 27) showed higher selectivities for the δ receptor over the μ receptor than the corresponding SN-28 derivatives with the 3-hydroxy group (SN-11, 23, 28). Derivatives with the 4-hydroxy group showed potent agonist activities for the δ receptor in the [(35)S]GTPγS binding assay. Although the 17-cyclopropylmethyl derivative (SN-11) with a 3-hydroxy group showed the lowest selectivity for the δ receptor among the morphinan derivatives, the agonist activity toward the δ receptor was the most potent for candidates with the 3-hydroxy group.     

Some biological activities of a series of 9a-homo-9,11-epoxy prostanoic acid analogues

A number of stereochemical variants at C-8, C-12 and C-15 of 9a-homo-9,11-epoxy prostaglandins (PGs) have been examined for in vivo activity on blood pressure, bronchial resistance, tracheal segment pressure, heart rate and on intestinal and uterine contractility in artificially respired anaesthetised guinea-pigs; and on blood pressure and blood platelet aggregation in rats (using the extra-corporeal filter-aorta loop technique). In vitro tests for smooth muscle activity were carried out on the isolated rat fundus strip, the guinea-pig tracheal chain and the rat uterus. The following was found:

1. In the guinea-pig, in vivo, all the homo-epoxy PGs were vasopressor and bronchoconstrictor following bolus injections of 250 μg i.v. The effects on heart rate, and intestinal and uterine contractility were equivocal. The configurations at the chiral centres, C-8, C-12 and C-15 play an important role in determining potency. The 15-(S)-hydroxy derivatives were the most potent in stimulating vascular and respiratory muscle. The 8-iso configuration appeared to enhance potency amongst the 15-(S)-hydroxy compounds. The 15-(R)-hydroxy configuration markedly reduced constrictor potency. The same pattern of activity was seen on rat blood pressure, in vivo. The 15-(S)-hydroxy configuration combined with the 8-iso configuration had the most potent constrictor activity, while the 15-(R)-hydroxy group negated this and even led, in the case of the natural configuration at C-8 and C-12, to vasodepression.

2. In vitro, the activity on the rat fundus and guinea-pig tracheal chain followed the same pattern. The 15-(S)-hydroxy derivatives were very much more potent than the 15-(R)-hydroxy derivatives at contracting the smooth muscle preparations. Uterine muscle appeared to be relaxed by the PGs with the natural configuration at C-8 and C-12, with the 15-(R)-hydroxy compound exhibiting greater activity.

3. Inhibition of ADP-induced rat blood platelet aggregation after “intra-arterial” administration was shown only by the derivatives with a single change in the natural configuration either at C-8 or at C-15. Additional changes either resulted in inactivity or, in the case of the 8,12-di-iso-15-(S)-hydroxy compound, even reversed the effect to aggregation.

The inhibition of aggregation was long lasting with both the 8-iso-15-(S)-hydroxy derivative and the 8,12-nat-15-(R)-hydroxy derivative. In the case of the latter compound, GBR-30731, activity increased during the 30 min after administration. GBR-30731 deserves further investigation as a platelet aggregation inhibitor because of its relatively low smooth muscle stimulant (sometimes even relaxant effects) and its long lasting platelet aggregation inhibiting activity./lt     

Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors

A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.     

Characterization and in vivo production of three glycolipids from Candida Bogoriensis: 13-glucopyranosylglucopyranosyloxydocosanoic acid and its mono- and diacetylated derivatives

Three glycosides of 13-hydroxydocosanoic acid isolated from Candida bogoriensis were characterized by quantitating the amount of carbohydrate, acetate, and hydroxy acid in each, and by gas-liquid chromatography and mass spectrometry of their methyl ester, trimethylsilyl ether derivatives. One of the glycosides was the diacetylated derivative of 13-glucosylglucosyloxydocosanoic acid previously characterized by Tulloch, Spencer, and Deinema (Can. J. Chem., 46: 345 [1968]), in which the disaccharide had the beta(1 --> 2) sophorose linkage and the acetyl groups were attached to the 6' and 6" positions of the glucose residues. The other two glycosides were 13-glucosylglucosyloxydocosanoic acid and its monoacetylated derivative. A comparison of the mass spectra of derivatives indicates that the acetyl group of the monoacetyl lipid is on the internal glucose. Methyl 13-glucosyloxydocosanoate was produced by acid hydrolysis of the methyl ester of the unacetylated glycolipid and was characterized by the same techniques as the other glycolipids. Time course of production of the three glycolipids is consistent with the diacetylated derivative being the first extra-cellular product and the other two glycolipids being formed by deacetylation. 13-Hydroxy[13-(3)H]docosanoic acid, methyl 13-hydroxy[13-(3)H]docosanoate, and 9-hydroxy[11,12-(3)H]-stearic acid were each incorporated into the glycolipid fraction.     

花生茎叶酚性成分研究

运用大孔树脂对花生茎叶提取液进行富集,不同浓度乙醇洗脱,硅胶、RP-18、Sephadex LH-20等多种材料进一步分离纯化,研究花生茎叶化学成分,并通过理化方法和光谱分析对化合物进行结构鉴定。结果表明:从花生茎叶大孔树脂10%乙醇洗脱部位中分离并鉴定了10个化合物,分别为邻苯二甲酸二异丁酯(1)、水杨酸(2)、儿茶酚(3)、对羟基苯甲酸(4)、(反)-3,4-二羟基苯丙烯酸(5)、对羟基苯酚(6)、邻苯二甲酸二丁酯(7)、3,4-二羟基苯乙醇(8)、对羟基苯乙醇(9)、3,4-二羟基苯甲酸(10)。除化合物1、2和4外,其余均为首次从该植物中分离得到。     

Isolation and characterization of a glycolipid from Dictyostelium discoideum

A glycolipid was isolated from a lipid extract of the cellular slime mold Dictyostelium discoideum and characterized. From the results of analyses by thin-layer chromatography and infrared spectrometry, it was identified as a steryl glycoside. The steryl glycoside was further analyzed by gas-liquid chromatography/mass spectrometry as a trimethylsilyl ether derivative, and its quantitative and qualitative changes during the development of D. discoideum were examined. Δ²²-Stigmastenyl-d-glucoside was the major constituent of the steryl glycoside and comprised more than 90% of the total steryl glycoside fraction in cells at all stages of development. The content of the steryl glycoside was higher in vegetative-stage cells, late aggregation-stage cells, and 1-day sorocarps than in cells of other stages. The glycolipid fraction was often contaminated by a lipid which was also isolated and identified as a ceramide containing 2-hydroxy fatty acids and 4D-hydroxysphinganine.     

The influence of protective groups on diastereofacial selectivity of Diels-Alder cycloaddition reactions

The diastereofacial selectivity of both inter- and intramolecular Diels-Alder reactions with dienes having an allylic stereogenic center has been studied by varying the allylic oxygen protective group. Four different hydroxy protective groups were investigated including benzyl, t-butyldiphenylsilyl, triethylsilyl, and t-butyldimethylsilyl ethers. For intermolecular reactions, the benzyl ether derivative gave the highest sπ-facial selectivity through a transition state in which the allylic stereocenter favors the CH eclipsed conformation. For intramolecular cycloadditions, the t-butyldimethylsilyl group gave a slightly higher selectivity than the benzyl ether derivative through a transition state in which the allylic stereocenter favors the CO eclipsed conformation. The opposite diastereofacial selectivity observed for inter- and intramolecular reactions is explained by considering both steric and electronic effects. © 1995 Wiley-Liss, Inc.     

Essential structure of orexin 1 receptor antagonist YNT-707, Part II: Drastic effect of the 14-hydroxy group on the orexin 1 receptor antagonistic activity

The 14-dehydration- and 14-H derivatives of the orexin 1 receptor (OX₁R) antagonist YNT-707 (2) were synthesized. The obtained derivatives showed higher affinities for OX₁R than the corresponding 14-hydroxy derivatives. The conformational analysis suggested that the 17-sulfonamide groups in the derivatives without the 14-hydroxy group have a greater tendency to be oriented toward the upper side of the D-ring compared with the 14-hydroxy derivatives. Additionally, the 14-dehydration-derivative with 6α-amide side chain showed significantly higher affinity than the 14-hydroxy derivative, while the corresponding 14-H derivative showed only slightly higher affinity. Thus, the 14-hydroxy group strongly affects the affinity of the antagonist for the OX₁R.