RESUMO
Three different Mitsunobu reactions have been investigated for the synthesis of 1-deoxymannojirimycin (1-DMJ) from d-fructose. The highest yielding and most practical synthesis can be undertaken on a 10 g scale with minimal chromatography. In the key step, N,O-di-Boc-hydroxylamine reacts with methyl 1,3-isopropylidene-α-d-fructofuranose under Mitsunobu conditions to give 14. Acidic hydrolysis affords nitrone 15, which reduces quantitatively via catalytic hydrogenolysis to afford 1-DMJ (4) in 55% overall yield from d-fructose (cf. 37% for azide route and 29% for nosyl route).
Assuntos
1-Desoxinojirimicina , Frutose , 1-Desoxinojirimicina/química , Frutose/químicaRESUMO
Amidine synthesis by amine addition to nitriles normally requires high temperatures or harsh catalysts. Here, we report that boronate esters can facilitate amidination of proximal amines with moderate heating. With amidines present in a number of drugs and the synthetic handle provided by the boron, this chemistry should find useful applications.
RESUMO
Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacterium and instigate intracellular signalling in the immune cell. There are structural similarities between the structures of TDM and phosphatidyl inositol mannoside (PIM). We thus hypothesized that these latter structures might also modulate an immune response in a similar manner. To test this, we synthesized a series of new mannose derivatives modified with fatty esters at the 6-position and assessed the release of inflammatory cytokines in human U937 macrophages under the induction of lipopolysaccharides (LPS) after glycolipid treatment. The results showed that the amount of two major cytokines-tumour necrosis factor (TNF)-α and interleukin (IL)-6-released from LPS-stimulated U937 cells decreased significantly when compared to a control upon treatment with the prepared glycolipids, thus indicating a reduction in cytokine production by the macrophages.
RESUMO
Simple alkyl-sulfonylacetamides have potent antitubercular activity and significantly decrease mycolic acid levels in mycobacteria. Although these compounds were originally designed to inhibit the ketoacyl synthase domain of fatty acid synthase, structure-activity relationships and biochemical evidence do not fully support fatty acid synthase as the target. In 2004, an enzyme family involved in the activation and transfer of fatty acids as acyl-adenylates was identified in mycobacteria, separate from the universal acetyl-CoA carrier mechanism. These fatty acyl-AMP ligases (FAAL), encoded by the FadD family play important roles in the biosynthesis of mycolic acids along with fatty acid metabolism and are hypothesised here to be the molecular target of the sulfonylacetamides. Due to structural similarities with the ligase's natural substrate, it is believed these compounds are exerting action via competitive inhibition of these highly potent molecular targets. The primary aim of this investigation was to synthesize an extended library of sulfonylacetamide derivatives, building upon existing structural activity relations to validate the molecular mechanism with the aid of molecular modelling, while also attempting to explore novel structural isosteres for further drug design and development. Sulfonylacetamide derivatives were modified based on the putative molecular target resulting in derivatives with improved activities towards Mycobacteriumtuberculosis (H37Rv). The most active novel derivatives reported were 19, 22b, 22c and 46 displaying MIC90 levels of 1.4, 16.0, 13.0 and 5.9 µg/mL, respectively.
Assuntos
Mycobacterium tuberculosis , Acetamidas/farmacologia , Antituberculosos/farmacologia , Ácidos Micólicos/metabolismo , Ácidos Graxos/metabolismo , Ácido Graxo SintasesRESUMO
IN THE TITLE COMPOUND (SYSTEMATIC NAME: {(3aS,5S,6R,6aS)-3a-[(benz-yloxy)meth-yl]-6-hy-droxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl}methyl 4-methyl-benzene-sulfonate), C23H28O8S, the absolute structure and relative stereochemistry of the four chiral centres have been established by X-ray crystallography, with the absolute configuration inferred from the use of l-sorbose as the starting material. The central furan-ose ring adopts a slightly twisted envelope conformation (with the C atom bearing the methyl-benzene-sulfonate substituent as the flap) from which three substituents depart pseudo-axially (-CH2-O-benzyl, -OH and one acetonide O atom) and two substituents pseudo-equatorially (-CH2-O-tosyl and second acetonide O atom). The dioxalane ring is in a flattened envelope conformation with the fused CH C atom as the flap. In the crystal, mol-ecules pack in columns along [010] linked by O-Hâ¯O hydrogen bonds involving the furan-ose hy-droxy group and furan-ose ether O atom.
RESUMO
This review covers the literature in the past 15 years on glycosidase inhibitors lacking a basic nitrogen (for example iminosugars/azasugars) with a focus on natural terpenoids, and mono- and polycyclic aromatic hydrocarbons. From quite diverse structures, insight into inhibitor structural features that may be applicable to optimisation of all glycosidase inhibitors including iminosugars are identified.
Assuntos
Glicosídeo Hidrolases , Imino Açúcares , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Imino Açúcares/química , Imino Açúcares/farmacologiaRESUMO
Galectin-8 is a ß-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl ß-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity toward galectin-8N in the range of 5-33 µM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound (Kd 5.72 µM) holding 7-fold tighter than the disaccharide lactose.
Assuntos
Desenho de Fármacos , Galactosídeos/síntese química , Galectinas/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Citocinas/genética , Feminino , Galactosídeos/química , Galactosídeos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , TermodinâmicaRESUMO
A fluorescent boronate receptor with a unique response to free sialic acid has been developed; this divergent response system may find use in design of other fluorophores to discriminate between structurally similar analytes.
Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Monossacarídeos/química , Ácido N-Acetilneuramínico/química , Compostos de Boro/síntese química , Estrutura Molecular , Monossacarídeos/síntese químicaRESUMO
The title compound, C(10)H(8)O(3), has been synthesized as part of our investigations into the generation of new anti-bacterial agents and serves as a building block for the synthesis of compound libraries. The compound crystallizes with two independent mol-ecules in the asymmetric unit. The transoid propynyl ester groups are coplanar with the 2-hydroxy-benzoate group with maximum deviations of -0.3507â (3) and 0.1591â (3)â Å for the terminal carbons, with intra-molecular O-Hâ¯O hydrogen bonding providing rigidity to the structure and ensuring that the reactivity of the alkyne is not compromised by steric factors. The propynyl group forms inter-molecular C-Hâ¯O inter-actions with the phenolic O atom. Supra-molecular chains along the b axis are found for both mol-ecules with links by weak O-Hâ¯O inter-molecular inter-actions in the first independent mol-ecule and C-Hâ¯O inter-actions in the second.
RESUMO
Many deadly infections are produced by microorganisms capable of sustained survival in macrophages. This reduces exposure to chemadrotherapy, prevents immune detection, and is akin to criminals hiding in police stations. Therefore, the use of glyco-nanoparticles (GNPs) as carriers of therapeutic agents is a burgeoning field. Such an approach can enhance the penetration of drugs into macrophages with specific carbohydrate targeting molecules on the nanocarrier to interact with macrophage lectins. Carbohydrates are natural biological molecules and the key constituents in a large variety of biological events such as cellular communication, infection, inflammation, enzyme trafficking, cellular migration, cancer metastasis and immune functions. The prominent characteristics of carbohydrates including biodegradability, biocompatibility, hydrophilicity and the highly specific interaction of targeting cell-surface receptors support their potential application to drug delivery systems (DDS). This review presents the 21st century development of carbohydrate-based nanocarriers for drug targeting of therapeutic agents for diseases localized in macrophages. The significance of natural carbohydrate-derived nanoparticles (GNPs) as anti-microbial drug carriers is highlighted in several areas of treatment including tuberculosis, salmonellosis, leishmaniasis, candidiasis, and HIV/AIDS.
Assuntos
Anti-Infecciosos/uso terapêutico , Carboidratos/química , Macrófagos/efeitos dos fármacos , Nanopartículas/química , Animais , Anti-Infecciosos/química , Infecções Bacterianas/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Micoses/tratamento farmacológico , Viroses/tratamento farmacológicoRESUMO
The crystal structure of the title compound, C(27)H(45)N(3), has been determined as part of our investigation into the hydro-phobic modification of amino-glycoside anti-biotics. The isopropyl group showed disorder for the tertiary carbon (equal occupancies), with high thermal motion for the peripheral atoms of the isopropyl and azide groups also apparent in the structure. The axial disposition of the azide group is consistent with the clean inversion of stereochemistry at C-3 under Mitsunobu conditions.
RESUMO
Glycosidases have important anti-cancer, anti-viral and anti-diabetic properties. This review covers the literature in the past 15 years since our initial review in this journal on "neutral" glycosidase inhibitors lacking a basic nitrogen found in iminosugars and azasugars or inhibitors that are neutral by virtue of being "charge-balanced" (zwitterionic). These structurally diverse inhibitors include lactones, lactams, epoxides such as cyclophellitol, and sulfonium ion derivatives of the natural product salacinol. Synthetic efforts toward cyclophillitol, salicinol and derivatives are also highlighted. Importantly, certain metals can inhibit glycosidases and care must be taken to remove residual catalysts from synthetic material to be tested against these enzymes.
Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/metabolismo , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The effect of different leaving groups on the substitution versus elimination outcomes with C-5 d-glucose derivatives was investigated. The stereochemical configurations of 3-O-benzyl-1,2-O-iso-propyl-idene-5-O-methane-sulfonyl-6-O-tri-phenyl-methyl-α-d-gluco-furan-ose, C36H38O8S (3) [systematic name: 1-[(3aR,5R,6S,6aR)-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxol-5-yl)-2-(trit-yloxy)ethyl methane-sulfonate], a stable inter-mediate, and 5-azido-3-O-benzyl-5-de-oxy-1,2-O-iso-propyl-idene-6-O-tri-phenyl-methyl-ß-l-ido-furan-ose, C35H35N3O5 (4) [systematic name: (3aR,5S,6S,6aR)-5-[1-azido-2-(trit-yloxy)eth-yl]-6-benz-yloxy-2,2-di-methyl-tetra-hydro-furo[2,3-d][1,3]dioxole], a substitution product, were examined and the inversion of configuration for the azido group on C-5 in 4 was confirmed. The absolute structures of the mol-ecules in the crystals of both compounds were confirmed by resonant scattering. In the crystal of 3, neighbouring mol-ecules are linked by C-Hâ¯O hydrogen bonds, forming chains along the b-axis direction. The chains are linked by C-Hâ¯π inter-actions, forming layers parallel to the ab plane. In the crystal of 4, mol-ecules are also linked by C-Hâ¯O hydrogen bonds, forming this time helices along the a-axis direction. The helices are linked by a number of C-Hâ¯π inter-actions, forming a supra-molecular framework.
RESUMO
We report the synthesis of a series of benzene sulfonamides containing triazole-O-glycoside tails for evaluation as carbonic anhydrase (CA) inhibitors. These glycoconjugates were synthesized by the 1,3-dipolar cycloaddition reaction of 4-azidobenzenesulfonamide with O-propynyl glycosides. Compounds were assessed for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA I and II and the tumor-associated isozyme hCA IX (h = human). Against hCA I these compounds were either micromolar or low-nanomolar inhibitors, while against hCA II and IX inhibition in the range of 6.8-53 and 9.7-107 nM, respectively, was observed. The most potent inhibitor against hCA IX was the galactose derivative 8 (Ki = 9.7 nM); this is so far the most potent glycoconjugate inhibitor reported for the tumor-associated hCA IX. These carbohydrate-tethered sulfonamides may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly.
Assuntos
Anidrase Carbônica III/química , Anidrase Carbônica II/química , Anidrase Carbônica I/química , Inibidores da Anidrase Carbônica/síntese química , Galactosídeos/síntese química , Glicosídeos/síntese química , Sulfonamidas/síntese química , Triazóis/síntese química , Inibidores da Anidrase Carbônica/química , Galactosídeos/química , Glicosídeos/química , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Triazóis/químicaRESUMO
Selective accumulation of an exogenous enzyme or activating agent at a target cell allows use of prodrugs that will be unmasked only at this site. This can reduce the side effects of chemotherapy and allow more potent drugs to be used in various treatments. Examples of this two-step prodrug therapy include antibody- (ADEPT, ADAPT), genetic- (GDEPT, VDEPT) and macromolecule-based approaches (PDEPT, LEAPT). Carbohydrate chemistry and glycobiology feature in each of these areas and is the focus of this review.
Assuntos
Carboidratos/química , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Pró-Fármacos , Anticorpos/administração & dosagem , Anticorpos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Portadores de Fármacos/química , Enzimas/administração & dosagem , Enzimas/química , Terapia Genética/métodos , Humanos , Lectinas/química , Substâncias Macromoleculares/química , Polímeros/químicaRESUMO
Aryl and heteroaryl sulfonamides (ArSO(2)NH(2)) are therapeutically used to inhibit the catalytic activity of carbonic anhydrases (CAs). Using a "click-tail" approach a novel class of glycoconjugate benzene sulfonamides have been synthesized that contain diverse carbohydrate-triazole tails. These compounds were assessed for their ability to inhibit three human CA isozymes in vitro: cytosolic hCA I and hCA II and transmembrane, tumor-associated hCA IX. This isozyme has a minimal expression in normal tissue but is overexpressed in hypoxic tumors and its inhibition is a current approach toward new cancer therapies. The qualitative structure-activity for all derivatives demonstrated that the stereochemical diversity present within the carbohydrate tails effectively interrogated the CA active site topology, to generate several inhibitors that were potent and selective toward hCA IX, an important outcome in the quest for potential cancer therapy applications based on CA inhibition.
Assuntos
Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Sequência de Carboidratos , Dióxido de Carbono/química , Glicosilação , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Dados de Sequência MolecularRESUMO
Unlike the related aminoglycoside neomycin B, N-protected tobramycin can be selectively esterified at its sole, primary hydroxyl group under Mitsunobu conditions. However, depending on the reaction conditions, the reaction can take a different course with intramolecular cyclization of an N-Boc amine leading to formation of an unusual tobramycin pyrrolidine derivative as the major reaction product.
Assuntos
Ligação Competitiva , Nitrogênio/química , Pró-Fármacos/química , Pró-Fármacos/síntese química , Pirrolidinas/química , Tobramicina/química , Tobramicina/síntese química , Técnicas de Química Sintética , Ciclização , Esterificação , ÉsteresRESUMO
Intracellular and extracellular functions of human galectin-1 are influenced by its redox surroundings due to the presence of six cysteines within its amino acid sequence. Galectin-1 recognises intracellular-membrane-anchored Ras proteins that act as molecular switches regulating multiple signal transduction pathways. Human tumours frequently express Ras proteins that have become continuously activated due to point mutations, and this typically leads to deregulation of tumour cell growth, angiogenesis and invasion of metastatic cancer cells. Of significance is that galectin-1 preferably recognises H-Ras, one of the human Ras isoforms, and in particular galectin-1 recognition of the H-Ras farnesyl moiety is paramount to H-Ras membrane anchorage, a prerequisite step for H-Ras-mediated signal transduction regulating normal cell growth and malignant transformation. Herein the impact of the redox state on galectin-1's ability to interact with farnesyl analogues is explored. We demonstrate for the first time that reduced galectin-1 directly binds farnesyl and does so in a carbohydrate-independent manner. A K28T mutation abolishes farnesyl recognition by reduced dimeric galectin-1 whilst its carbohydrate-binding activity is retained, thus demonstrating the presence of an independent region on galectin-1 pertaining to growth inhibitory activity. Intriguingly, oxidised galectin-1 also recognises farnesyl, the biological implication of this novel finding is yet to be elucidated. Further, the redox effect on galectin-1 extracellular function was investigated and we discover that oxidised galectin-1 demonstrates a protective effect upon acute lymphoblastic leukaemia cells challenged by oxidative stress.
Assuntos
Galectina 1/metabolismo , Linhagem Celular , Galectina 1/química , Galectina 1/genética , Humanos , Peróxido de Hidrogênio/metabolismo , Oxirredução , Mutação Puntual/genética , Estrutura Secundária de Proteína , Espécies Reativas de Oxigênio , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
Boric acid catalyzes the selective esterification of alpha-hydroxycarboxylic acids without causing significant esterification to occur with other carboxylic acids. The procedure is simple, high-yielding, and applicable to the esterification of alpha-hydroxy carboxylates in the presence of other carboxylic acids including beta-hydroxyacids within the same molecule. [reaction: see text]