RESUMO
The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.
Assuntos
Aldeídos , Fármacos Antiobesidade , Hidrazonas , Obesidade , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Fármacos Antiobesidade/química , Hidrazonas/farmacologia , Hidrazonas/química , Hidrazonas/síntese química , Hidrazonas/farmacocinética , Hidrazonas/uso terapêutico , Camundongos , Relação Estrutura-Atividade , Aldeídos/química , Masculino , Obesidade/tratamento farmacológico , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Humanos , Camundongos Obesos , Estrutura MolecularRESUMO
Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver ß-galactosidase and ß-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver ß-glucosidase and ß-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of ß-glucosidase or ß-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of ß-glucosidase and ß-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower ß-glucosidase and ß-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of ß-galactosidase and ß-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Simulação de Acoplamento Molecular , beta-Galactosidase , beta-Glucosidase , beta-Galactosidase/antagonistas & inibidores , beta-Galactosidase/metabolismo , Bovinos , Animais , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , beta-Glucosidase/antagonistas & inibidores , beta-Glucosidase/metabolismo , Estrutura Molecular , Relação Dose-Resposta a Droga , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/químicaRESUMO
A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC50 = 9.3 µM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.
Assuntos
Inibidores de Glicosídeo Hidrolases , alfa-Glucosidases , alfa-Glucosidases/metabolismo , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Inibidores de Glicosídeo Hidrolases/farmacologia , Glicosídeo Hidrolases , Estrutura MolecularRESUMO
A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from D-tartrate-derived nitrone 18. The DAB peptides 16 are derivatives of trans,trans-3,4-dihydroxy-L-proline. Glycosidase inhibition assay found four of them to be weak and selective bovine liver ß-galactosidase inhibitors, and the C-2' methyl substituted compound 23b showed the most potent ß-galactosidase inhibition (IC50 = 0.66 µM). Molecular docking studies revealed different docking modes of compound 23b compared to those of other DAB-peptides, and partial similarity of compound 23b to DGJ.
Assuntos
Dipeptídeos , Glicosídeo Hidrolases , Animais , Bovinos , Simulação de Acoplamento Molecular , Peptídeo C , beta-Galactosidase , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
A series of α-1-C-alkyl DAB (1,4-dideoxy-1,4-imino-d-arabinitol) and LAB (1,4-dideoxy-1,4-imino-l-arabinitol) derivatives with aryl substituents have been designed as analogues of broussonetine W (12), and assayed as glycosidase inhibitors. While the inhibition spectrum of α-1-C-alkyl DAB derivative 16 showed a good correlation to that of broussonetine W (12), introduction of substituents on the terminal aryl (17a-f) or hydroxyl groups at C-1' position of the alkyl chains (18a-e) decreased their α-glucosidase inhibitions but greatly improved their inhibitions of bovine liver ß-glucosidase and ß-galactosidase. Furthermore, epimerization of C-1' configurations of compounds 18a-e clearly lowered their inhibition potency of bovine liver ß-glucosidase and ß-galactosidase. Notably, some of the α-1-C-alkyl DAB derivatives were also found to have potent human lysosome ß-glucosidase inhibitions. In contrast, enantiomers of compounds 18a-e and 1'-epi-18a-e generally showed increased α-glucosidase inhibitions, but sharply decreased bovine liver ß-glucosidase and ß-galactosidase inhibitions. Molecular docking calculations unveiled the novel two set of binding modes for each series of compounds; introduction of C-1' hydroxyl altered the conformations of the pyrrolidine rings and orientation of their long chains, resulting in improved accommodation in the hydrophobic grooves. The compounds reported herein are very potent ß-glucosidase and ß-galactosidase inhibitions with novel binding mode; and the structure-activity relationship provides guidance for design and development of more pyrrolidine pharmacological chaperones for lysosomal storage diseases.
Assuntos
alfa-Glucosidases , beta-Glucosidase , Animais , Bovinos , Humanos , alfa-Glucosidases/metabolismo , beta-Galactosidase , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Low anterior resection syndrome (LARS) is one of the common postoperative complications in patients with rectal cancer, which seriously affects their postoperative recovery and quality of life (QoL). Electroacupuncture therapy is one of the characteristic therapies of traditional Chinese medicine. There are few reports on the prevention and treatment of LARS by electroacupuncture therapy. AIM: To explore the clinical effectiveness of electroacupuncture in managing rectal cancer patients with postoperative LARS. METHODS: A total of 50 patients with LARS after rectal cancer surgery were retrospectively selected as the research subjects. According to the treatment methods, they were divided into an observation group (n = 25) and a control group (n = 25). During the four-week treatment period, the control group received standard defecation function training, while the observation group received electroacupuncture care and traditional defecation function training. The anal pressure index (which includes anal resting pressure, anal systolic pressure, and maximum tolerable volume), European Organization of Research and Treatment of Cancer (EORTC) QoL C30 (QLQ-C30) score, LARS Scale (LARSS) score, Wexner anal incontinence scale score, Xu Zhongfa five-item 10-point scale score, and the occurrence of adverse reactions were compared between the two groups before and after treatment. RESULTS: The experimental group showed considerably enhanced LARSS scores compared to those in the control group after four weeks of treatment. In the first week, second week, and fourth week, the LARSS score and Wexner anal incontinence scale score decreased, and the Xu Zhong method five-item 10-point scale score increased, with significant differences (P < 0.05). The experimental group showed substantial improvements in anal resting pressure, anal systolic pressure, and maximum tolerance volume after undergoing 4 wk of therapy in the untreated group (P < 0.05). The experimental group's QLQ-C30 score on the EORTC QoL questionnaire was higher than that of the control group during the 1st, 2nd, and 4th wk (P < 0.05). No significant variation between the groups in the frequency of adverse reactions (P > 0.05) was observed. CONCLUSION: Electroacupuncture positively impacted LARS following rectal cancer surgery, effectively improving clinical symptoms and anal pressure indicators and patients' standard of life.
RESUMO
A series of C-6 fluorinated casuarine derivatives have been synthesized via organocatalytic stereoselective α-fluorination of iminosugar-based aldehydes or direct nucleophilic fluorination of polyhydroxylated pyrrolizidines. Glycosidase assays against various glycosidases allowed systematic structure-activity relationship (SAR) study using molecular docking calculations. Introduction of fluorine atom(s) at C-6 position removed the trehalase and maltase inhibitory activities of all casuarine derivatives, and greatly increased their specificity towards amyloglucosidase. Inhibition of the fluorinated casuarines depended on the configuration of C-6 fluorine, of which 6-deoxy-6-epi-6-fluoro-casuarine (24) was found approximately 40-fold potent than its parent compound 6-epi-casuarine (2) as a potent and specific inhibitor of amyloglucosidase. Molecular docking calculations showed that replacement of the C-6 hydroxyls by fluorine atom(s) removed the original interactions with trehalase, but helped to reinforce the binding with amyloglucosidase via newly established fluorine related hydrogen bonding or untypical anion-π interactions. To further investigate the quantitative SARs of casuarine derivatives, the CoMFA and CoMSIA models on amyloglucosidase were established, indicating the dominating effect of electrostatic field in amyloglucosidase inhibition. The 3D-QSAR models were validated to be reliable and can be used for further optimization of casuarine-related iminosugars, as well as design and development of anti-diabetic and immunomodulatory drugs.
Assuntos
Glucana 1,4-alfa-Glucosidase , Trealase , Simulação de Acoplamento Molecular , Glucana 1,4-alfa-Glucosidase/metabolismo , Trealase/metabolismo , Flúor , Relação Quantitativa Estrutura-Atividade , Relação Estrutura-Atividade , Glicosídeo HidrolasesRESUMO
L-ido-Deoxynojirimycin (L-ido-DNJ) itself showed no affinity for human lysosomal acid α-glucosidase (GAA), whereas 5-C-methyl-L-ido-DNJ showed a strong affinity for GAA, comparable to the glucose analog DNJ, with a Ki value of 0.060 µM. This excellent affinity for GAA and enzyme stabilization was observed only when methyl and ethyl groups were introduced. Docking simulation analysis revealed that the alkyl chains of 5-C-alkyl-L-ido-DNJs were stored in three different pockets, depending on their length, thereby the molecular orientation was changed. Comparison of the binding poses of DNJ and 5-C-methyl-L-ido-DNJ showed that they formed a common ionic interaction with Asp404, Asp518, and Asp616, but both the binding orientation and the distance between the ligand and each amino acid residue were different. 5-C-Methyl-L-ido-DNJ dose-dependently increased intracellular GAA activity in Pompe patient fibroblasts with the M519V mutation and also promoted enzyme transport to lysosomes. This study provides the first example of a strategy to design high-affinity ligands by introducing alkyl branches into rare sugars and L-sugar-type iminosugars to change the orientation of binding.
Assuntos
1-Desoxinojirimicina , Inibidores de Glicosídeo Hidrolases , Imino Açúcares , alfa-Glucosidases , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/farmacologia , Aminoácidos , Domínio Catalítico , Glucose/análogos & derivados , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Imino Açúcares/química , Imino Açúcares/farmacologia , Ligantes , Ligação Proteica , alfa-Glucosidases/químicaRESUMO
Enantiomeric series of C-4 hydroxymethyl depleted DAB and LAB derivatives (trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines), designed as ß-glucosidase inhibitors by molecular docking calculations, have been synthesized in 2 steps from l- and d-tartaric acid derived enantiomeric cyclic nitrones 29L and 29D, respectively. Both series of C-4 hydroxymethyl depleted DAB and LAB derivatives 28Da-e and 28La-e, which are structurally trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines, were potent and selective human lysosome acid ß-glucosidase (GCase) inhibitors, of which 28Dd and 28Ld with C-4 biphenyls showed the highest potency relative to other compounds of the same series. The work provided a series of pyrrolidine-type potent and selective GCase inhibitors with minimal hydroxyl substitutions and synthetic procedures. Structure-activity relationship study revealed not only the rationality of hydrophobic and aromatic properties of the binding sites in GCase, but also the great potential of pyrrolidine family in development of new GCase inhibitors with minimized undesirable side effects. The results indicate a strategy for the development of drugs for the treatment of related diseases targeting acid ß-glucosidase, such as Gaucher disease and Parkinson's disease.
Assuntos
Doença de Gaucher , Inibidores Enzimáticos/química , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase , Humanos , Simulação de Acoplamento Molecular , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , beta-GlucosidaseRESUMO
C-7-fluorinated derivatives of two important polyhydroxylated pyrrolizidines, casuarine and australine, were synthesized with organocatalytic stereoselective α-fluorination of aldehydes as the key step. The strategy is extensively applicable to some synthetically challenging fluorinated iminosugars and carbohydrates. The docking studies indicated that the potent inhibitions of trehalase and amyloglucosidase by the fluorinated polyhydroxylated pyrrolizidines are due to the interaction modes dominated by fluorine atoms in these iminosugars with the amino acids' residues of the corresponding enzymes. Steady interactions were established between the C-7 fluoride and a hydrophobic pocket in amyloglucosidase by untypical anion-π interactions. These unexpected docking modes and related structure-activity relationship studies emphasize the value of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.
Assuntos
Glucana 1,4-alfa-Glucosidase , Glicosídeo Hidrolases , Alcaloides , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirróis , Alcaloides de PirrolizidinaRESUMO
Two series of C-4 alkylated and arylated LAB (1,4-dideoxy-1,4-imino-l-arabinitol) and DAB (1,4-dideoxy-1,4-imino-d-arabinitol) derivatives, synthesized in 6 steps from enantiomeric cyclic nitrones derived from l- and d-tartaric acid, were designed and assayed against various glycosidases. C-4 Branched LAB alkyl and phenyl derivatives 5La-d showed potent α-glucosidase inhibition, particularly against human lysosomal acid α-glucosidase; C-4 DAB derivatives 5Da-d, with small alkyl groups, showed enhanced inhibition of rat intestinal maltase and sucrase. Both enantiomeric C-4 arylated derivatives 5Lf-l and 5Df-l exhibited potent and selective α-glucosidase inhibition; and compound 5Li with a para-electron donating group (EDG) on its C-4 aryl group, showed the most potent rat intestinal sucrase inhibition. Docking studies showed similar hydrogen bonding modes for the iminosugar skeletons of DAB (1) and LAB (2) with ntMGAM,. While C-4 alkylated LAB derivatives showed high similarity in their binding modes with the active site of ntMGAM, binding modes of the DAB derivatives relied on the size of C-4 alkyl groups with methyl and butyl showed the optimum interactions. Furthermore, C-4 arylation improved the interactions of LAB derivatives with enzymes by T-shaped π-π stack with residue Trp-406; for C-4 arylated DAB derivatives, the π-π stack interactions were found with distinct planar distortions caused by EDGs or EWGs on the C-4 aryls. The results reported herein provided insights for the design and development of DAB and LAB related α-glucosidase inhibitors, and may also contribute to the future development of anti-viral, anti-diabetic and anti-Pompe disease drugs.
Assuntos
Glicosídeo Hidrolases , Lítio , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Radioisótopos , RatosRESUMO
Pseudouridimycin (1), a potent antibiotic against both Gram-positive and Gram-negative bacteria including multi-drug-resistant strains with a new mode of action isolated from Streptomyces sp., was synthesized by a convergent strategy from 5'-amino-pseudouridine 5 and N-hydroxy-dipeptide 26 in 23% total yield. The key intermediate 26 was synthesized by hydroxylaminolysis of the nitrone derived from glutamine and subsequent glycylation with glycine chloride. The synthetic method provides an efficient and practical way for the synthesis of N-hydroxylated peptidyl nucleoside.
Assuntos
Nucleosídeos/análogos & derivadosRESUMO
In recent years, the function of pharmacological chaperones as a "thermodynamic stabilizer" has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced a nanomolar affinity for GAA with a Ki value of 0.0047 µM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 µM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation temperature (Tm) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.
Assuntos
1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/farmacologia , Inibidores Enzimáticos/farmacologia , alfa-Glucosidases/metabolismo , Alquilação , Inibidores Enzimáticos/síntese química , Fibroblastos/metabolismo , Doença de Depósito de Glicogênio Tipo II , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Conformação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , alfa-Glucosidases/efeitos dos fármacos , alfa-Glucosidases/genéticaRESUMO
Inspired by Roush's pioneering work on rare sugars, we have developed a scalable, stereoselective, de novo synthesis of orthogonally protected C2-fluoro digitoxose and cymarose, utilizing Sharpless kinetic resolution and organocatalytic fluorination as key steps. The utility of this strategy is demonstrated by the synthesis of a fluorinated analogue of digoxin, which indicates the fluorine on the sugar ring may have a significant impact on biological activity.
Assuntos
Digoxina , Flúor , Halogenação , Hexoses , EstereoisomerismoRESUMO
Four diastereomers belonging to the family of casuarines, including casuarine (1), 6-epi-casuarine (2), 7-epi-casuarine (13) and 6,7-diepi-casuarine (14), have been synthesized from D-arabinose-derived cyclic nitrone 7 and nitrone-derived aldehyde 4 by a stereocomplementary strategy. Glycosidase inhibition comparison showed that 6-epi-casuarine (2) exhibits enhanced inhibition of trehalase (IC50 = 9.7 µM) and 6,7-diepi-casuarine (14) leads to specific inhibition of trehalase.
RESUMO
5-C-Alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives have been designed and synthesized efficiently from an l-sorbose-derived cyclic nitrone. The DNJ and l-ido-DNJ derivatives with C-5 alkyl chains ranging from methyl to dodecyl were assayed against various glycosidases to study the effect of chain length on enzyme inhibition. Glycosidase inhibition study of DNJ derivatives showed potent and selective inhibitions of α-glucosidase; DNJ derivatives with methyl, pentyl to octyl, undecyl and dodecyl as C-5 branched chains showed significantly improved rat intestinal maltase inhibition. In contrast, most 5-C-alkyl-l-ido-DNJ derivatives were weak or moderate inhibitors of the enzymes tested, with only three compounds found to be potent α-glucosidase inhibitors. Docking studies showed different interaction modes of 5-C-ethyl-DNJ and 5-C-octyl-DNJ with ntMGAM and also different binding modes of 5-C-alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives; the importance of the degree of accommodation of the C-5 substituent in the hydrophobic groove and pocket may account for the variation of glycosidase inhibition in the two series of derivatives. The results reported herein are helpful in the design and development of α-glucosidase inhibitors; this may lead to novel agents for the treatment of viral infection and type II diabetes.
Assuntos
Inibidores de Glicosídeo Hidrolases/uso terapêutico , Glicosídeo Hidrolases/metabolismo , Simulação de Acoplamento Molecular/métodos , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of ß-N-acetylhexosaminidases (ß-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Pirrolidinas/química , Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/síntese química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Animais , Ciclização , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Ratos , Estereoisomerismo , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
N-Substituted derivatives of 1,4-dideoxy-1,4-imino-d-mannitol (DIM), the pyrrolidine core of swainsonine, have been synthesized efficiently and stereoselectively from d-mannose with 2,3:5,6-di-O-isopropylidene DIM (10) as a key intermediate. These N-substituted derivatives include N-alkylated, N-alkenylated, N-hydroxyalkylated and N-aralkylated DIMs with the carbon number of the alkyl chain ranging from one to nine. The obtained 33 N-substituted DIM derivatives were assayed against various glycosidases, which allowed a systematic evaluation of their glycosidase inhibition profiles. Though N-substitution of DIM decreased their α-mannosidase inhibitory activities, some of the derivatives showed significant inhibition of other glycosidases.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Manitol/análogos & derivados , Animais , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/metabolismo , Humanos , Imino Furanoses/síntese química , Imino Furanoses/química , Imino Furanoses/farmacologia , Concentração Inibidora 50 , Manitol/síntese química , Manitol/química , Manitol/farmacologia , Ratos , Swainsonina/químicaRESUMO
Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from l-arabino-nitrone (ent-14), l-lyxo-nitrone (ent-3-epi-14), and l-xylo-nitrone (2-epi-14) in five steps, in 26%-31% overall yield. The natural product broussonetine M (3) and 10'-epi-3 were potent inhibitors of ß-glucosidase (IC50 = 6.3 µM and 0.8 µM, respectively) and ß-galactosidase (IC50 = 2.3 µM and 0.2 µM, respectively); while their enantiomers, ent-3 and ent-10'-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC50 = 1.2 µM and 1.3 µM, respectively) and rat intestinal maltase (IC50 = 0.29 µM and 18 µM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10' hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.