Structural insights into the mechanism of translational inhibition by the fungicide sordarin

The translational machinery has been found to be the target for a number of antibiotics. One such antibiotic sordarin selectively inhibits fungal translation by impairing the function of elongation factor 2 (eEF2) while being ineffective to higher eukaryotes. Surprisingly, sordarin is not even equally effective in impairing translation for all fungal species. The binding cavity of sordarin on eEF2 has been localized by X-ray crystallographic study and its unique specificity towards sordarin has been attributed to the species specific substitutions within a stretch of amino acids (sordarin specificity region, SSR) at the entrance of the cavity. In this study, we have analyzed the sordarin-binding cavity of eEF2 from different species both in isolated and ribosome-bound forms in order to decipher the mechanism of sordarin binding selectivity. Our results reveal that the molecular architecture as well as the microenvironment of the sordarin-binding cavity changes significantly from one species to another depending on the species specific substitutions within the cavity. Moreover, eEF2 binding to ribosome aggravates the effects of these substitutions. Thus, this study, while shedding light on the molecular mechanism underpinning the selective inhibitory effects of sordarin, will also be a helpful guide for future studies aiming at developing novel antifungal drugs with broader spectrum of activity.     

Programming Rapid Functional Group Diversification into a Solid-State Reaction: Aryl Nitriles for Self-Assembly,Click Reactivity,and Discovery of Coexisting Supramolecular Synthons

A method to rapidly diversify the molecules formed in organic crystals is introduced, with aryl nitriles playing a novel dual role as both hydrogen-bond acceptors and modifiable organic groups. The discovery of coexisting supramolecular synthons in the same crystal is also described. The general concept is demonstrated by using a bis(aryl nitrile) alkene that undergoes a hydrogen-bond-directed intermolecular [2+2] photodimerization to form a tetra(aryl nitrile)cyclobutane. The product is readily converted by click reactivity to a tetra(aryl tetrazole) and by hydrolysis to a tetra(aryl carboxylic acid). The integration of aryl nitriles into solid-state reactions opens broad avenues to post-modify products formed in crystalline solids for rapid diversification.     

Preparation and Analytical Application of a New Chelating Ion Exchange Resin Containing Thioglycolic Acid

Starting from copolymerization of acrylonitrile and divinylbenzene by emulsion polymerization technique, a macroporous, crosslinked polyacrylonitrile copolymer was synthesized. The nitrile groups on the copolymer resin were converted into carboxylic acid groups by hydrolysis with strong alkaline solution of sodium hydroxide to obtain the resin matrix with carboxylic acid groups. A new chelating ion exchange resin containing alkylthioglycolate was prepared by esterification of carboxylic acid groups on the resin matrix and thioglycolic acid with 1,6-hexanediol as binding part. After studies of the basic characters, ion exchange ability, exchange rate and acidity of the medium, it was found that the new resin obtaind was highly selective for silver(I), mercury(II), gold(III) and bismuth(III) in acidic-aqueous solution. Separation of these metal ions from each other and concentration of these metal ions from very dilute solution were studied by liquid chromatography using a short column of this new resin. The analytical applications of this new resin are reported.     

Enantioselective nitrile anion cyclization to substituted pyrrolidines. A highly efficient synthesis of (3S,4R)-N-tert-butyl-4-arylpyrrolidine-3-carboxylic acid

[reaction: see text] A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94-99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans-pyrrolidine carboxylic acid target compound in >99.9% chemical and optical purity. This chemistry was also shown to be applicable to both electronically neutral and rich substituted phenyl substrates.     

A practical synthesis of (-)-kainic acid

A highly practical stereoselective total synthesis of (-)-kainic acid is described. This synthesis features the stereoselective alkylation of an iodolactone intermediate that was efficiently prepared from (+)-carvone and introduction of carboxylic acid by hydrolysis of a nitrile accompanied by epimerizaion. This synthetic route enabled us to obtain 14.6 g of (-)-kainic acid.     

Retention of stereochemistry in the microwave assisted synthesis of 1H-tetrazole bioisosteric moiety from chiral phenyl-acetic acid derivatives

Chiral substituted phenylethyl-1H-tetrazoles were built-up from the corresponding carboxylic acid derivatives by a useful three-step synthesis. The procedure, that preserves the chiral center from racemization, was successfully applied to a selection of several hit compounds by conversion of the carboxylic acid moiety to the nitrile derivatives and subsequent reaction with trimethylstannyl azide, under microwave conditions. A useful application to the corresponding tetrazole analogue has been found also in the conversion of the aminoacidic moiety like (R)-N-Cbz-phenylglycine showing a wide potential synthetic application.     

In situ mineralization of hydroxyapatite on electrospun chitosan-based nanofibrous scaffolds

A biocomposite of hydroxyapatite (HAp) with electrospun nanofibrous scaffolds was prepared by using chitosan/polyvinyl alcohol (CS/PVA) and N-carboxyethyl chitosan/PVA (CECS/PVA) electrospun membranes as organic matrix, and HAp was formed in supersaturated CaCl2 and KH2PO4 solution. The influences of carboxylic acid groups in CECS/PVA fibrous scaffold and polyanionic additive poly(acrylic acid) (PAA) in the incubation solution on the crystal distribution of the HAp were investigated. Field-emission scanning electron microscopy (FE-SEM), energy-dispersive spectroscopy (EDS), wide-angle X-ray diffraction (WAXD), and Fourier transform infrared (FTIR) were used to characterize the morphology and structure of the deposited mineral phase on the scaffolds. It was found that addition of PAA to the mineral solution and use of matrix with carboxylic acid groups promoted mineral growth and distribution of HAp. MTT testing and SEM imaging from mouse fibroblast (L929) cell culture revealed the attachment and growth of mouse fibroblast on the surface of biocomposite scaffold, and that the cell morphology and viability were satisfactory for the composite to be used in bioapplications.     

Fe(0)-mediated synthesis of tri- and tetra-substituted olefins from carbonyls: an environmentally friendly alternative to Cr(II)

Fe(0) was investigated as a cost-effective, environmentally friendly alternative to Cr(II) for the olefination of carbonyls by activated polyhalides. In many instances, Fe(0) was equivalent or superior to Cr(II). Notably, Fe(0), but not Cr(II), proved compatible with a wide range of functionality, inter alia, unprotected phenol, aryl nitro, carboxylic acid, and alkyl nitrile. A surprising reversal of stereoselectivity for aldehydes versus ketones was observed using both metals. The resultant alpha-halo-alpha,beta-unsaturated or alpha,beta-unsaturated carboxylic acids, esters, and nitriles are common structural elements in numerous compounds of interest as well as key intermediates in the preparation of other functionality.     

Boronic Acid Catalysis for Mild and Selective [3+2] Dipolar Cycloadditions to Unsaturated Carboxylic Acids

Herein, the concept of boronic acid catalysis (BAC) for the activation of unsaturated carboxylic acids is applied in several classic dipolar [3+2] cycloadditions involving azides, nitrile oxides, and nitrones as partners. These cycloadditions can be used to produce pharmaceutically interesting, small heterocyclic products, such as triazoles, isoxazoles, and isoxazolidines. These cycloadducts are formed directly and include a free carboxylic acid functionality that can be employed for further transformations, thereby avoiding prior masking or functionalization. In all cases, BAC provides faster reactions, under milder conditions, with much improved product yields and regioselectivities. In some instances, such as triazole formation from the reaction of azides with 2‐alkynoic acids, catalysis with ortho‐nitrophenylboronic acid circumvents the undesirable product decarboxylation observed when using thermal activation. By using NMR spectroscopic studies, the boronic acid catalyst was shown to provide activation by a LUMO‐lowering effect in the unsaturated carboxylic acid, likely via a monoacylated hemiboronic ester intermediate.     

Preparation and analytical properties of a chelating resin containing cysteine groups

A macroporous, cross-linked polyacrylonitrile copolymer was synthesized, the nitrile groups were converted to carboxylic acid by hydrolysis, and these carboxylic acid groups were treated with L-cysteine and 1,6-hexanediol (binding agent). Studies of the basic characteristics of this resin showed that it was highly selective for silver(I), mercury(II), gold(III) and platinum(IV) in aqueous acidic solution, the maximum capacities being 0.97, 0.65, 1.22 and 0.39 mmol g^-1 of dry resin, respectively. These four metal ions can be separated from each other, or concentrated from very dilute solutions, on a short column of the resin. The effects of different acids and of various common metal ions are reported.     

Biocatalytic Synthesis of Highly Enantiopure 1,4-Benzodioxane-2-carboxylic Acid and Amide

Catalyzed by Rhodococcus erythropolis AJ270, a nitrile hydratase and amidase containing microbial whole-cell catalyst, at 10 ℃ and with the use of methanol as a co-solvent, nitrile and amide biotransformations produce 2S-1,4-benzodioxane-2-carboxamide and 2R-1,4-benzodioxane-2-carboxylic acid in high yields with excellent enantioselectivity.     

Scope of a novel three-component synthesis of highly functionalized pyridines(dagger)

A mechanistically unique three-component synthesis provides a variety of functionalized pyridine derivatives in fair to excellent yields. The scope of this reaction was studied with respect to the alkoxyallene, the nitrile, and the carboxylic acid. Due to the 4-hydroxy group, these pyridine derivatives are suitable precursors for subsequent palladium-catalyzed reactions. Suzuki couplings of the corresponding pyridyl nonaflates lead to a variety of pyridine and bipyridine derivatives.     

Facile solid phase synthesis of 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines using a tetrafunctional scaffold

Solid phase synthesis of 1, 2-disubstituted-6-nitro-1,4-dihydroquinazolines is described. The new tetrafunctional scaffold N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was prepared by nitration of 3-amino-3-(2-fluorophenyl)propionic acid. The scaffold was anchored to Rink resin via its carboxylic group and treated with primary amines to displace the arylfluorine followed by cyclization with aryl isothiocyanates in the presence of DIC upon Alloc deprotection to afford 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines in high yield.     

Acyl chlorides of 2,2,5,5-tetramethyl-3-imidazolin-1-oxyl-4-0-acylhydroximic acids

Acylation of nitroenamine derivatives of imidazolidin-1-oxyl with carboxylic acid chlorides leads to 0-acylhydroximic acid chloride derivatives of 3-imidazolin-1-oxyl. The reaction proceeds apparently through a nitrile oxide. It was shown for the 0-benzoyl derivative that reaction of the obtained acyl chlorides with nucleophilic reagents usually gives products of chlorine atom substitution with simultaneous cleavage of the acyl group.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 444–450, February, 1991.     

Polyester-based carborane-containing dendrons

New carborane-containing dendrons based on a 2,2-bis(hydroxymethyl)propanoic acid scaffold have been prepared for applications in boron neutron capture therapy. A generation-2 carborane-containing dendron carrying 40 boron atoms was the highest generation synthetically available due to the steric crowding. The structure of this dendron has been simulated by molecular dynamics. A 10-carbon linker carrying a carboxylic group has been installed at the focal point of the dendron to distance the attachment point from the sterically hindered core.     

A convergent synthesis of the imidazopyridine scaffold of fluorescent alkaloid ageladine A

A convergent synthesis of the imidazopyridine scaffold of fluorescent alkaloid ageladine A (1) has been achieved, employing 3-amino-2-chloropyridine as the staring material. A carboxylic acid was introduced using n-butyllithium and dry ice as the key reaction.     

Synthesis of 1-functionalyzed 3-(diethoxyphosphorylmethyl)-4,5,6,7-tetrahydrobenzo[<Emphasis Type="Italic">c</Emphasis>]furans

A series of 3-(diethoxyphosphorylmethyl)-4,5,6,7-tetrahydrobenzo[c]furans functionalized in the position 1 including the unsubstituted phosphonate, diethylaminomethyl derivative, carboxylic acid, its ester, chloride, amide, and nitrile was synthesized. For the first time in the furan series decarboxylation of PO-ester of phosphonocarboxylic acid was carried out. Some specific features of behavior of the derivatives of 4,5,6,7-tetrahydrobenzo[c]furan in the reactions with thionyl chloride, phosphorus pentachloride, ammonia, and N-bromosuccinimide unusual for common alkylfurans were found.     

Synthesis and biological evaluation of 3-amino-propan-1-ol based poly(ether imine) dendrimers

A general synthetic strategy for the rapid construction of poly(ether imine) dendrons and dendrimers with a nitrogen core, originating from 3-amino-propan-1-ol, is described. A new trifunctional monomer, namely, 3-[bis-(3-hydroxypropyl)amino]propan-1-ol, was used in a divergent synthesis of dendrimers up to the third generation. This method permitted installation of, either alcohol, amine, nitrile, ester or carboxylic acid groups at the peripheries the dendrimers. Cytotoxicity studies on water-soluble carboxylic acid terminated dendrimers were conducted and these studies revealed that poly(ether imine) dendrimers were non-toxic. These results illustrate that poly(ether imine) dendrimers are useful for biological studies.     

Solid-phase synthesis of 5-isoxazol-4-yl-[1,2,4]oxadiazoles

A library of isoxazole and 1,2,4-oxadiazole-containing diheterocyclic compounds has been prepared. Our strategy was explored in solution phase first as follows. PMB-protected 3-butyn-2-ol was deprotonated with nBuLi, acylated with methyl chloroformate, and then employed in a nitrile oxide 1,3-dipolar cycloaddition (benzaldehyde oxime in the presence of bleach) to afford the isoxazole-substituted carboxylic acid methyl ester. Ester saponification with aqueous NaOH followed by a two-step condensation with benzamidoxime gave the final isoxazole-oxadiazole diheterocyclic product in good yield. With some modifications, we next explored this chemistry on Wang resin, which led to 18 final products that were cleaved from polymer beads with 50% TFA in dichloromethane.     

A rapid and diverse construction of 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through double Reformatsky reaction

A rapid and diverse synthesis of biologically important 6-substituted-5,6-dihydro-4-hydroxy-2-pyrones through a double Reformatsky reaction of aldehydes to δ-hydroxy-β-ketoesters followed by lactonization is described. Due to the high functional group tolerance and reaction site discrimination between aldehyde, nitrile, and ester groups in the substrate, the protocol can provide the dihydropyrones with bromo, nitro, carboxylic acid, and β-ketoester groups, which are suitable for the further derivatizations. Furthermore, the protocol has been successfully applied to the rapid total synthesis of naturally occurring Yangonin.