The antibacterial properties of sulfur containing flavonoids

Some dithiocarbamic esters bearing a flavanone backbone, as well as their corresponding 1,3-dithiolium salts were tested against Staphylococcus aureus and Escherichia coli. The 1,3-dithiolium tricyclic flavonoids display good inhibitory properties against both Gram-positive and Gram-negative pathogens.     

Prostaglandin fluorides in synthesis of natural prostaglandin derivatives at carboxyl group

Methods of synthesis of prostaglandin fluorides were developed and their properties were investigated. These compounds were shown to be convenient synthetic precursors for obtaining esters and amides of natural prostaglandins and their fluorodeoxy analogues.     

Enzymatic synthesis of 1,3-dihydroxyphenylacetoyl-sn-glycerol: Optimization by response surface methodology and evaluation of its antioxidant and antibacterial activities

In this study, the enzymatic synthesis of phenylacetoyl glycerol ester was carried out as a response to the increasing consumer demand for natural compounds. 1,3-dihydroxyphenylacetoyl-sn-Glycerol (1,3-di-HPA-Gly), labeled as “natural” compound with interesting biological properties, has been successfully synthesized for the first time in good yield by a direct esterification of glycerol (Gly) with p-hydroxyphenylacetic acid (p-HPA) using immobilized Candida antarctica lipase as a biocatalyst. Spectroscopic analyses of purified esters showed that the glycerol was mono- or di-esterified on the primary hydroxyl group. These compounds were evaluated for their antioxidant activity using two different tests. The glycerol di-esters (1,3-di-HPA-Gly) showed a higher antiradical capacity than that of the butyl hydroxytoluene. Furthermore, compared to the p-HPA, synthesized ester (1,3-di-HPA-Gly) exhibited the most antibacterial effect mainly against Gram + bacteria. Among synthesized esters the 1,3-di-HPA-Gly was most effective as antioxidant and antibacterial compound. These findings could be the basis for a further exploitation of the new compound, 1,3-di-HPA-Gly, as antioxidant and antibacterial active ingredient in the cosmetic and pharmaceutical fields.     

Determination of absolute configuration of 1,3-diols by the modified Mosher's method using their di-MTPA esters.

1,3-Diols are frequently involved in biologically important compounds and, therefore, determination of the stereochemistry of these structural elements, in particular those in acyclic systems, has been one of the focuses of attention in natural products chemistry. The modified Mosher's method, commonly used for the determination of the absolute configuration of secondary alcohols, was applied to determine the absolute configuration of 1,3-diols with their di-MTPA esters. Several epimeric pairs of syn- and anti-1,3-diols with known absolute configurations were converted to the corresponding di-MTPA esters and the iDelta;delta values were then calculated. For the acyclic syn-1,3-diols, the iDelta;delta values were systematically arranged as predicted from the basic concept of the modified Mosher's method, demonstrating that the method is valid for these compounds. In contrast, the iDelta;delta values were irregularly arranged for the acyclic anti-1,3-diols and, accordingly, this method is not valid for these cases. These results are complementary to those of the previously reported CD exciton chirality method and, hence, the combined use of the modified Mosher's method and the CD exciton chirality method can determine the absolute configuration of the acyclic 1,3-diols. Also, this method is successfully applicable to cyclic 1,3-diols irrespective of their relative stereochemistry.     

Specificity of two different purified acylcarnitine hydrolases from rat liver, their identity with other carboxylesterases, and their possible function

One of the previously described five purified monoglyceride-cleaving carboxylesterases from rat liver microsomes proved to be a carnitine ester hydrolase. This esterase, with an isoelectric point of 5.2, is most active with medium-chain acyl-L-carnitines (C12-C14). The esterase is also remarkably active with 1,3-diglycerides, especially 1,3-dioctanoylglycerol, that are hydrolyzed faster than the corresponding 1-monoglycerides and triglycerides. Only one of the other four purified carboxylesterases has moderate acylcarnitine-hydrolyzing activity. An altered procedure for the separation of the two microsomal acylcarnitine-cleaving enzymes is described. Both enzymes hydrolyze carnitine esters optimally at pH 8 and both are inactive with acetylcarnitine, palmitoyl-CoA, and butyrylthiocholine. The possible natural functions of the hydrolases are discussed. Besides their detoxifying action on natural membrane-lysing detergents (like carnitine esters and lysophospholipids), these enzymes could be involved in the transport of carnitine out of the liver.     

Resolution of prostaglandin p-nitrophenacyl esters by liquid chromatography and conditions for rapid, quantitiative p-nitrophenacylation.

The p-nitrophenacyl esters of a number of closely related and isomeric prostaglandins were resolved by HPLC on a microparticulate silica gel column (Zorbax-Sil, DuPont). Ten F-series prostaglandin analogs, eight E-series prostaglandin analogs, the isomeric 15(R)- and 15(S)-methyl prostaglandins of the E- and F-series and, lastly, PGA2 and PGB2 were chromatographed under conditions generating 2,000 to 7,000 theoretical plates. Conditions are described for quantitative conversion of prostaglandins to p-nitrophenacyl esters in less than 6 minutes at room temperature. Linear peak height and peak area plots were obtained for in-situ esterified PGE2 p-nitrophenacyl ester over the range of 0.4 - 3.1 mug. The lower limit of detection of this ester is about 1 ng. A linear relationship is observed between silica gel TLC 1/Rf values and HPLC retention times as predicted by theory.     

Detection of prostaglandins by high-performance liquid chromatography after conversion to p-(9-anthroyloxy)phenacyl esters

p-(9-Anthroyloxy)phenacyl bromide (panacyl bromide) undergoes rapid reaction with the carboxyl group of prostaglandins in the presence of N,N-diisopropylethylamine in acetonitrile-tetrahydrofuran (4:1). The resulting prostaglandin panacyl esters are strongly uv absorbing with a lambda max at 253 nm and an epsilon of 174,280 in acetonitrile. The lower limit of detection of prostaglandins was approximately 200 pg with uv detection (254 nm) and about 30 pg with fluorescent detection (exitation 253 and emission 445 nm) using normal-phase HPLC. The reactivity of panacyl bromide with 23 prostaglandins as well as prostaglandins released by human lung tissues was investigated.     

Facile synthesis of acid-labile polymers with pendent ortho esters

This work presents a facile approach for preparation of acid-labile and biocompatible polymers with pendent cyclic ortho esters, which is based on the efficient and mild reactions between cyclic ketene acetal (CKA) and hydroxyl groups. Three CKAs, 2-ethylidene-1,3-dioxane (EDO), 2-ethylidene-1,3-dioxolane (EDL), and 2-ethylidene-4- methyl-1,3-dioxolane (EMD) were prepared from the corresponding cyclic vinyl acetals by catalytic isomerization of the double bond. The reaction of CKAs with different alcohols and diols was examined using trace of p-toluenesulfonic acid as a catalyst. For the monohydroxyl alcohols, cyclic ortho esters were formed by simple addition of the hydroxyl group toward CKAs with ethanol showing a much greater reactivity than iso-propanol. When 1,2- or 1,3-diols were used to react with the CKAs, we observed the isomerized cyclic ortho esters besides the simple addition products. Biocompatible polyols, that is, poly(2-hydroxyethyl acrylate) (PHEA) and poly(vinyl alcohol) (PVA) were then modified with CKAs, and the degree of substitution of the pendent ortho esters can be easily tuned by changing feed ratio. Both the small molecule ortho esters and the CKA-modified polymers demonstrate the pH-dependent hydrolysis profiles, which depend also on the chemical structure of the ortho esters as well as the polymer hydrophobicity.     

Wax esters synthesis from heavy fraction of sheep milk fat and cetyl alcohol by immobilised lipases

Wax esters were obtained from lipase-catalysed alcoholysis of triglycerides with cetyl alcohol, using n-hexane as solvent. The heavy triglyceride fraction (HTF), obtained by fractionation of sheep milk fat, was used as raw material. In the natural fat mixture GC analysis showed that palmitic, myristic, stearic and oleic acids are the most abundant fatty acids which are useful to produce wax esters. Reactions were tested for different amounts of Lipozyme RMIM catalyst, and the optimum concentration of 10 mg catalyst/ml solution has been determined. The formation of the four main products, i.e. cetyl myristate, cetyl palmitate, cetyl oleate and cetyl stearate, was determined by HPLC/ELSD quantitative analysis. The optimum water activity in the reaction medium a_w=0.35 in the case of Lipozyme RMIM, and a_w=0.53 for Novozym 435 was found. Lipozyme RMIM (immobilised sn-1,3-specific lipase from Rhizomucor miehei) was more active than Novozym 435 (immobilised nonspecific lipase-B from Candida antarctica) towards wax esters production. The acyl migration of 2-monoglycerides was suggested as a crucial step to explain the higher yields produced by the 1,3-specific lipase.     

中国野鸦椿属植物化学成分及药理活性研究进展

野鸦椿属植物归属于省沽油科,主要分布于东亚以及东南亚,我国分布有两个种。该属植物化学成分结构丰富,包括酯类、三萜类、黄酮类等,药理活性广泛,如抗炎、抗肝纤维化、抗氧化等。本文从化学成分及药理活性方面对野鸦椿属植物的研究进行综述,以期为该属植物的深入研究与开发提供文献参考。     

1,3-Diacylglycero-2-phosphocholines--synthesis, aggregation behaviour and properties as inhibitors of phospholipase D

A series of 1,3-diacylglycero-2-phosphocholines (1,3-PCs) with acyl chain lengths of C8-C18 were synthesised by chemical introduction of the phosphocholine moiety into the regioisomerically pure 1,3-diacylglycerols, which were obtained from glycerol and the vinyl esters of fatty acid by means of lipase from Rhizomucor mihei. The 1,3-PCs being regioisomers of the natural glycerophospholipids were studied with respect to their aggregation behaviour in the absence and in the presence of sodium dodecylsulfate (SDS) as well as their properties as substrates and inhibitors of phospholipase D (PLD) from cabbage. While the main structures of the pure 1,3-PCs were micelles (C8), liposomes (C10, C12) or planar bilayers (C14, C16, C18), the addition of SDS resulted in the formation of mixed micelles (C8, C10) and mixed liposomes (C12, C14, C16, C18). None of the 1,3-PCs was found to be hydrolysed by PLD, whereas all of them showed inhibitory properties in the standard assay for PLD. The inhibitory power was strongest with 1,3-didecanoylglycero-2-phosphocholine (IC50 = 43 microM).     

Resolution of prostaglandin p-nitrophenacyl esters by liquid chromatography and conditions for rapid, quantitative p-nitrophenacylation

The p-nitrophenacyl esters of a number of closely related and isomeric prostaglandins were resolved by HPLC on a microparticulate silica gel column (Zorbax-Sil®, DuPont). Ten F-series prostaglandin analogs, eight E-series prostaglandin analogs, the isomeric 15(R)- and 15(S)- methyl prostaglandins of the E- and F-series and, lastly, PGA₂ and PGB₂ were chromatographed under conditions generating 2,000 to 7,000 theoretical plates. Conditions are described for quantitative conversion of prostaglandins to p-nitrophenacyl esters in less than 6 minutes at room temperature. Linear peak height and peak area plots were obtained for esterified PGE₂ p-nitrophenacyl ester over the range of 0.4 – 3.1 μg. The lower limit of detection of this ester is about 1 ng. A linear relationship is observed between silica gel TLC 1/R_f values and HPLC retention times as predicted by theory.     

A novel downstream process for highly pure 1,3‐propanediol from an efficient fed‐batch fermentation of raw glycerol by Clostridium pasteurianum

An efficient downstream process without prior desalination was developed for recovering 1,3‐propanediol (1,3‐PDO) with high purity and yield from broth of a highly productive fed‐batch fermentation of raw glycerol by Clostridium pasteurianum. After removal of biomass and proteins by ultrafiltration, and concentration by water evaporation, 1,3‐PDO was directly recovered from the broth by vacuum distillation with continuous addition and regeneration of glycerol as a supporting agent. Inorganic salts in the fermentation broth were crystallized but well suspended by a continuous flow of glycerol during the distillation process, which prevented salt precipitation and decline of heat transfer. On the other hand, ammonium salt of organic acids were liberated as ammonia gas and free organic acids under vacuum heating. The latter ones formed four types of 1,3‐PDO esters of acetic acid and butyric acid, which resulted in yield losses and low purity of 1,3‐PDO (< 80%). In order to improve the efficiency of final 1,3‐PDO rectification, we examined alkaline hydrolysis to eliminate the ester impurities. By the use of 20% (w/w) water and 2% (w/w) sodium hydroxide, > 99% reduction of 1,3‐PDO esters was achieved. This step conveniently provided free 1,3‐PDO and the sodium salt of organic acids from the corresponding esters, which increased the 1,3‐PDO yield by 7% and prevented a renewed formation of esters. After a single stage distillation from the hydrolyzed broth and a followed active carbon treatment, 1,3‐PDO with a purity of 99.63% and an overall recovery yield of 76% was obtained. No wastewater with high‐salt content was produced during the whole downstream process. The results demonstrated that the monitoring and complete elimination of 1,3‐PDO esters are crucial for the efficient separation of highly pure 1,3‐PDO with acceptable yield from fermentation broth of raw glycerol.     

Use of high performance liquid chromatography of methylbenzocoumarin esters of prostaglandins in their quantitative fluorimetric analysis

A method is suggested for quantitative fluorimetric analysis of natural prostaglandins (PGs). It is based on preparation of the fluorescent methylbenzocoumarine PG esters after their reaction with 4-bromomethyl-7.8-benzocoumarine (Br-MBC). Conditions for the reverse-phase high-performance liquid chromatography were evaluated, which permitted separating PGs into groups and according to the degree of unsaturation. Sensitivity and linear dependence of the ester fluorescence on the PG concentration make this method suitable for the quantitative analysis of PGs in different biological objects.     

New bisphosphorothioates and bisphosphoroamidates: synthesis, molecular modeling and determination of insecticide and toxicological profile

A series of new compounds, N,N'-bis(dialkylphosphoryl)diamines and S,S'-bis(dialkylphosphoryl)-1,3-propanedithiols were prepared by a Todd-Atherton like reaction of dialkylphosphites with symmetrical diamines and 1,3-propanedithiols in a biphasic system [F.R. Athertoon, H.T. Howard, A.R. Todd, J. Chem. Soc. (1948) 1106-1111; F.R. Athertoon, H.T. Openshaw, A.R. Todd, J. Chem. Soc. (1945) 660-663]. The structures were characterized by IR, 1H NMR, 13C NMR and mass spectrometry. Compounds with butoxy, isobutoxy and isopropoxy groups linked in the phosphorus atom showed the lowest LD50 values when tested against Musca domestica and Stomoxys calcitrans. The pharmacological and toxicological evaluation of N,N'-bis(diisobutylphosphoryl)-1,3-propylenediamine and S,S'-bis(diisobutylphosphoryl)-1,3-propanedithiol, which were very active against M. domestica and S. calcitrans, demonstrated that these compounds present no toxicological effects against mice in a concentration of 200mg/kg. An explanation for the observed activity profile is presented based on results obtained in a molecular modeling study with insect and mammalian acetylcholinesterase models.     

Biochemistry of prostaglandins A

This review considers modern concepts on the structural-functional properties and antiproliferative, antitumor, and antiviral effects of cyclopentenone prostaglandins A and mechanisms underlying their actions. Possible directions of pharmacological application of these compounds and their analogs are discussed.     

Monoterpene-based chiral β-amino acid derivatives prepared from natural sources: syntheses and applications

Natural monoterpenes have proved to be good starting materials for the synthesis of β-amino acid derivatives. In the past decade, a number of well-known synthetic procedures have been applied for the preparation of monoterpene-based β-amino acid derivatives, e.g. from β-lactams via the 1,2-dipolar cycloaddition of chlorosulfonyl isocyanate to commercial or readily available monoterpenes [e.g. (+)- and (−)-α- or δ-pinene, (+)-3- and 2-carene, (+)- and (−)-apopinene], the conjugate addition of amides to monoterpene-based α,β-unsaturated esters or the transformations of (−)-cis-pinonoic acid prepared by the oxidative cleavage of (+)- and (−)-verbenone. β-Amino acid derivatives are excellent building blocks for versatile transformations, e.g. multicomponent reactions resulting in β-lactams, syntheses of 1,3-heterocycles and diaminopyrimidine derivatives or the formation of peptides containing an H12 helix. 1,3-Amino alcohol derivatives prepared from β-amino esters have been applied as chiral catalysts in enantioselective transformations. Several of these compounds are of noteworthy pharmacological importance, such as tyrosine kinase Axl inhibitor diaminopyrimidine-coupled β-aminocarboxamides, MDR inhibitor thiourea derivatives of β-amino esters or 2-imino-1,3-oxazines, which exhibit marked growth inhibitory activity on multiple cancer cell lines. The present review summarizes recent developments relating to the syntheses, applications and pharmaceutical importance of monoterpene-based β-amino acids and their derivatives.     

Resolution of prostaglandin p-nitrophenacyl esters by liquid chromatography and conditions for rapid, quantitative p-nitrophenacylation

The p-nitrophenacyl esters of a number of closely related and isomeric prostaglandins were resolved by HPLC on a microparticulate silica gel column (Zorbax-Sil ®, DuPont). Ten F-series prostaglandin analogs, eight E-series prostaglandin analogs, the isomeric 15(R)- and 15(S)-methyl prostaglandins of the E- and F-series and, lastly, PGA₂ and PGB₂ were chromatographed under conditions generating 2,000 to 7,000 theoretical plates. Conditions are described for quantitative conversion of prostaglandins to p-nitrophenacyl esters in less than 6 minutes at room temperature. Linear peak height and peak area plots were obtained for in-situ esterified PGE₂ p-nitrophenacyl ester over the range of 0.4 – 3.1 μg. The lower limit of detection of this ester is about 1 ng. A linear relationship is observed between silica gel TLC 1/R_f values and HPLC retention times as predicted by theory.     

The ultrastructure of renomedullary interstitial cells in short duration hypercalcemia induced by vitamin D3.

Under short duration hypercalcemia induced by pharmacological doses of vitamin D3 significant ultrastructural changes were observed in the renomedullary interstitial cells of rats. The most striking alteration was the degranulation of these cells accompanied with the increase in volume of the rough and smooth-surfaced endoplasmic reticulum, enlargement of the Golgi apparatus and occurence of osmiophilic inclusions probably of lipid nature in mitochondria. The ultrastructural changes can be regarded as an expression of the increase of a synthetic and secretory activity of the renomedullary interstitial cells and they may be associated with an enhanced production of prostaglandins or other lipid hormonal substances than prostaglandins under condition of hypercalcemia.     

Lipase‐catalyzed kinetic resolution of novel antitubercular benzoxazole derivatives

Novel benzoxazole derivatives were synthesized, and their antitubercular activity against sensitive and drug‐resistant Mycobacterium tuberculosis strains (M. tuberculosis H₃₇Rv, M. tuberculosis sp. 210, M. tuberculosis sp. 192, Mycobacterium scrofulaceum, Mycobacterium intracellulare, Mycobacterium fortuitum, Mycobacterium avium, and Mycobacterium kansasii) was evaluated. The chemical step included preparation of ketones, alcohols, and esters bearing benzoxazole moiety. All racemic mixtures of alcohols and esters were separated in Novozyme SP 435‐catalyzed transesterification and hydrolysis, respectively. The transesterification reactions were carried out in various organic solvents (tert‐butyl methyl ether, toluene, diethyl ether, and diisopropyl ether), and depending on the solvent, the enantioselectivity of the reactions ranged from 4 to >100. The enzymatic hydrolysis of esters was performed in 2 phase tert‐butyl methyl ether/phosphate buffer (pH = 7.2) system and provided also enantiomerically enriched products (ee 88‐99%). The antitubercular activity assay has shown that synthesized compounds exhibit an interesting antitubercular activity. Racemic mixtures of alcohols, (±)‐4‐(1,3‐benzoxazol‐2‐ylsulfanyl)butan‐2‐ol ((±)‐ 3a ), (±)‐4‐[(5‐bromo‐1,3‐benzoxazol‐2‐yl)sulfanyl]butan‐2‐ol ((±)‐ 3b ), and (±)‐4‐[(5,7‐dibromo‐1,3‐benzoxazol‐2‐yl)sulfanyl]butan‐2‐ol ((±)‐ 3c ), displayed as high activity against M. scrofulaceum, M. intracellulare, M. fortuitum, and M. kansasii as commercially available antituberculosis drug‐Isoniazid. Moreover, these compounds exhibited twice higher activity toward M. avium (MIC 12.5) compared with Isoniazid (MIC 50).