RESUMO
A series of quaternary diammonium salts derivatives of 1,4:3,6-dianhydro-l-iditol were synthesized, using isommanide (1,4:3,6-dianhydro-d-mannitol) as a starting material. Both aromatic (pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), (3-carboxamide)pyridine; N-methylimidazole) and aliphatic (trimethylamine, N,N-dimethylhexylamine, N,N-dimethyloctylamine, N,N-dimethyldecylamine) amines were used, giving eight gemini quaternary ammonium salts (QAS). All salts were tested for their antimicrobial activity against yeasts, Candida albicans and Candida glabrata, as well as bacterial Staphylococcus aureus and Escherichia coli reference strains. Moreover, antibacterial activity against 20 isolates of S. aureus collected from patients with skin and soft tissue infections (n = 8) and strains derived from subclinical bovine mastitis milk samples (n = 12) were evaluated. Two QAS with octyl and decyl residues exhibited antimicrobial activity, whereas those with two decyl residues proved to be the most active against the tested pathogens, with MIC of 16-32, 32, and 8 µg/mL for yeast, E. coli, and S. aureus reference and clinical strains, respectively. Only QAS with decyl residues proved to be cytotoxic in MTT assay against human keratinocytes (HaCaT), IC50 12.8 ± 1.2 µg/mL. Ames test was used to assess the mutagenic potential of QAS, and none of them showed mutagenic activity in the concentration range 4-2000 µg/plate.
Assuntos
Compostos de Amônio Quaternário , Álcoois Açúcares/química , Álcoois Açúcares/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Candida albicans , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Escherichia coli , Células HaCaT , Humanos , Testes de Sensibilidade Microbiana , Testes de Mutagenicidade , Mutagênicos/síntese química , Mutagênicos/química , Mutagênicos/farmacologia , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Staphylococcus aureus , Álcoois Açúcares/síntese químicaRESUMO
We investigated the inhibition kinetics of VhGlcNAcase, a GH20 exo-ß-N-acetylglucosaminidase (GlcNAcase) from the marine bacterium Vibrio campbellii (formerly V. harveyi) ATCC BAA-1116, using TMG-chitotriomycin, a natural enzyme inhibitor specific for GH20 GlcNAcases from chitin-processing organisms, with p-nitrophenyl N-acetyl-ß-d-glucosaminide (pNP-GlcNAc) as the substrate. TMG-chitotriomycin inhibited VhGlcNAcase with an IC50 of 3.0 ± 0.7 µM. Using Dixon plots, the inhibition kinetics indicated that TMG-chitotriomycin is a competitive inhibitor, with an inhibition constant Ki of 2.2 ± 0.3 µM. Isothermal titration calorimetry experiments provided the thermodynamic parameters for the binding of TMG-chitotriomycin to VhGlcNAcase and revealed that binding was driven by both favorable enthalpy and entropy changes (ΔH° = -2.5 ± 0.1 kcal/mol and -TΔS° = -5.8 ± 0.3 kcal/mol), resulting in a free energy change, ΔG°, of -8.2 ± 0.2 kcal/mol. Dissection of the entropic term showed that a favorable solvation entropy change (-TΔSsolv° = -16 ± 2 kcal/mol) is the main contributor to the entropic term.
Assuntos
Acetilglucosaminidase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Álcoois Açúcares/farmacologia , Termodinâmica , Vibrio/enzimologia , Acetilglucosaminidase/metabolismo , Configuração de Carboidratos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Cinética , Álcoois Açúcares/síntese química , Álcoois Açúcares/químicaRESUMO
Four chain-extended analogs (12a-12d) and two related de-O-sulfonated analogs (13a and 13c) by introducing alkyl groups (a: R = C3H7, b R = C6H13, c: R = C8H17, d: R = C10H21) to the side chains of salacinol (1), a natural α-glucosidase inhibitor from Ayurvedic traditional medicine "Salacia", were synthesized. The α-glucosidase inhibitory activities of all the synthesized analogs were evaluated in vitro. Against human intestinal maltase, the inhibitory activities of 12a and 13a with seven-carbon side chain were equal to that of 1. In contrast, analogs (12b-12d, and 13c) exhibited higher level of inhibitory activity against the same enzyme than 1 and had equal or higher potency than those of the clinically used anti-diabetics, voglibose, acarbose, and miglitol. Thus, elongation of the side chains of 1 was effective for specifically increasing the inhibitory activity against human intestinal maltase.
Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Intestinos/enzimologia , Salacia/química , Álcoois Açúcares/farmacologia , Sulfatos/farmacologia , alfa-Glucosidases/metabolismo , Animais , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Ayurveda , Conformação Molecular , Ratos , Relação Estrutura-Atividade , Álcoois Açúcares/síntese química , Álcoois Açúcares/química , Sulfatos/síntese química , Sulfatos/químicaRESUMO
Leucyl-tRNA synthetase (LeuRS) is a clinically validated target for the development of antimicrobials. This enzyme catalyzes the formation of charged tRNALeu molecules, an essential substrate for protein translation. In the first step of catalysis LeuRS activates leucine using ATP, forming a leucyl-adenylate intermediate. Bi-substrate inhibitors that mimic this chemically labile phosphoanhydride-linked nucleoside have proven to be potent inhibitors of different members of the aminoacyl-tRNA synthetase family but, to date, they have demonstrated poor antibacterial activity. We synthesized a small series of 1,5-anhydrohexitol-based analogues coupled to a variety of triazoles and performed detailed structure-activity relationship studies with bacterial LeuRS. In an in vitro assay, Kiapp values in the nanomolar range were demonstrated. Inhibitory activity differences between the compounds revealed that the polarity and size of the triazole substituents affect binding. X-ray crystallographic studies of N. gonorrhoeae LeuRS in complex with all the inhibitors highlighted the crucial interactions defining their relative enzyme inhibitory activities. We further examined their in vitro antimicrobial properties by screening against several bacterial and yeast strains. While only weak antibacterial activity against M. tuberculosis was detected, the extensive structural data which were obtained could make these LeuRS inhibitors a suitable starting point towards further antibiotic development.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Inibidores Enzimáticos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Álcoois Açúcares/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Candida albicans/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Leucina-tRNA Ligase/isolamento & purificação , Leucina-tRNA Ligase/metabolismo , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Neisseria gonorrhoeae/enzimologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Álcoois Açúcares/síntese química , Álcoois Açúcares/químicaRESUMO
Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure-activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Pró-Fármacos/farmacologia , Álcoois Açúcares/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HCT116 , Humanos , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-Atividade , Álcoois Açúcares/síntese química , Álcoois Açúcares/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus is one of alternative ways to suppress growth of tumor tissue. Eight N-benzyl substituted 1,4-imino-l-lyxitols with basic functional groups (amine, amidine, guanidine), hydroxyl and fluoro groups were prepared, optimized their syntheses and tested for their ability to inhibit several α-mannosides from the GH family 38 (GMIIb, LManII and JBMan) as models for human Golgi and lysosomal α-mannoside II. All compounds were found to be selective inhibitors of GMIIb. The most potent structure bearing guanidine group, inhibited GMIIb at the micromolar level (Kiâ¯=â¯19⯱â¯2⯵M) while no significant inhibition (>2â¯mM) of LManII and JBMan was observed. Based on molecular docking and pKa calculations this structure may form two salt bridges with aspartate dyad of the target enzyme improving its inhibitory potency compared with other N-benzyl substituted derivatives published in this and previous studies.
Assuntos
Inibidores Enzimáticos/química , Imino Açúcares/química , Álcoois Açúcares/química , alfa-Manosidase/antagonistas & inibidores , Animais , Domínio Catalítico , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Álcoois Açúcares/síntese química , Álcoois Açúcares/metabolismo , alfa-Manosidase/química , alfa-Manosidase/metabolismoRESUMO
Here, a facile method for the preparation of polymeric particles from a sugar molecule, maltitol (ML) in single step was reported via microemulsion polymerization/crosslinking technique with a high yield, 89⯱â¯6%. Furthermore, poly(Maltitol) (p(ML)) particles were chemically modified to induce different physicochemical characteristic using different anionic and cationic modifying agents such as taurine (TA) and diethylenetriamine (DETA) to prepare m-p(ML)/TA and m-p(ML)/DETA. The blood compatibility of the p(ML) particles and their modified forms were tested with fresh blood, and found that p(ML) and m-(ML)/DETA particles are blood compatible with about 5% hemolysis, and above 80% blood clotting indices. Moreover, the cytotoxicity results against L929 fibroblast cell line revealed that p(ML) based particle are biocompatible up to 100⯵g/mL with 85% cell viability regardless of their nature, and at 200⯵g/mL dosage of p(ML), m-p(ML)/TA and m-p(ML)/DETA particles, the cell viabilities were determined as 83.33, 64.03 and 73.89% on for L929 fibroblast cells implying the slightly less biocompatibility nature of m-p(ML)/TA in accord with the blood compatibility results. Additionally, the apoptotic and necrotic indices were determination for p(ML) based particles on L929 fibroblast cells, and the results revealed that these particles do not induce any and stress on the cells. Also, it does not have genotoxic effect as determined against CHO cells.
Assuntos
Materiais Biocompatíveis/química , Maltose/análogos & derivados , Polímeros/química , Álcoois Açúcares/química , Açúcares/química , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromossomos/efeitos dos fármacos , Cromossomos/metabolismo , Ciprofloxacina/química , Ciprofloxacina/metabolismo , Cricetinae , Cricetulus , Portadores de Fármacos/química , Hemólise/efeitos dos fármacos , Humanos , Maltose/síntese química , Maltose/química , Maltose/farmacologia , Tamanho da Partícula , Poliaminas/química , Álcoois Açúcares/síntese química , Álcoois Açúcares/farmacologia , Taurina/químicaRESUMO
A facile and highly diastereoselective approach toward the synthesis of potent salacinol-type α-glucosidase inhibitors, originally isolated from plants of the genus "Salacia", was developed using the S-alkylation of thiosugars with epoxides in HFIP (â¼90%, dr, α/ß = â¼ 26/1). The dr ratio of the product was significantly improved by the protocol as compared to that of the conventional S-alkylation of thiosugars (dr, α/ß = â¼ 8/1). The protocol could be used for gram scale synthesis of the desired compounds. The 3'-O-benzylated salacinol analogs, which are the most potent in vitro inhibitors to date, were synthesized and evaluated in vivo; all analogs suppressed blood glucose levels in maltose-loaded mice, at levels comparable to those of the antidiabetic agent, voglibose.
Assuntos
Inibidores de Glicosídeo Hidrolases/farmacologia , Álcoois Açúcares/farmacologia , Sulfatos/farmacologia , alfa-Glucosidases/metabolismo , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Intestinos/enzimologia , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Álcoois Açúcares/síntese química , Álcoois Açúcares/química , Sulfatos/síntese química , Sulfatos/químicaRESUMO
Biomass has been long exploited as an anthropogenic energy source; however, the 21st century challenges of energy security and climate change are driving resurgence in its utilization both as a renewable alternative to fossil fuels and as a sustainable carbon feedstock for chemicals production. Deconstruction of cellulose and hemicellulose carbohydrate polymers into their constituent C5 and C6 sugars, and subsequent heterogeneously catalyzed transformations, offer the promise of unlocking diverse oxygenates such as furfural, 5-hydroxymethylfurfural, xylitol, sorbitol, mannitol, and gluconic acid as biorefinery platform chemicals. Here, we review recent advances in the design and development of catalysts and processes for C5-C6 sugar reforming into chemical intermediates and products, and highlight the challenges of aqueous phase operation and catalyst evaluation, in addition to process considerations such as solvent and reactor selection.
Assuntos
Hexoses/química , Pentoses/química , Ácidos/química , Álcalis/química , Catálise , Furaldeído/síntese química , Gluconatos/síntese química , Isomerismo , Oxirredução , Álcoois Açúcares/síntese químicaRESUMO
The focus of this research was to apply the in situ coating technology for producing paracetamol- (PCT-) containing pastilles for paediatric use from a eutectic of two sugar alcohols (sorbitol, xylitol) in one step. This type of melt-technology is more cost-efficient and simpler than other conventional tableting technologies, whereby the formation of the pastilles and their coating occur upon the same fabrication step. We managed to produce pastilles having a softer core and a harder, resistant shell in one cooling step. Adding polyethylene glycol (PEG) 2000 or 6000 to the PCT-containing eutectic, the dissolution rate of PCT could be considerably increased, especially when using PEG 2000, reaching equal dissolution characteristics both under mouth- and gastric-specific conditions. Distributions of the components within the pastilles have been determined by X-ray scattering and Raman spectroscopy. Physico-chemical parameters of the xylitol-sorbitol eutectic and their changes upon adding PCT and PEGs have been determined, and it has been revealed that xylitol and sorbitol form a new entity with a distinguished crystal structure. The significant changes in viscosity were explained and the interaction in the eutectic mixture was investigated using Fourier transform infrared spectroscopy (FT-IR). The uniformity of the physical parameters of the pastilles (including size, weight and drug content) also demonstrates the feasibility of using the cost-efficient and simple one-step eutectic-cooling technology for manufacturing pastilles.
Assuntos
Acetaminofen/síntese química , Álcoois Açúcares/síntese química , Tecnologia Farmacêutica/métodos , Acetaminofen/farmacocinética , Química Farmacêutica , Solubilidade , Álcoois Açúcares/farmacocinética , Comprimidos com Revestimento Entérico , Difração de Raios X/métodosRESUMO
The scope of a one-pot tandem approach for the synthesis of C-1 alkyl iminoalditol derivatives with a Staudinger/aza-Wittig/Grignard cascade has been evaluated. The reaction conditions have been optimized for two azidodeoxy aldose substrates and a range of Grignard reagents. The nature of both, substrate as well as nucleophile, was found to control the stereoselectivity of the alkyl addition to the cyclic iminium intermediate at position C-1. This approach enabled the synthesis of a collection of C-alkyl iminoalditols, which were biologically evaluated as inhibitors against a set of standard glycoside hydrolases. All compounds were found to exhibit highly selective inhibition of ß-glucosidase activity.
Assuntos
Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Álcoois Açúcares/síntese química , beta-Glucosidase/antagonistas & inibidores , Alcanos/química , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/química , Mimetismo Molecular , Polissacarídeos/química , Estereoisomerismo , Relação Estrutura-Atividade , Álcoois Açúcares/química , beta-Glucosidase/químicaRESUMO
A series of N,N-bis(glycityl)amines with promising anti-cancer activity were prepared via the reductive amination of pentoses and hexoses, and subsequently screened for their ability to selectively inhibit the growth of cancerous versus non-cancerous cells. For the first time, we show that this class of compounds possesses anti-proliferative activity, and, while the selective killing of brain cancer (LN18) cells versus matched (SVG-P12) cells was modest, several of the amines, including d-arabinitylamine 1a and d-fucitylamine 1g, exhibited low micromolar IC50 values for HL60 cells. Moreover, these two amines showed good selectivity towards HL60 cells when compared to non-cancerous HEK-293 cells. The compounds also showed low micromolar inhibition of the leukaemic cell line, THP-1. The modes of action of amines 1a and 1g were then determined using yeast chemical genetics, whereby it was established that both compounds affect similar but distinct sets of biochemical pathways. Notably purine nucleoside monophosphate biosynthesis was identified as an enriched mechanism. The rapid synthesis of the amines and their unique mode of action thus make them attractive targets for further development as anti-cancer drugs.
Assuntos
Amino Açúcares/farmacologia , Antineoplásicos/farmacologia , Álcoois Açúcares/farmacologia , Amino Açúcares/síntese química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Doxorrubicina/farmacologia , Células HEK293 , Humanos , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Relação Estrutura-Atividade , Álcoois Açúcares/síntese química , tRNA Metiltransferases/genética , tRNA Metiltransferases/metabolismoRESUMO
A group of 3'-epi-neoponkoranol analogs with different hydrophobic substituents attached at 3'-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against α-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho-substituted benzyl groups showed best α-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against α-glucosidase enzymes. The strongest α-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3'-attached substituent and particularly the ortho-substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each α-glucosidase.
Assuntos
Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Álcoois Açúcares/química , Álcoois Açúcares/farmacologia , Tiofenos/química , Tiofenos/farmacologia , alfa-Glucosidases/metabolismo , Compostos de Benzil/síntese química , Compostos de Benzil/química , Compostos de Benzil/farmacologia , Linhagem Celular , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases/síntese química , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Álcoois Açúcares/síntese química , Tiofenos/síntese químicaRESUMO
Invariant natural killer T (iNKT) cells recognize CD1d/glycolipid complexes and upon activation with synthetic agonists display immunostimulatory properties. We have previously described that the non-glycosidic CD1d-binding lipid, threitolceramide (ThrCer) activates murine and human iNKT cells. Here, we show that incorporating the headgroup of ThrCer into a conformationally more restricted 6- or 7-membered ring results in significantly more potent non-glycosidic analogs. In particular, ThrCer 6 was found to promote strong anti-tumor responses and to induce a more prolonged stimulation of iNKT cells than does the canonical α-galactosylceramide (α-GalCer), achieving an enhanced T-cell response at lower concentrations compared with α-GalCer both in vitro, using human iNKT-cell lines and in vivo, using C57BL/6 mice. Collectively, these studies describe novel non-glycosidic ThrCer-based analogs that have improved potency in iNKT-cell activation compared with that of α-GalCer, and are clinically relevant iNKT-cell agonists.
Assuntos
Ceramidas/imunologia , Células T Matadoras Naturais/imunologia , Álcoois Açúcares/imunologia , Animais , Antígenos CD1d/imunologia , Ceramidas/síntese química , Ceramidas/química , Ceramidas/farmacologia , Citocinas/imunologia , Galactosilceramidas/imunologia , Galactosilceramidas/farmacologia , Humanos , Imunoterapia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/fisiologia , Neoplasias/imunologia , Álcoois Açúcares/síntese química , Álcoois Açúcares/química , Álcoois Açúcares/farmacologiaRESUMO
A series of eight stereoisomeric N-(tetrahydroxy bicyclo-[5.1.0]oct-2S*-yl)phthalimides were prepared in one to four steps from N-(bicyclo[5.1.0]octa-3,5-dien-2-yl)phthalimide (±)-7, which is readily available from cyclooctatetraene (62 % yield). The structural assignments of the stereoisomers were established by (1) Hâ NMR spectral data as well as X-ray crystal structures for certain members. The outcomes of several epoxydiol hydrolyses, particularly ring contraction and enlargement, are of note. The isomeric phthalimides as well as the free amines did not exhibit ß-glucosidase inhibitory activity at a concentration of less than 100â µM.
Assuntos
Compostos Bicíclicos com Pontes/síntese química , Ftalimidas/síntese química , Álcoois Açúcares/síntese química , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ftalimidas/química , Ftalimidas/farmacologia , Estereoisomerismo , Álcoois Açúcares/química , Álcoois Açúcares/farmacologia , beta-Galactosidase/antagonistas & inibidoresRESUMO
The synthesis and a preliminary investigation of the base pairing properties of (6' â 4')-linked 1',5'-anhydro-L-ribo-hexitol nucleic acids (α-L-HNA) have herein been reported through the study of a model oligoadenylate system in the mirror image world. Despite its considerable preorganization due to the rigidity of the "all equatorial" pyranyl sugar backbone, α-L-HNA represents a versatile informational biopolymer, in view of its capability to cross-communicate with natural and unnatural complements in both enantiomeric forms. This seems the result of an inherent flexibility of the oligonucleotide system, as witnessed by the singular formation of iso- and heterochiral associations composed of regular, enantiomorphic helical structures. The peculiar properties of α-L-HNA (and most generally of the α-HNA system) provide new elements in our understanding of the structural prerequisites ruling the stereoselectivity of the hybridization processes of nucleic acids.
Assuntos
Adenina/síntese química , Ácidos Nucleicos/síntese química , Oligonucleotídeos/síntese química , Álcoois Açúcares/síntese química , Adenina/química , Pareamento de Bases , Modelos Moleculares , Conformação de Ácido Nucleico , Ácidos Nucleicos/química , Oligonucleotídeos/química , RNA/química , Estereoisomerismo , Álcoois Açúcares/químicaRESUMO
The anomeric arylthio group and the hydroxyl-protecting groups of thioglycosides were optimized to construct carbohydrate building blocks for automated electrochemical solution-phase synthesis of oligoglucosamines having 1,4-ß-glycosidic linkages. The optimization study included density functional theory calculations, measurements of the oxidation potentials, and the trial synthesis of the chitotriose trisaccharide. The automated synthesis of the protected potential N,N,N-trimethyl-d-glucosaminylchitotriomycin precursor was accomplished by using the optimized building block.
Assuntos
Carboidratos/química , Álcoois Açúcares/síntese química , Carboidratos/síntese química , Estrutura Molecular , Streptomyces/química , Álcoois Açúcares/química , Tioglicosídeos/química , Trissacarídeos/síntese química , Trissacarídeos/químicaRESUMO
INTRODUCTION: policosanol, a mixture of eight primary aliphatic alcohols purified from sugar cane wax, contains octacosanol as major component. D-002, a mixture of six primary aliphatic alcohols purified from beeswax, presents triacontanol as the main component. Although both substances are high molecular weight alcohol mixtures, they have different compositions and pharmacological effects such as their distinct effects on arachidonic acid metabolism enzymes; whereas policosanol inhibits cyclooxygenase (COX)-1, D-002 inhibits COX and 5-lipoxygenase (5-LOX) activities. OBJECTIVE: to study the effects of octacosanol and triacontanol, which are main components of policosanol and D-002, respectively on the COX and the 5-LOX enzyme in vitro activities. METHODS: triacontanol and octacosanol were suspended in a Tween-20/H2O (2 %) (0.6-5000 g/mL) vehicle. The effects of adding these alcohols on COX-1, COX-2 and 5-LOX enzymes activities were assessed in rat platelet microsomes, rat seminal vesicle microsomes and rat polymorphonuclear (PMN) preparations, respectively. Indomethacin (0.4µg/mL) was used as reference inhibitor of COX-1 and COX-2, and Lyprinol as 5-LOX inhibitor. RESULTS: octacosanol showed significant, marked (70% with highest concentration) (IC50=143.54 g/mL) and dose-dependent (r=0.991, p <0.001) inhibitory action on COX-1 activity. However, Triacontanol did not affect COX-1, but inhibited significantly, depending on dose (r=0.985, p <0.001) the COX-2 activity to 50 % with 1250 g/mL. In contrast, octacosanol did not change COX-2 activity. Indomethacin inhibited both COX-1 and COX-2 by 83 %. Octacosanol addition was ineffective whereas triacontanol had significant, dose-dependent (r=0.978, p<0.001) and marked effect (79 %) on the 5-LOX activity (IC50=58.74 g/mL). Lyprinol inhibited 5-LOX by 89 %. The inhibitions induced by octacosanol and triacontanol were competitive. CONCLUSIONS: in vitro addition of octacosanol and triacontanol caused differential effects on COX-1, COX-2 and 5-LOX enzyme activities. Whereas octacosanol markedly inhibited COX-1 activity and did not change those of COX-2 and 5-LO, triacontanol markedly inhibited 5-LOX activity, but had moderate effect on COX-2 and did not change COX-1 activity.
INTRODUCCIÓN: el policosanol, mezcla de ocho alcoholes purificados de la cera de la caña de azúcar, contiene octacosanol como componente mayoritario. El D-002, mezcla de seis alcoholes alifáticos primarios purificada de la cera de abejas, presenta triacontanol como el componente mayoritario. Aunque ambas sustancias son mezclas de alcoholes de alto peso molecular, exhiben diferente composición y perfil farmacológico como son sus efectos sobre las enzimas del metabolismo del ácido araquidónico: mientras el policosanol inhibe la actividad de ciclooxigenasa (COX)-1, el D-002 inhibe las actividades de la COX y la 5-lipooxigenasa (5-LOX). OBJETIVO: investigar los efectos del octacosanol y el triacontanol, principales componentes del policosanol y el D-002, respectivamente, sobre las actividades de las enzimas COX y 5-LOX in vitro. MÉTODOS: el policosanol y el triacontanol se suspendieron en vehículo Tween-20/H2O (2 %) (0.6-5000g/mL). Los efectos de la adición de estos alcoholes sobre las actividades de las enzimas COX-1, COX-2 y 5-LOX se evaluaron en microsomas de plaquetas de ratas, microsomas de vesículas seminales de ratas y en preparaciones de polimorfonucleares (PMN) de ratas, respectivamente. Se utilizó indometacina (0.4 µg/mL) como inhibidor de referencia de COX-1 and COX-2 y Lyprinol como inhibidor de 5-LOX. RESULTADOS: la adición de octacosanol inhibió la actividad de COX-1 de modo significativo, marcado (70 % con la concentración mayor) (CI50=143.54 g/mL) y dependiente de la dosis (r=0.991, p <0.001). La adición de triacontanol, sin embargo, no afectó COX-1, pero inhibió de modo significativo y dependiente de la dosis (r=0.985, p <0.001) la actividad de la COX-2 hasta 50 % con 1250 g/mL. En contraste, el octacosanol no modificó la actividad de la COX-2. La indometacina inhibió COX-1 y COX-2 en un 83 %. Mientras la adición del octacosanol no fue efectiva, el triacontanol inhibió de modo significativo, dependiente de la dosis r=0.978, p <0.001) y marcadamente (79 %) la actividad de la 5-LOX (CI50=58.74 g/mL). El Lyprinol inhibió la 5-LOX en un 89 %. Las inhibiciones inducidas por el octacosanol y el triacontanol fueron competitivas. CONCLUSIONES: la adición in vitro de octacosanol y triacontanol produjo efectos diferenciales sobre las actividades enzimáticas de COX-1, COX-2 y 5-LOX. Mientras el octacosanol inhibió marcadamente la actividad de COX-1, sin afectar COX-2 y 5-LOX; el triacontanol inhibió marcadamente 5-LOX, pero moderadamente COX-2, y no cambió la actividad de COX-1.
Assuntos
Ratos , Álcoois Açúcares/síntese química , Álcoois Açúcares/farmacologia , Ativação EnzimáticaRESUMO
Mixtures of partially O-methylated alditol acetate standards of galactofuranose were synthesized rapidly. Methyl galactofuranosides were obtained with a yield of 79.9% within 4h under optimized reaction conditions. Methylation of methyl glycosides was carried out in the presence of BaO/Ba(OH)2·8H2O, giving rise to mixtures of partially methylated glycosides. The batch containing the most diverse structures of methyl ethers was converted into partially O-methylated alditol acetates (PMAAs) and then subjected to GC-MS. These PMAAs could be used as GC-MS standards for simultaneous identification of galactofuranose units with diverse linkages in complex carbohydrates.
Assuntos
Acetatos/síntese química , Galactose/química , Álcoois Açúcares/síntese química , Acetatos/química , Configuração de Carboidratos , Galactose/análogos & derivados , Cromatografia Gasosa-Espectrometria de Massas , Ácido Clorídrico/química , Metilação , Álcoois Açúcares/químicaRESUMO
Polyhydroxylated pyrrolidines, such as biologically important azafuranoses represented by the natural product (+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer, were elaborated from a commercially available enantiomerically pure (2R)-hydroxymethylaziridine by highly stereoselective directed reactions in more than 61% overall yield. At first, the nucleophile 2-trimethylsilyloxyfuran was directed to (2R)-aziridine-2-carboxaldehyde by ZnBr2 to yield the unusual anti-addition product as a single isomer via the chelation-controlled transition. The ring opening of aziridine was followed by conjugate addition to give a cis-fused bicycle, which was converted to the target molecule after the required reductive operations.