Microwave-assisted synthesis of N-glycolylneuraminic acid derivatives

A rapid, efficient and scalable synthesis of biologically-relevant N-glycolylneuraminic acid derivatives from the natural N-acetyl (Neu5Ac) precursors has been developed. Microwave irradiation provides accelerated de-N-acetylation compared to more traditional methods, with optimised NaOH-promoted de-N-acetylation in only 15 min. The prepared amines were readily re-N-acylated to afford the corresponding N-glycolyl (Neu5Gc) analogues.     

Extending the possibility of an N-Troc-protected sialic acid donor toward variant sialo-glycoside synthesis

The potential of an N-Troc-protected sialic acid donor, equipped with phenylsulfenyl functionality as a leaving group, has been explored. As a result, the entitled donor was proven to be highly reactive and to have broad applicability toward the synthesis of variant sialo-glycans, which have N-glycolyl, de-N-acetyl, 1,5-lactam and 8-O-sulfo sialic acid analogs.     

Oncinotine-Type Spermidine Alkaloids from Oncinotis tenuiloba. Transformation of N-acetyloncinotin-12-one to N,N′-diacetylinandenin-12-one

From extracts of Oncinotis tenuiloba STAPF , two novel polyamine alkaloids, oncinotin-11-one ( 5 ) and oncinotin-12-one ( 6 ), were isolated. Peracetylation of 6 provided the N-acetyl derivative 11 as well as N,N′-diacetylinandenin-10-en-12-one ( 12 ) due to a β-elimination-type side reaction resulting in ring enlargement of 11 (Scheme 1). Deuteration of 12 yielded 13 , showing the same retention time as N,N′-diacetylinandenin-12-one ( 14 ), when co-HPLC was performed together with different keto-isomeric N,N′-diacetylinandeninones. Structure elucidation was extended by Schmidt degradation of 6 and N,N′-diacetyl(10,11-²H₂)inandenin-12-one ( 13 ); the degradation products were identified by GC and ESI-MS. The structure of 5 was proposed on the basis of spectroscopic means. Comparison of the spectroscopic data of 5 with those obtained from synthetic material as well as co-HPLC of the N-acetyl derivative 20 together with the corresponding synthetic compound revealed the identity of the substances and confirmed the structure of 5 . Additionally, oncinotine ( 2 ) and neooncinotine ( 3 ) were isolated, separated, and identified with authentic samples by co-HPLC of their N-acetyl derivatives 8 and 9 , respectively.     

Synthesis of Morpholine-Based Analogues of (−)-Zampanolide and Their Biological Activity

We describe the convergent synthesis of three prototypical examples of a new class of analogues of the complex, cytotoxic marine macrolide (−)-zampanolide that incorporate an embedded N-substituted morpholine moiety in place of the natural tetrahydropyran ring. The final construction of the macrolactone core was based on a high-yielding intramolecular HWE olefination, while the hemiaminal-linked side chain was elaborated through a stereoselective, BINAL-H-mediated addition of (Z,E)-sorbamide to a macrocyclic aldehyde precursor. The synthesis of the common functionalized morpholine building block involved two consecutive epoxide openings with tosylamide and the product of the first opening reaction, respectively, as nucleophiles. Of the three morpholino-zampanolides investigated, the N-acetyl and the N-benzoyl derivatives both exhibited nanomolar antiproliferative activity, thus being essentially equipotent with the natural product. In contrast, the activity of the N-tosyl derivative was significantly reduced.     

Quantification of tryptic peptides in quadrupole ion trap using high-mass signals derived from isotope-coded N-acetyl dipeptide tags

Isotope-labeled N-acetyl dipeptides (Ac-Xxx-Ala) are coupled to the primary amines of tryptic peptides and then analyzed by tandem mass spectrometry. Amide bond cleavage between Xxx and Ala provides both low- and high-mass isotope-coded signals for quantification of peptides. Especially, facile cleavage at the modified lysine side chain yields very strong high-mass quantitation signals in a noise-free region. Tagging tryptic peptides with isobaric N-acetyl dipeptides is a viable strategy for accurate quantification of proteins, which can be used with most quadrupole ion trap mass spectrometers carrying the 1/3 mass cut-off problem.     

Low-temperature polymerization of lactams by using as catalyst the salt derived from NaAlEt4 and monomer and with several compounds as initiator

Low-temperature polymerization of α-pyrrolidone, α-piperidone, and ?-caprolactam was examined by using the salts derived from NaAlEt₄ and monomer, sodium lactamates, or the salt derived from AlEt₃ and monomer as catalyst and with N-acetyl lactams, ethyl acetate, or lactones as initiator. Sodium lactamate catalyst gave unsatisfactory results in the cases of ethyl acetate or lactones initiators, and gave the following order for the relative efficiency of initiators: N-acetyl lactam > ?-caprolactone ≥ ethyl acetate > β-propiolactone. The polymerization results obtained by the salt from NaAlEt₄ catalyst–ethyl acetate initiator system were nearly the same as those with N-acetyl lactam. The increases in the degree of polymerization and in the yield of polymer were observed in case of the salt from NaAlEt₄ catalyst-lactone initiator system, particularly in the cases of α-piperidone and ?-caprolactam. Also an incorporation of initiator into polymer chain was observed.     

Synthesis and Structural Analysis of Aspergillus fumigatus Galactosaminogalactans Featuring α-Galactose, α-Galactosamine and α-N-Acetyl Galactosamine Linkages

Galactosaminogalactan (GAG) is a prominent cell wall component of the opportunistic fungal pathogen Aspergillus fumigatus. GAG is a heteropolysaccharide composed of α-1,4-linked galactose, galactosamine and N-acetylgalactosamine residues. To enable biochemical studies, a library of GAG-fragments was constructed featuring specimens containing α-galactose-, α-galactosamine and α-N-acetyl galactosamine linkages. Key features of the synthetic strategy include the use of di-tert-butylsilylidene directed α-galactosylation methodology and regioselective benzoylation reactions using benzoyl-hydroxybenzotriazole (Bz-OBt). Structural analysis of the Gal, GalN and GalNAc oligomers by a combination of NMR and MD approaches revealed that the oligomers adopt an elongated, almost straight, structure, stabilized by inter-residue H-bonds, one of which is a non-conventional C−H⋅⋅⋅O hydrogen bond between H5 of the residue (i+1) and O3 of the residue (i). The structures position the C-2 substituents almost perpendicular to the oligosaccharide main chain axis, pointing to the bulk solvent and available for interactions with antibodies or other binding partners.     

Hydrolysis of amides. Kinetics and mechanism of the basic hydrolysis of N-acylpyrroles,N-acylindoles and N-acylcarbazoles

The hydroxide ion catalyzed hydrolysis of N-formyl, N-acetyl and N-benzoylpyrroles, -indoles and -carbazoles has been studied in water at 25.0°. The rate constants of formation of the tetrahedral intermediate are strongly increased by releasing steric hindrance in the acyl portion as shown by the higher reactivity of N-formyl derivatives in comparison with N-acetyl and N-benzoyl derivatives.     

Efficient Syntheses of Methyl 2-Amino-2-Deoxy-3,4,6-Tri-O-Benzyl-α-D-Glucopyranoside and its 2-tert-Butoxycarbonylamino- and 2-Methylamino Derivatives from N-Acetyl-D-Glucosamine

ABSTRACT

The synthesis of the title compounds started with N-acetylglucosamine which was converted into the corresponding methyl glycoside and O-protected with benzyl groups. Subsequent N-protection as its N-BOC-N-acetyl derivative and sequential removal of the N-acetyl group and of the BOC group led in good yield to the target compounds in multigram amounts.     

Predicted Influence of N-Acetyl Group Content on the Conformational Extension of Chitin and Chitosan Chains

ABSTRACT

Conformational analysis of chitosan molecules has been performed using the MM3(92) force field to investigate the role played by the acetamido groups on the stiffness of these chains. A high dielectric constant value was needed to model an aqueous environment and to reproduce the distribution of the N-acetyl glucosamine group orientation that is observed by NMR. Disaccharidic fragments, differently substituted at C2, were selected as models for chitin and chitosan chains. Their conformational space has been explored by means of adiabatic mapping of the glycosidic Φ,Ψ torsion angles. Although the overall features of all the potential energy surfaces created appear similar, the accessible conformational space of a glycosidic bond is affected by the nature of the substituent at C2 on the non-reducing residue of the disaccharide unit. This is illustrated by the differences in the calculated partition functions together with the predicted average homonuclear and heteronuclear coupling constants. Computed maps were used to predict polymeric unperturbed dimensions, characteristic ratio and persistence length of idealized chitin and chitosan chains, by Monte Carlo methods. Pure chitosan is predicted to be more coiled than pure chitin chains. At low N-acetyl group contents, chain extension appears to be dependent on the degree of substitution. Average chain dimensions increase monotonically for increases in content up to 60% of N-acetyl groups, but show no significant variation at higher contents. For molecules consisting of 50% amino and 50% N-acetylated residues, random, alternate and block patterns of substitution have been investigated. It has also been shown that the spatial extension of the polymer chains is dependent on the primary structure. Comparison with the literature experimental data is difficult because of the extreme diversity of the reported conformationally dependent values. However, such study provides a unique insight into the dependence of these two factors (degree of acetylation and distribution of acetyl groups) on the stiffness and flexibility of different chitin and chitosan chains.     

Regioselectively Modified Cellulose and Chitosan Derivatives for Mono- and Multilayer Surface Coatings of Hemocompatible Biomaterials

In this study different synthetic strategies were developed and applied to introduce solely or in combination heparin/heparansulfate-like functional groups such as N-sulfo, O-sulfo, N-acetyl, and N-carboxymethyl groups into chitosan and cellulose with highest possible regioselectivity and completeness and defined distribution along the polymer chain. Completely substituted 6-amino-6-deoxycellulose and related derivatives were prepared from tosylcellulose (DS 2.02; C₆ 1.0) by nucleophilic substitution with azido groups only in the 6-position at 50 °C with subsequent reduction to amino groups and completely removing tosyl groups in the 2,3-position. 2,6-Di-O-sulfocellulose was prepared using the reactivity difference between C-2, C-6 and C-3 of cellulose. The reactivity difference between amino groups and hydroxyl groups was used to prepare various N-substituted derivatives. Partially 2,6-di-O-sulfated cellulose was obtained from trimethylsilylcellulose by the insertion of sulfurtrioxide into the Si–O ether linkage. Partially 3-O-sulfocellulose was synthesized by protecting C-2 and C-6 with trifluoroacetyl groups. A copper–chitosan complex was used to synthesize 6-O-sulfochitosan with a DS of 1.0 at C-6 and various partially 6-O-desulfonated products are possible. Using the phthalimido group to increase the solubility of chitosan in DMF, the regioselectivity of 3-O-sulfo groups was improved by regioselective 6-O-desulfonation of nearly complete 3,6-O-disulfochitosan. The platelet adhesion properties of immobilized regioselectively modified water-soluble derivatives on membranes have been tested in vitro. Some regioselectively modified chitosan and cellulose derivatives are potential candidates for the surface coatings of biomaterials if the regioselective reactions are somewhat further optimized.     

Partial molar volumes and adiabatic compressibilities ofN-acetyl-DL-serinamide andN-acetyl-L-threonmamide in dilute aqueous solutions

Densities and sound velocities in dilute aqueous solutions ofN-acetyl-DL-serinamide andN-acetyl-L-threoninamide were measured at 5, 15, 25, 35, and 45°C. Partial molar volumes and partial molar adiabatic compressibilities of these amino acid derivatives at infinite dilution were determined. The partial molar quantities for the parent amino acids, serine and threonine, were also determined and compared with the acetyl amide derivatives. The contribution of the side chain of theN-acetyl amino acid amide or amino acid to the partial molar quantities were estimated from the difference between the partial molar quantities for the solute studied and those for the corresponding species,N-acetyl-glycinamide or glycine, without the side chain.     

Synthetic and antimicrobial studies of N-substituted-pyrazoline-based new bisheterocycles

In the present study, the four series of N-acetyl/N-carbothioamide/N-carboxamide/N-phenyl-based new bispyrazolines have been synthesized. These symmetrical bisheterocyclic products were prepared efficiently from the ring-closure reactions of new bischalcones 2a-d with appropriate cyclizing agents (hydrazine hydrate, thiosemicarbazide, semicarbazide, and phenyl hydrazine) under the alkaline ethanolic conditions. The compounds 2a-d were obtained by treating hydroxyl-substituted chalcone 1 with various dihalogenated reagents (α,α′-dibromo-o/m/p-xylene and 4,4′-bischloromethyl-diphenyl) in anhydrous K₂CO₃/dry acetone/Bu₄N⁺I⁻ medium. The structures of all the newly synthesized products have been authenticated with the help of their IR, ¹H-NMR, ¹³C-NMR, and ESI-MS spectral data and their purity was corroborated with the help of elemental analysis and thin-layer chromatography results. The in vitro antimicrobial screening of the newly synthesized intermediates and final bisheterocycles has also been performed by using the serial tube dilution technique against the selected number of microorganisms. The final bisheterocycles revealed better antibacterial and antifungal potencies as compared to their corresponding bischalcones. Among the symmetrical bisheterocyclic products, N-acetyl and N-carbothioamide-substituted bispyrazolines were found to exhibit potential antimicrobial properties than the other products.     

Synthesis of multivalent N-acetyl lactosamine modified quantum dots for the study of carbohydrate and galectin-3 interactions

Ternary core/shell CdSeS/ZnS-QDs coated with N-acetyl lactosamine was prepared as a fluorescent probe to study the interactions of N-acetyl lactosamine and galectin-3. The synthesis of N-acetyl lactosamine was achieved through the ‘azidoiodoglycosylation’ method. The amount of ligand coated on QDs was determined by ¹H NMR and ICP-OES. The interactions between carbohydrates and galectin-3 were measured using SPR. The results revealed that the affinity of galectin-3 with di- and multivalent N-acetyl lactosamine increased 20 and 184-fold, respectively. The prepared glyco-QDs could be used as an efficient fluorescent probe to study carbohydrates and galectin-3 interactions.     

Gangliosides from the starfishEvasterias echinosoma: identification of a disialoganglioside containing 8-O-methyl-N-acetylneuraminic acid andN-formylgalactosamine

Gangliosides were isolated from the starfishEvasterias echinosoma and their structures were elucidated by chemical and physicochemical methods. Two major gangliosides were found to be disialogangliosides, whose carbohydrate chain is based on the trisaccharide β-N-acylgalactosaminyl-(l→3)-β-galactosyl-(l→4)-β-glucose (acyl is formyl or acetyl), both residue at of 8-O-methyl-N-acetylneuraminic acid being attached to theN-acylgalactosamine residue at positions 3 and 6. The minor components are disialogangliosides with linear carbohydrate chains in which the terminal sialic acid residue is attached to the penultimateN-acetylneuraminic acid residue at positions 4, 8, or 9. The lipid part of the gangliosides consists of sphingenine and unsubstituted fatty acids (mainly, palmitic and stearic acids). Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 156–161, January, 2000.     

Azolides. VII—Restricted rotation in N-acylindoles and carbazoles. Anisotropy effect of the carbonyl group

The barrier to internal rotation about the N? C bond and the E/Z configuration of some N-acetyl and N-formylindole derivatives have been determined and discussed in terms of electronic and steric effects. The barriers to internal rotation have been determined for certain N-acetylcarbazoles and some new N-formyl derivatives of carbazole. Experimental proof is also given, showing that contrary to the provisions of the classical model of carbonyl anisotropy, the protons (α and peri positions) next to the oxygen of the acyl group are displaced to high frequencies. This result allows one to determine the preferred configuration of N-acetyl derivatives of perimidine and 1H-naphtho[1,8-de]triazine.     

Synthesis and Photochemistry of 5,5-Dimethyl-1H-pyrrol-2(5H)-one and of Some N-Substituted Derivatives

In two steps, 5,5-dimethyl-1H-pyrrol-2(5H)-one ( 3a ) was prepared from 5,5-dimethylpyrrolidine-2,4-dione ( = dimethyltetramic acid; 4 ) in 71% overall yield (Scheme 1) and further converted to N-substituted derivatives 3b–f via acylation, alkylation, or methoxycarbonylation of its anion (Scheme 2). The substituents on the N-atom exert a strong influence on the photochemical reactivity ([2 + 2] photocycloaddition to 2,3-dimethylbut-2-ene, photocyclodimerisation, photoreduction) of these aza-enones 3 (Scheme 3). In general, N-alkyl compounds react much slower and with less efficiency than either the (N-unsubstituted) title compound 3a or its N-acetyl and N-(methoxycarbonyl) derivatives 3e and 3f , respectively. These compounds behave similarly to the corresponding lactone, 5,5-dimethyl-2(5H)-furanone, studied previously.     

Gangliosides from the starfishEvasterias echinosoma: identification of a disialoganglioside containing 8-O-methyl-N-acetylneuraminic acid andN-formylgalactosamine

Gangliosides were isolated from the starfishEvasterias echinosoma and their structures were elucidated by chemical and physicochemical methods. Two major gangliosides were found to be disialogangliosides, whose carbohydrate chain is based on the trisaccharide β-N-acylgalactosaminyl-(l→3)-β-galactosyl-(l→4)-β-glucose (acyl is formyl or acetyl), both residue at of 8-O-methyl-N-acetylneuraminic acid being attached to theN-acylgalactosamine residue at positions 3 and 6. The minor components are disialogangliosides with linear carbohydrate chains in which the terminal sialic acid residue is attached to the penultimateN-acetylneuraminic acid residue at positions 4, 8, or 9. The lipid part of the gangliosides consists of sphingenine and unsubstituted fatty acids (mainly, palmitic and stearic acids). Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 156–161, January, 2000.     

Applications of biopolymers I: chitosan

Abstract  

Chitosan is prepared from chitin, the second most abundant natural polymer in the world. It is primarily composed of glucosamine and N-acetyl glucosamine residues with a 1,4-β-linkage. It can be obtained by deacetylation of chitin, which is produced from shells of crustaceans, insects, and other sources. Chitosan is a nontoxic, biodegradable, and biocompatible natural polymer and can be used in a wide range of applications such as in the areas of biomedicine, membranes, drug delivery systems, hydrogels, water treatment, food packaging, etc. In this paper, some novel applications of this biopolymer in different fields are reviewed.     

SYNTHESIS AND BIOLOGICAL ACTIVITIES OF NEW INDOLE DERIVATIVES CONTAINING SULFIDE AND/OR SULFONE MOIETIES. PART I

Abstract

4-Amino-halonitrodiphenyl sulfides(I) and/or 4-amino-halonitrodiphenyl sulfones have been found to react with isatin, N-acetyl isatin, isatin-N-Mannich bases, indole-3-carboxaldehyde and N-substituted indole-3-carboxaldehyde producing the corresponding indole derivatives. The biological activity of some of these products was screened against selected strains of bacteria.