RESUMEN
Cyclodextrins (CDs) are a group of cyclic oligosaccharides produced from starch or starch derivatives. They contain six (αCD), seven (ßCD), eight (γCD), or more glucopyranose monomers linked via α-1,4-glycosidic bonds. CDs have a truncated cone shape with a hydrophilic outer wall and a less hydrophilic inner wall, the latter forming a more apolar internal cavity. Because of this special architecture, CDs are soluble in water and can simultaneously host lipophilic guest molecules. The major advantage of inclusion into CDs is increased aqueous solubility of such lipophilic substances. Accordingly, we present studies where the complexation of natural compounds such as propolis and dietary plant bioactives (e.g., tocotrienol, pentacyclic triterpenoids, curcumin) with γCD resulted in improved stability, bioavailability, and bioactivity in various laboratory model organisms and in humans. We also address safety aspects that may arise from increased bioavailability of plant extracts or natural compounds owing to CD complexation. When orally administered, α- and ßCD-which are inert to intestinal digestion-are fermented by the human intestinal flora, while γCD is almost completely degraded to glucose units by α-amylase. Hence, recent reports indicate that empty γCD supplementation exhibits metabolic activity on its own, which may provide opportunities for new applications.
Asunto(s)
Productos Biológicos/química , Ciclodextrinas/química , Fenómenos Fisiológicos de la Nutrición , Plantas/química , Ciclodextrinas/efectos adversos , Ciclodextrinas/síntesis químicaRESUMEN
Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann-Pick typeâ C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6A -amino-6A -deoxy-ß-cyclodextrin and 3A -amino-3A -deoxy-2A (S),3A (S)-ß-cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of ß-cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.
Asunto(s)
Antioxidantes/farmacología , Ciclodextrinas/farmacología , Deferasirox/análogos & derivados , Deferasirox/farmacología , Quelantes del Hierro/farmacología , Animales , Antioxidantes/síntesis química , Células CHO , Cricetulus , Ciclodextrinas/síntesis química , Deferasirox/síntesis química , Células Hep G2 , Humanos , Quelantes del Hierro/síntesis química , Multimerización de Proteína/efectos de los fármacos , alfa-Sinucleína/metabolismoRESUMEN
Niclosamide, previously used as an anthelmintic drug is currently being repurposed for its anticancer activity. Niclosamide is a brick like biopharmaceutical classification system (BCS) class II drug with poor aqueous solubility and dissolution consequently leading to low bioavailability. By considering the physicochemical properties and geometry of niclosamide, inclusion complex with cyclodextrin was prepared by freeze drying method and characterized using FT-IR, DSC, PXRD, and 1HNMR. In silico molecular modeling study was performed to study the possible interactions between niclosamide and cyclodextrin. The anticancer activity of niclosamide formulation was evaluated through in vitro cell cytotoxicity study using various cancer cell lines. The potential of niclosamide complex for improvement of the bioavailability was evaluated in male BALB/c mice. In vitro cytotoxicity studies indicated significantly higher cytotoxicity at lower concentrations and the pharmacokinetic studies showed significant improvement in Cmax and Tmax of niclosamide from cyclodextrin complex in comparison to pure niclosamide alone.
Asunto(s)
Antineoplásicos/síntesis química , Ciclodextrinas/síntesis química , Composición de Medicamentos/métodos , Reposicionamiento de Medicamentos/métodos , Niclosamida/síntesis química , Animales , Anticestodos/síntesis química , Anticestodos/metabolismo , Antineoplásicos/metabolismo , Ciclodextrinas/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Células HCT116 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Niclosamida/metabolismoRESUMEN
Biotin/(strept)avidin self-assembly is a powerful platform for nanoscale fabrication and capture with many different applications in science, medicine, and nanotechnology. However, biotin/(strept)avidin self-assembly has several well-recognized drawbacks that limit performance in certain technical areas and there is a need for synthetic mimics that can either become superior replacements or operational partners with bio-orthogonal recognition properties. The goal of this tutorial review is to describe the recent progress in making high affinity synthetic association partners that operate in water or biological media. The review starts with a background summary of biotin/(strept)avidin self-assembly and the current design rules for creating synthetic mimics. A series of case studies are presented that describe recent success using synthetic derivatives of cyclodextrins, cucurbiturils, and various organic cyclophanes such as calixarenes, deep cavitands, pillararenes, and tetralactams. In some cases, two complementary partners associate to produce a nanoscale complex and in other cases a ditopic host molecule is used to link two partners. The article concludes with a short discussion of future directions and likely challenges.
Asunto(s)
Avidina/química , Biotina/química , Calixarenos/síntesis química , Ciclodextrinas/síntesis química , Compuestos Macrocíclicos/síntesis química , Estreptavidina/química , Calixarenos/química , Ciclodextrinas/química , Humanos , Compuestos Macrocíclicos/químicaRESUMEN
Asymmetrically substituted 6(I-VII)-O-t-butyldimethylsilyl(TBDMS)-3(I-VII)-O-ethyl-2(I-VII)-O-methyl-beta-cyclodextrin (MeEt-CD) and 6(I-VII)-O-TBDMS-2(I-VII)-O-ethyl-3(I-VII)-O-methyl-beta-cyclodextrin (EtMe-CD) were synthesised to evaluate the role of the substitution pattern in positions 2 and 3 on the enantioselectivity, in particular in view of their application to routine analysis in fast enantioselective gas chromatography (Es-GC). The chromatographic properties and enantioselectivities of the new derivatives were tested by separating the enantiomers of a series of medium-to-high volatility racemates in the flavour and fragrance field, and compared to those of the corresponding symmetrically substituted 6(I-VII)-O-TBDMS-2(I-VII),3(I-VII)-O-methyl-beta-CD (MeMe-CD) and 6(I-VII)-O-TBDMS-2(I-VII),3(I-VII)-O-ethyl-beta-CD (EtEt-CD), and were then applied to analysis of real-world essential oil (e.o.) samples. A new synthetic process including the sonochemical approach to obtain synthetic reproducibility and significant yields of the per-substituted derivatives with acceptable reaction times was developed. The results show that asymmetrically substituted methyl/ethyl CDs compared to the methyl or ethyl symmetrical derivatives in general provide better enantioselectivity in terms of both enantiomer resolution and number of separated chiral compounds, and show how the substitution pattern in positions 2 and 3 of the CD ring can influence the separation. Moreover, these new CD derivatives with better enantioselectivity are also shown to be very useful in routine analysis for the exhaustive control of samples containing several chiral characterizing markers in a single run.
Asunto(s)
Cromatografía de Gases/métodos , Ciclodextrinas/química , Aromatizantes/química , Perfumes/química , Ciclodextrinas/síntesis química , Aceites de Plantas/química , EstereoisomerismoRESUMEN
A 6A,6A'-dicyclohexylamine-6B,6B'-diselenide-bis-beta-cyclodextrin (6-CySeCD) was designed and synthesized to imitate the antioxidant enzyme glutathione peroxidase (GPX). In this novel GPX model, beta-cyclodextrin provided a hydrophobic environment for substrate binding within its cavity, and a cyclohexylamine group was incorporated into cyclodextrin in proximity to the catalytic selenium in order to increase the stability of the nucleophilic intermediate selenolate. 6-CySeCD exhibits better GPX activity than 6,6'-diselenide-bis-cyclodextrin (6-SeCD) and 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (Ebselen) in the reduction of H(2)O(2), tert-butyl hydroperoxide and cumenyl hydroperoxide by glutathione, respectively. A ping-pong mechanism was observed in steady-state kinetic studies on 6-CySeCD-catalyzed reactions. The enzymatic properties showed that there are two major factors for improving the catalytic efficiency of GPX mimics. First, the substrate-binding site should match the size and shape of the substrate and second, incorporation of an imido-group increases the stability of selenolate in the catalytic cycle. More efficient antioxidant ability compared with 6-SeCD and Ebselen was also seen in the ferrous sulfate/ascorbate-induced mitochondria damage system, and this implies its prospective therapeutic application.
Asunto(s)
Cloro/química , Ciclodextrinas/química , Ciclodextrinas/metabolismo , Glutatión Peroxidasa/metabolismo , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Selenio/química , beta-Ciclodextrinas/química , beta-Ciclodextrinas/metabolismo , Animales , Catálisis , Bovinos , Ciclodextrinas/síntesis química , Cinética , Mitocondrias Cardíacas/metabolismo , Estructura Molecular , Compuestos de Organoselenio/síntesis química , Estrés Oxidativo , beta-Ciclodextrinas/síntesis químicaRESUMEN
Biphenylylacetic acid (BPAA) was linked to the free hydroxyl group of 2,6-di-O-methyl-beta-Cyclodextrin (DM-beta-CyD) through an ester linkage to obtain the site specific release of the drug to the colon. The conjugate at 1:1 mole ratio was separated from the reaction mixture by semipreparative reverse-phase HPLC and characterized by 1H-NMR, 13C-NMR, IR spectroscopy, mass spectrometry and elemental analysis. Chemico-physical characteristics, such as water solubility and dissolution rate, were evaluated comparatively to the BPAA-DM-beta-CyD inclusion complex. Hydrolysis rates were investigated in media simulating gastro-intestinal fluids and at pH 7.4 in the presence of porcine liver esterase. A rapid release of the drug was observed at acid pH value. In all cases a first order kinetic was observed, characterized by t1/2 value of 1.19, 19 and 4 h for chemical hydrolysis at pH 1.1, at pH 7.4 and enzymatic hydrolysis, respectively. In vitro permeation studies through caco-2 cells confirmed the ability of DM-beta-CyD to increase the absorption of included BPAA. A slow permeation was observed for the drug conjugate to DM-beta-CyD due to the slow release of BPAA.
Asunto(s)
Ciclodextrinas/síntesis química , Ciclodextrinas/farmacocinética , Fenilacetatos/síntesis química , Fenilacetatos/farmacocinética , beta-Ciclodextrinas , Células CACO-2 , Evaluación Preclínica de Medicamentos/métodos , Humanos , SolubilidadRESUMEN
The development of vaginal medications, especially antifungal medications, requires that the drug is solubilized as well as retained at or near the mucosa for sufficient periods of time to ensure adequate bioavailability. Itraconazole is a broad-spectrum antifungal agent, which has been used for some time orally and intravenously but for which a vaginal formulation has not yet been developed. We present here a novel itraconazole formulation intended for vaginal use based on hydroxypropyl-beta-cyclodextrin (HPbetaCD), a functional excipient that increases drug solubility and generates a mucoadhesive system in the presence of other ingredients. An aqueous phase was prepared by solubilizing itraconazole with HCl in the presence of propylene glycol and then adding an aqueous solution of HPbetaCD. After pH adjustment, the itraconazole/HPbetaCD solution was added to the oil phase (paraffin oil, trihydroxystearate, and cetyl dimethicon copolyol) and the desired cream containing 1%, 2%, and 2.5% drug obtained by homogenization. Primary irritation studies and subchronic toxicity studies using a rabbit vaginal model indicated that the formulation was safe, well tolerated, and retained in the vaginal space. Clinical investigations indicated that application of 5 g of a 2% cream was very well tolerated and itraconazole was not systemically absorbed. Additional studies in women found that the itraconazole cream was highly effective in reducing or eliminating fungal cultures with few adverse effects. These studies suggested that an HPbetaCD-based, emulsified wax cream formulation was a useful and effective dosage form for treating vaginal candidiasis.
Asunto(s)
Itraconazol/química , Itraconazol/uso terapéutico , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Antifúngicos/administración & dosificación , Antifúngicos/química , Antifúngicos/uso terapéutico , Disponibilidad Biológica , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Ciclodextrinas/administración & dosificación , Ciclodextrinas/síntesis química , Ciclodextrinas/uso terapéutico , Formas de Dosificación , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Femenino , Humanos , Itraconazol/administración & dosificación , Itraconazol/toxicidad , Conejos , Solubilidad , Soluciones/química , Soluciones/uso terapéutico , Cremas, Espumas y Geles Vaginales/administración & dosificación , Cremas, Espumas y Geles Vaginales/uso terapéutico , Enfermedades Vaginales/tratamiento farmacológico , Enfermedades Vaginales/microbiologíaRESUMEN
L-Arginine was immobilized into a supramolecular-structured polyrotaxane to examine the generation of nitric oxide, with a view to improving antithrombosis and the blood compatibility of polymeric biomaterials. L-Arginine was immobilized to the hydroxyl groups of alpha-cyclodextrins in the polyrotaxane via an ester linkage, and the nitric oxide generation and L-arginine release behavior were characterized. L-Arginine-immobilized polyrotaxane was insoluble in water, but was found to generate nitric oxide when placed in Tris-HCI buffer supplemented with activators. L-Arginine-immobilized polyrotaxane exhibited sustained nitric oxide generation for a period of 250 h. L-Arginine was completely released by non-enzymatic hydrolysis from 200 h to 700 h, with a lag-time for the first 200 h. Consequently, after the generation of nitric oxide and the release of L-arginine from the L-arginine-immobilized polyrotaxane, the residual component will be a polyrotaxane with superior biocompatibility and mechanical properties. These results suggest that L-arginine-immobilized polyrotaxane can be useful in a wide range of medical applications, including use as a nitric oxide generative system for antithrombosis, coating and blending materials of hydrophobic extracorporeal circuits, and implantable catheters.
Asunto(s)
Materiales Biocompatibles/síntesis química , Ciclodextrinas/síntesis química , Ciclodextrinas/metabolismo , Óxido Nítrico/metabolismo , Poloxámero/síntesis química , Poloxámero/metabolismo , Rotaxanos , alfa-Ciclodextrinas , Arginina/metabolismo , Materiales Biocompatibles/metabolismo , Citrulina/metabolismo , Ciclodextrinas/química , Cinética , Óxido Nítrico Sintasa/metabolismoRESUMEN
A series of mono- and per-6-substituted cyclodextrin derivatives were synthesized as synthetic receptors (or host molecules) of rocuronium bromide, the most widely used neuromuscular blocker in anaesthesia. By forming host-guest complexes with rocuronium, these cyclodextrin derivatives reverse the muscle relaxation induced by rocuronium in vitro and in vivo and therefore can be used as reversal agents of the neuromuscular blocker to assist rapid recovery of patients after surgery. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, e.g., compound 14 (Org 25969), is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine. The structure-activity relationships are consistent with this supramolecular mechanism of action and are discussed herein. These include the effects of binding cavity size and hydrophobic and electrostatic interaction on the reversal activities of these compounds.
Asunto(s)
Androstanoles/química , Ciclodextrinas/síntesis química , Fármacos Neuromusculares no Despolarizantes/síntesis química , gamma-Ciclodextrinas , Animales , Cristalografía por Rayos X , Ciclodextrinas/química , Ciclodextrinas/farmacología , Diafragma/efectos de los fármacos , Diafragma/inervación , Evaluación Preclínica de Medicamentos , Cobayas , Interacciones Hidrofóbicas e Hidrofílicas , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Modelos Moleculares , Fármacos Neuromusculares no Despolarizantes/química , Rocuronio , Electricidad Estática , Relación Estructura-Actividad , SugammadexRESUMEN
A diselenide, 2,2'-diseleno-bis-beta-cyclodextrin (2-SeCD), was synthesized to imitate the antioxidant enzyme glutathione peroxidase (GPX). The GPX mimic accepts a variety of hydroperoxides as substrates. The GPX activities, reduction of H(2)O(2), tert-butyl hydroperoxide and cumenyl hydroperoxide by glutathione, are 7.4, 4.5 and 10.2 U/micromol, respectively. In contrast to ebselen (PZ51), the diselenide displays high GPX-like activity. The reduction of hydroperoxide by glutathione in the presence of a radical trap shows that the mimic catalyzes the reaction via a non-radical mechanism. A ping-pong mechanism was observed in the steady-state kinetic studies of the 2-SeCD-catalyzed reaction.
Asunto(s)
Ciclodextrinas/síntesis química , Glutatión Peroxidasa/química , Animales , Antioxidantes/química , Azoles/química , Catálisis , Ciclodextrinas/metabolismo , Glutatión/química , Peróxido de Hidrógeno/química , Isoindoles , Cinética , Hígado/enzimología , Estructura Molecular , Compuestos de Organoselenio/química , Oxidación-Reducción , Conejos , Selenio/metabolismo , Especificidad por SustratoRESUMEN
The production of cyclodextrins (CDs) by cyclodextrin-glycosyl-transferase (CGTase) from Bacillus firmus was studied, with respect to the effect of the source of starch upon CD yield and on the selectivity for producing gamma-CD. Cyclodextrin production tests were run for 24 h at 50 degrees C, pH 8.0, and 1 mg/L of CGTase, and substrates were maltodextrin or the starches of rice, potato, cassava, and corn hydrolyzed up to D.E. 10. Cornstarch was the best substrate for producing gamma-CD. Later, glycyrrhizin (2.5% [w/v]), which forms a stable complex with gamma-CD, was added to the cornstarch reaction medium and increased the yield of gamma-CD to about four times that produced with only maltodextrin, but the total yield of CDs remained practically unchanged. Therefore, the results showed that the studied CGTase is capable of giving relatively high yield of gamma-CD in the presence of glycyrrhizin as complexant and cornstarch as substrate.
Asunto(s)
Ciclodextrinas/biosíntesis , Ciclodextrinas/síntesis química , Glucosiltransferasas , gamma-Ciclodextrinas , Bacillus/enzimología , Glucosiltransferasas/metabolismo , Cinética , Manihot , Oryza , Polisacáridos/metabolismo , Solanum tuberosum , Almidón/metabolismo , Especificidad por Sustrato , Zea maysRESUMEN
Novel heterobranched cyclodextrins (CDs), N-acetylglucosaminyl-cyclodextrins (GlcNAc-CD), were synthesized from a mixture of GlcNAc and alpha, beta, or gamma CD by the reverse reaction of N-acetylhexosaminidase from jack bean. Optimum pH and temperature for the production of GlcNAc-alpha CD by N-acetylhexosaminidase were pH 4.9 and 50-70 degrees C, respectively. The maximum yield of GlcNAc-alpha CD was 17.5% (mol/mol) at the concentration of 1 M GlcNAc and 0.25 M alpha CD. The reverse reaction product, GlcNAc-alpha CD, was separated into two peaks by HPLC analysis on the ODS column. Their structures were identified as 6-O-beta-D-N-acetylglucosaminyl-alpha CD and 2-O-beta-D-N-acetylglucosaminyl-alpha CD by FAB-MS and NMR spectroscopies. N-Acetylhexosaminidase from jack bean also synthesized N-acetylgalactosaminyl-alpha CD from N-acetylgalactosamine and alpha CD.
Asunto(s)
Ciclodextrinas/síntesis química , Fabaceae/enzimología , Plantas Medicinales , alfa-Ciclodextrinas , beta-N-Acetilhexosaminidasas/química , beta-N-Acetilhexosaminidasas/metabolismo , Cromatografía/métodos , Ciclodextrinas/química , Portadores de Fármacos/síntesis química , Concentración de Iones de Hidrógeno , Espectroscopía de Resonancia Magnética , Temperatura , Factores de TiempoRESUMEN
Di- and tri-mannosyl-cyclomaltoheptaoses (beta-cyclodextrins, beta CDs), which were synthesized together with monomannosyl-beta CD in a large-scale production by reverse action of alpha-mannosidase from jack bean, were isolated and purified by HPLC. The structures of seven isomers of di-mannosyl-beta CD and six isomers of tri-mannosyl-beta CD were elucidated by FABMS and NMR spectroscopy, and by enzymatic methods.
Asunto(s)
Ciclodextrinas/aislamiento & purificación , Fabaceae/enzimología , Manosidasas/química , Plantas Medicinales , beta-Ciclodextrinas , Cromatografía Líquida de Alta Presión , Ciclodextrinas/síntesis química , Espectroscopía de Resonancia Magnética , Espectrometría de Masa Bombardeada por Átomos Veloces , alfa-ManosidasaRESUMEN
Transgalactosylated derivatives of cyclomalto-hexaose (alpha CD), -heptaose (beta CD), and -octaose (gamma CD) were synthesized by alpha-galactosidase from coffee bean using melibiose as a donor and alpha CD, beta CD or gamma CD as an acceptor. Mono- and di-O-alpha-D- galactosylated CDs were isolated and purified by HPLC. Their structures were elucidated by fast-atom bombardment mass spectrometry (FABMS) and 13C NMR spectroscopy. For structural determination of positional isomers of 6(1),6n-di-O-alpha-D-galactosyl-CDs, digestion products with cyclodextrin glucanotransferase were analyzed by HPLC and FABMS.