RESUMO
2,3,4-Tri-O-benzyl-D-xylopyranose was used as a starting material in the preparation of the corresponding triene, which underwent smooth cyclization to a polyhydroxylated hydrindane, as a single diastereoisomer. The analogous triene prepared from D-glucose did not undergo any cyclization even under high pressure.
Assuntos
Carbaçúcares/síntese química , Xilose/análogos & derivados , Mimetismo Biológico , Carbaçúcares/química , Ciclização , Estrutura Molecular , Estereoisomerismo , Xilose/químicaRESUMO
A convenient synthesis of novel 3-deoxy-5-hydroxy-1-aminocarbasugars was developed here. The benzyl-protected glucose-derived ketone 12 was selectively converted in high yield to enone 13via retro-Michael elimination of BnOH. The double bond of 13 was regio- and stereo-selectively reduced by the induction of C4-α-OBn to the multi-functionalized 15. 15 contained all the functionalities with similar configurations to carbasugars but with 3-H and 5-OH in the ring, and it would be a very interesting building block for organic synthesis or for bioactive compounds. As one application, 15 was further transformed into 1-amino-carbasugars by the reductive amination and final deprotection of benzyls. The targets were subjected to the in vitro inhibitory activity test against sucrase or maltase. The inhibitory activity of 17b, 17h or 17j against sucrase was nearly similar to that of voglibose. In comparison with voglibose, in vivo results similarly showed that 17b, 17h or 17j could lower the post-prandial blood glucose level after sucrose loading in healthy male ICR mice, while miglitol or acarbose was less effective. The molecular modeling study of some targets or voglibose with human sucrase could explain the inhibiting action.
Assuntos
Carbaçúcares/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/farmacologia , alfa-Glucosidases/metabolismo , Animais , Carbaçúcares/síntese química , Carbaçúcares/química , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Modelos Moleculares , Estrutura Molecular , Sacarase/antagonistas & inibidores , Sacarase/metabolismoRESUMO
Understanding the enzyme reaction mechanism can lead to the design of enzyme inhibitors. A Claisen rearrangement was used to allow conversion of an α-1,4-disaccharide into an α-1,3-linked glycosyl carbasugar to target the endo-α-mannosidase from the GH99 glycosidase family, which, unusually, is believed to act through a 1,2-anhydrosugar "epoxide" intermediate. Using NMR and X-ray crystallography, it is shown that glucosyl carbasugar α-aziridines can act as reasonably potent endo-α-mannosidase inhibitors, likely by virtue of their shape mimicry and the interactions of the aziridine nitrogen with the conserved catalytic acid/base of the enzyme active site.
Assuntos
Carbaçúcares/farmacologia , Dissacarídeos/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Manosidase/antagonistas & inibidores , Carbaçúcares/síntese química , Carbaçúcares/química , Dissacarídeos/química , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Estrutura Molecular , Relação Estrutura-Atividade , alfa-Manosidase/metabolismoRESUMO
Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate's structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.
Assuntos
Carbaçúcares/farmacologia , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Biocatálise , Carbaçúcares/síntese química , Carbaçúcares/química , Domínio Catalítico , Cicloexenos/síntese química , Cicloexenos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Galactose/análogos & derivados , Glicosídeo Hidrolases/química , Cinética , Simulação de Dinâmica Molecular , Teoria Quântica , Thermotoga maritima/enzimologiaRESUMO
Carbasugar sodium-glucose cotransporter 2 (SGLT2) inhibitors are highly promising drug candidates for the treatment of Type 2 diabetes mellitus (T2DM). However, the clinical usage of carbasugar SGLT2 inhibitors has been underexplored, due to the lengthy synthetic routes and the lack of structure-activity relationship (SAR) studies of these compounds. Herein, we report a concise and stereodivergent synthetic route towards some novel carbasugar SGLT2 inhibitors, featuring an underexploited, regioselective, and stereospecific palladium-catalyzed allyl-aryl coupling reaction. This synthetic strategy, together with computational modeling, revealed the unexpected SAR of these carbasugar SGLT2 inhibitors, and enabled the discovery of a highly selective and potent SGLT2 inhibitor.
Assuntos
Carbaçúcares/síntese química , Paládio/química , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Transportador 2 de Glucose-Sódio/química , Carbaçúcares/química , Carbaçúcares/farmacologia , Catálise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Relação Estrutura-AtividadeRESUMO
The glmS ribozyme is a bacterial gene-regulating riboswitch that controls cell wall synthesis, depending on glucosamine-6-phosphate as a cofactor. Due to the presence of this ribozyme in several human pathogen bacteria (e.g., MRSA, VRSA), the glmS ribozyme represents an attractive target for the development of artificial cofactors. The substitution of the ring oxygen in carbohydrates by functionalized methylene groups leads to a new generation of glycomimetics that exploits distinct interaction possibilities with their target structure in biological systems. Herein, we describe the synthesis of mono-fluoro-modified carba variants of α-d-glucosamine and ß-l-idosamine. (5aR)-Fluoro-carba-α-d-glucosamine-6-phosphate is a synthetic mimic of the natural ligand of the glmS ribozyme and is capable of effectively addressing its unique self-cleavage mechanism. However, in contrast to what was expected, the activity is significantly decreased compared to its non-fluorinated analog. By combining self-cleavage assays with the Bacillus subtilis and Staphylococcus aureus glmS ribozyme and molecular docking studies, we provide a structure-activity relationship for fluorinated carba-sugars.
Assuntos
Proteínas de Bactérias/metabolismo , Carbaçúcares/metabolismo , RNA Catalítico/metabolismo , Bacillus subtilis/metabolismo , Proteínas de Bactérias/química , Sítios de Ligação , Carbaçúcares/síntese química , Carbaçúcares/química , Cicloexanóis/síntese química , Cicloexanóis/química , Cicloexanóis/metabolismo , Cicloexilaminas/síntese química , Cicloexilaminas/química , Cicloexilaminas/metabolismo , Halogenação , Conformação Molecular , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , RNA Catalítico/química , Staphylococcus aureus/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We synthesized the naturally occurring carbasugar ampelomin A and its epimer from a common starting material. The enantiomerically pure starting material was obtained by base-catalyzed asymmetric Diels-Alder reaction of 3-hydroxy-2-pyrone and chiral acrylate. The total yield of ampelomin A was 14% in seven synthetic steps. The key step of the synthesis of ampelomin A was inversion of the stereochemistry at the C-6 position, which was achieved by stereoselective catalytic hydrogenation of the corresponding methylidene group. Further synthesis of the epimer was straightforward, because all stereogenic centers had already been introduced on the starting material; the total yield was 44% in four synthetic steps. Both the final products were obtained in pure form without contamination with undesired isomers. The reported (1)H NMR chemical shift of the C-7 methyl protons and the H-5axial coupling pattern of natural ampelomin A were inconsistent with those of our synthetic product. After careful comparison of the spectra and examination of the stable conformation obtained through MM2 calculations, we present revised NMR data for ampelomin A.
Assuntos
Carbaçúcares/síntese química , Reação de Cicloadição/métodos , Cicloexanos/síntese química , Acrilatos/química , Carbaçúcares/química , Catálise , Cicloexanos/química , Hidrogenação , Espectroscopia de Ressonância Magnética , Pironas/química , EstereoisomerismoRESUMO
2-Deoxy-α-d-ribose-1-phosphate is of great interest as it is involved in the biosynthesis and/or catabolic degradation of several nucleoside analogues of biological and therapeutic relevance. However due to the lack of a stabilising group at its 2-position, it is difficult to synthesize stable prodrugs of this compound. In order to overcome this lack of stability, the synthesis of carbasugar analogues of 2-deoxyribose-1-phosphate was envisioned. Herein the preparation of a series of prodrugs of two carbocyclic analogues of 2-deoxyribose-1-phosphate using the phosphoramidate ProTide technology, along with their biological evaluation against HIV and cancer cell proliferation, is reported.
Assuntos
Amidas/química , Amidas/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Ácidos Fosfóricos/química , Ácidos Fosfóricos/farmacologia , Ribosemonofosfatos/química , Ribosemonofosfatos/farmacologia , Amidas/síntese química , Fármacos Anti-HIV/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbaçúcares/síntese química , Carbaçúcares/química , Carbaçúcares/farmacologia , Linhagem Celular Tumoral , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Ácidos Fosfóricos/síntese química , Pró-Fármacos , Ribosemonofosfatos/síntese químicaRESUMO
Natural carbasugars are an important class of biologically active compounds. Due to their conformational freedom and the subtle difference in spectral characteristics between isomers, often their NMR-based structural assignments are erroneous. It is thus important to validate their structural identity through chemical synthesis. We report the first total syntheses and structural validation of five natural carbasugars, namely, lincitol A, lincitol B, uvacalol I, uvacalol J, and uvacalol K in their racemic forms, from a myo-inositol-derived common intermediate. This intermediate was synthesized by the vinylogous ring opening of myo-inositol orthoester cage under mild acidic conditions in six steps from myo-inositol. From this intermediate, we achieved the syntheses of (±)-lincitol A in six steps, (±)-lincitol B in seven steps, (±)-uvacalol I in five steps, (±)-uvacalol J in five steps, and (±)-uvacalol K in seven steps. The structure and relative stereochemistry of these natural products were confirmed by comparing the (1)H and (13)C NMR spectra of synthesised natural products with the reported data. These syntheses involved several unprecedented protecting-group manipulations and unexpected reactivities.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Carbaçúcares/síntese química , Carbaçúcares/química , Conformação Molecular , Estrutura Molecular , EstereoisomerismoRESUMO
The multistep synthesis of a novel UDP-C-cyclohexene, designed as a high energy intermediate analogue of the UDP-galactopyranose mutase (UGM) catalyzed isomerization reaction, is reported. The synthesis of the central carbasugar involved the preparation of a galactitol derivative bearing two olefins necessary for the construction of the cyclohexene ring by a ring-closing metathesis as a key step. Further successive phosphonylation, deprotection, and UMP coupling provided the target molecule. The final molecule was assayed against UGM and compared with UDP-C-Galf, the C-glycosidic UGM substrate analogue.
Assuntos
Carbaçúcares/síntese química , Cicloexanos/química , Glicosídeos/química , Glicosídeos/síntese química , Transferases Intramoleculares/antagonistas & inibidores , Difosfato de Uridina/química , Carbaçúcares/química , Carbaçúcares/farmacologia , Catálise , Glicosídeos/farmacologia , Transferases Intramoleculares/química , Isomerismo , Estrutura MolecularRESUMO
Asymmetric total synthesis of (+)-gabosine C, (+)-pericosine B, and (+)-pericosine C has been reported from readily available d-(-)-isoascorbic acid and d-ribose involving Grubbs ring closing metathesis, Morita-Baylis-Hillman (MBH) reaction, and Luche reduction.
Assuntos
Carbaçúcares/síntese química , Cicloexanóis/síntese química , Cicloexanonas/síntese química , Ácido Chiquímico/análogos & derivados , Ácido Ascórbico/química , Catálise , Estrutura Molecular , Oxirredução , Ribose/química , Ácido Chiquímico/síntese química , EstereoisomerismoRESUMO
A few bicyclic hybrid sugar molecules comprising of oxa-aza, oxa-oxa, and oxa-carbasugar fused skeletons were designed and synthesized from C-2 acetoxyglucal involving Ferrier rearrangement, Grignard addition, and ring-closing metathesis as key steps. The inhibitory activities of the synthesized molecules were tested against commercially available enzymes, which revealed the sugar-piperidine and sugar-pyran hybrids as potent and selective inhibitors.
Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Carbaçúcares/química , Carbaçúcares/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/química , Óxidos/química , Óxidos/farmacologia , Piperidinas/química , Piranos/químicaRESUMO
4,5-Dimethylenecyclohex-1-ene was subjected to a photooxygenation reaction to introduce oxygen functionalities. The endoperoxide obtained underwent an ene-reaction to form hydroperoxides with 1,3-diene structures. Further addition of singlet oxygen to the diene units resulted in the formation of tricyclic hydroperoxides having three oxygens in the molecule. Cleavage of the oxygen-oxygen bonds followed by epoxidation of the remaining C-C double bond and concomitant ring-opening reaction furnished the isomeric carbasugars.
Assuntos
Carbaçúcares/síntese química , Cicloexenos/química , Carbaçúcares/química , Peróxido de Hidrogênio/química , Estrutura Molecular , Oxirredução , Oxigênio Singlete/química , EstereoisomerismoRESUMO
A methodology is described for the highly efficient and divergent synthesis of pseudosugars which allows the stereoselective introduction of polar groups at either the α or the ß pseudoanomeric positions. Using this method, a series of 3-deoxycarbasugar analogues of mannose bearing a pyridyl group are rationally designed, prepared and tested for inhibition of Golgi α-mannosidase II.
Assuntos
Carbaçúcares/química , Inibidores Enzimáticos/síntese química , Complexo de Golgi/enzimologia , Manosidases/antagonistas & inibidores , Manosidases/química , Modelos Moleculares , Sítios de Ligação , Carbaçúcares/síntese química , Carbaçúcares/farmacologia , Técnicas de Química Combinatória , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Ligação Proteica , Swainsonina/química , Swainsonina/farmacologiaRESUMO
A stereodivergent synthesis of the first examples of 4-membered carbasugars has been achieved from vitamin C by way of an efficient intramolecular SmI2-mediated aldehyde-alkene coupling. In this key step, cylobutanes with four contiguous asymmetric centers are generated with a high level of stereocontrol.
Assuntos
Aldeídos/química , Alcenos/química , Carbaçúcares/síntese química , Carbaçúcares/química , Ciclização , Conformação Molecular , EstereoisomerismoRESUMO
The importance of glycosidase inhibitors and especially the bicyclic molecules has led to design and assessment of many analogs of naturally occurring molecules. This review focuses on the synthesis and enzyme inhibitions of a few selected (synthetic or non-naturally occurring) molecules that have been reported in the last decade, which allow one to draw some connection between varying the structural features and their effect on glycosidase inhibitions. It is expected that further improvements based on these features could lead to improved inhibitors.
Assuntos
Compostos Azabicíclicos/síntese química , Carbaçúcares/síntese química , Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Compostos Azabicíclicos/química , Carbaçúcares/química , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/metabolismo , Indolizidinas/química , Relação Estrutura-AtividadeRESUMO
Fluoro-C-glycosides and fluoro-carbasugars are a particular subclass of hydrolytically stable glycomimetics that are expected to have different, hopefully improved properties thanks to the stereoelectronic features of the fluoroalkyl moiety. This review summarizes the studies devoted to the synthesis of such structures as well as the studies regarding their conformational behaviour and their potential as carbohydrate analogues.
Assuntos
Carbaçúcares/química , Glicosídeos/química , Carbaçúcares/síntese química , Ciclização , Reação de Cicloadição , Fluoretação , Glicosídeos/síntese químicaRESUMO
A detailed protocol for the synthesis of North-methanocarba-thymidine (N-MCT), a potent antiviral nucleoside with a restricted bicyclo[3.1.0]hexane pseudosugar conformation, is presented. The process is described in two parts. The first basic protocol deals with the synthesis of the carbobicyclic pseudosugar precursor that can be utilized in the syntheses of other bicyclo[3.1.0]hexane nucleosides with natural and non-natural nucleobases. The second basic protocol describes the specific construction of the thymine base in a linear fashion from the carbobicyclic intermediate.
Assuntos
Antivirais/síntese química , Carbaçúcares/síntese química , Conformação de Ácido Nucleico , Timidina/análogos & derivados , Antivirais/química , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Carbaçúcares/química , Herpesvirus Humano 2/efeitos dos fármacos , Timina/químicaRESUMO
The Gram-negative encapsulated bacterium Neisseria meningitidis type A (MenA) is a major cause of meningitis in developing countries, especially in the sub-Saharan region of Africa. The development and manufacture of an efficient glycoconjugate vaccine against MenA is greatly hampered by the poor hydrolytic stability of its capsular polysaccharide, consisting of (1â6)-linked 2-acetamido-2-deoxy-α-d-mannopyranosyl phosphate repeating units. The replacement of the ring oxygen with a methylene group to get a carbocyclic analogue leads to the loss of the acetalic character of the phosphodiester and consequently to the enhancement of its chemical stability. Here we report the synthesis of oligomers (mono-, di- and trisaccharide) of carba-N-acetylmannosamine-1-O-phosphate as candidates for stabilized analogues of the corresponding fragments of MenA capsular polysaccharide. Each of the synthesized compounds contains a phosphodiester-linked aminopropyl spacer at its reducing end to allow for protein conjugation. The inhibition abilities of the synthetic molecules were investigated by a competitive ELISA assay, showing that only the carba-disaccharide is recognized by a polyclonal anti-MenA serum with an affinity similar to a native MenA oligosaccharide with average polymerization degree of 3.
Assuntos
Carbaçúcares/química , Hexosaminas/química , Neisseria meningitidis Sorogrupo A/química , Oligossacarídeos/química , Animais , Carbaçúcares/síntese química , Carbaçúcares/imunologia , Ensaio de Imunoadsorção Enzimática , Hexosaminas/síntese química , Hexosaminas/imunologia , Humanos , Meningite Meningocócica/prevenção & controle , Camundongos , Neisseria meningitidis Sorogrupo A/imunologia , Oligossacarídeos/síntese química , Oligossacarídeos/imunologia , Fosfatos/síntese química , Fosfatos/química , Fosfatos/imunologia , Soro/imunologiaRESUMO
Carba-NAD is a synthetic compound identical to NAD except for one substitution, where an oxygen atom adjacent to the anomeric linkage bearing nicotinamide is replaced with a methylene group. Because it is inert in nicotinamide displacement reactions, carba-NAD is an unreactive substrate analogue for NAD-consuming enzymes. SIRT3 and SIRT5 are NAD-consuming enzymes that are potential therapeutic targets for the treatment of metabolic diseases and cancers. We report an improved carba-NAD synthesis, including a pyrophosphate coupling method that proceeds in approximately 60% yield. We also disclose the X-ray crystal structures of the ternary complexes of SIRT3 and SIRT5 bound to a peptide substrate and carba-NAD. These X-ray crystal structures provide critical snapshots of the mechanism by which human sirtuins function as protein deacylation catalysts.