Complex formation of fenchone with α-cyclodextrin: NMR titrations.
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ABSTRACT:
SUBMITTER: Nowakowski M
PROVIDER: S-EPMC4082655 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Flunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state. RESULTS:The structural assignments of FLN and ?-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, ?-CD and their mixtures confirmed the formation of ?-CD-FLN inclusion complex in solution. 1H NMR titration data for ?-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of K a = 157 M-1 and change in Gibbs free energy of ?G?=?- 12.65 kJ mol-1. The binding constant of the ?-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the ?-CD cavity. The possible geometrical structures of the ?-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the ?-CD truncated cone. CONCLUSION:NMR spectroscopic studies of FLN, ?-CD and FLN:?-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into ?-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of ?-CD. The splitting of aromatic signals of FLN in the presence of ?-CD suggests chiral differentiation of the guest FLN by ?-CD.
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Project description:Racemic ketoprofen (KP) and β-cyclodextrin (β-CD) powder samples from co-precipitation (1), evaporation (2), and heating-under-reflux (3) were analysed using X-ray techniques and nuclear magnetic resonance (NMR) spectroscopy. On the basis of NMR studies carried out in an aqueous solution, it was found that in the samples obtained by methods 1 and 2, there were large excesses of β-CD in relation to KP, 10 and 75 times, respectively, while the sample obtained by method 3 contained equimolar amounts of β-CD and KP. NMR results indicated that KP/β-CD inclusion complexes were formed and the estimated binding constants were approximately 2400 M-1, showing that KP is quite strongly associated with β-CD. On the other hand, the X-ray single-crystal technique in the solid state revealed that the (S)-KP/β-CD inclusion complex with a stoichiometry of 2:2 was obtained as a result of heating-under-reflux, for which the crystal and molecular structure were examined. Among the methods used for the preparation of the KP/β-CD complex, only method 3 is suitable.
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Project description:Solutions of Brønsted acids with bases in aprotic solvents are not only common model systems to study the fundamentals of proton transfer pathways but are also highly relevant to Brønsted acid catalysis. Despite their importance the light nature of the proton makes characterization of acid-base aggregates challenging. Here, we track such acid-base interactions over a broad range of relative compositions between diphenyl phosphoric acid and the base quinaldine in dichloromethane, by using a combination of dielectric relaxation and NMR spectroscopy. In contrast to what one would expect for an acid-base titration, we find strong deviations from quantitative proton transfer from the acid to the base. Even for an excess of the base, multimers consisting of one base and at least two acid molecules are formed, in addition to the occurrence of proton transfer from the acid to the base and simultaneous formation of ion pairs. For equimolar mixtures such multimers constitute about one third of all intermolecular aggregates. Quantitative analysis of our results shows that the acid-base association constant is only around six times larger than that for the acid binding to an acid-base dimer, that is, to an already protonated base. Our findings have implications for the interpretation of previous studies of reactive intermediates in organocatalysis and provide a rationale for previously observed nonlinear effects in phosphoric acid catalysis.
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Project description:Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of ?1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (?CD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (?CD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-?CD to be twice as effective as HP?CD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with ?CDs are replicated with the safer and more effective ?CDs, clinical trials of adjuvant treatment with ?CDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HP?CD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.
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Project description:In this work, the nuclear magnetic resonance (NMR) and IR spectroscopic markers of the complexation between 5-fluorouracil (5-FU) and ?-cyclodextrin (?-CD) in solid state and in aqueous solution are investigated. In the attenuated total reflectance(ATR) spectra of 5-FU/?-CD products obtained by physical mixing, kneading and co-precipitation, we have identified the two most promising marker bands that could be used to detect complex formations: the C=O and C-F stretching bands of 5-FU that experience a blue shift by ca. 8 and 2 cm-1 upon complexation. The aqueous solutions were studied by NMR spectroscopy. As routine NMR spectra did not show any signs of complexation, we have analyzed the diffusion attenuation of spin-echo signals and the dependence of the population factor of slowly diffusing components on the diffusion time (diffusion NMR of pulsed-field gradient (PFG) NMR). The analysis has revealed that, at each moment, ~60% of 5-FU molecules form a complex with ?-CD and its lifetime is ca. 13.5 ms. It is likely to be an inclusion complex, judging from the independence of the diffusion coefficient of ?-CD on complexation. The obtained results could be important for future attempts of finding better methods of targeted anticancer drug delivery.
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Project description:Extensive characterization of the thermostable alpha-amylase of Clostridium thermosulfurogenes EM1, recently reclassified as Thermoanaerobacterium thermosulfurigenes, clearly demonstrated that the enzyme is a cyclodextrin glycosyltransferase (CGTase). Product analysis after incubation of the enzyme with starch revealed formation of alpha-, beta-, and gamma-cyclodextrins, as well as linear sugars. The specific activity for cyclization of this CGTase was similar to those of other CGTases, whereas the specific activity for hydrolysis was relatively high in comparison with other CGTases. Alignment of the amino acid sequence of the T. thermosulfurigenes enzyme with sequences from known bacterial CGTases showed high homology. The four consensus regions of carbohydrate-converting enzymes, as well as a C-terminal raw-starch binding motif, could be identified in the sequence.
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Project description:We studied the interaction between GroES and a single-ring mutant (SR1) of GroEL by the NMR titration of 15N-labeled GroES with SR1 at three different temperatures (20, 25 and 30°C) in the presence of 3 mM ADP in 100 mM KCl and 10 mM MgCl2 at pH 7.5. We used SR1 instead of wild-type double-ring GroEL to precisely control the stoichiometry of the GroES binding to be 1:1 ([SR1]:[GroES]). Native heptameric GroES was very flexible, showing well resolved cross peaks of the residues in a mobile loop segment (residue 17-34) and at the top of a roof hairpin (Asn51) in the heteronuclear single quantum coherence spectra. The binding of SR1 to GroES caused the cross peaks to disappear simultaneously, and hence it occurred in a single-step cooperative manner with significant immobilization of the whole GroES structure. The binding was thus entropic with a positive entropy change (219 J/mol/K) and a positive enthalpy change (35 kJ/mol), and the binding constant was estimated at 1.9×105 M-1 at 25°C. The NMR titration in 3 mM ATP also indicated that the binding constant between GroES and SR1 increased more than tenfold as compared with the binding constant in 3 mM ADP. These results will be discussed in relation to the structure and mechanisms of the chaperonin GroEL/GroES complex.
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Project description:Non-covalent interactions between molecules determine molecular recognition and the outcome of chemical and biological processes. Characterising how non-covalent interactions influence binding preferences is of crucial importance in advancing our understanding of these events. Here, we analyse the interactions involved in smell and specifically the effect of changing the balance between hydrogen-bonding and dispersion interactions by examining the complexes of the common odorant fenchone with phenol and benzene, mimics of tyrosine and phenylalanine residues, respectively. Using rotational spectroscopy and quantum chemistry, two isomers of each complex have been identified. Our results show that the increased weight of dispersion interactions in these complexes changes the preferred binding site in fenchone and sets the basis for a better understanding of the effect of different residues in molecular recognition and binding events.
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Project description:Cyclodextrin (CD) complexes are frequently used for enhancing the solubility or absorption of poorly water-soluble drugs. On the contrary, little is known about their complex formation with water-soluble drugs. Here, we have studied the interaction between 2-hydroxypropyl β-CD (HPβCD) and three water-soluble drugs, namely naloxone (NX), oxycodone (OC), and tramadol (TR), by isothermal titration calorimetry (ITC) combined with molecular modeling in view of the potential impact on drug release. The results showed that the complex formation of HPβCD with all three drugs occurs spontaneously. The complexes formed with NX and OC were found to be 2NX:1HPβCD and 3OC:2HPβCD, respectively. TR was found to form 2 complexes with HPβCD; of 1:2 and 1:1 complexation ratios. The binding of HPβCD to NX was greater than to OC due to the higher hydrophobicity of the structure of the former. Moreover, the binding affinity of HPβCD to TR was higher than to OC, which indicated the effect of the higher flexibility of the guest in increasing the binding affinity. In vitro drug release experiments from the various complexes revealed a significant impact of the stoichiometry of the complex on the release profiles. Accordingly, the co-administration of cyclodextrins with water-soluble drugs should be closely monitored, as it may result in unintentional complex formation that can potentially impact the drugs' gastrointestinal absorption.
| S-EPMC8410728 | biostudies-literature
Project description:Choline-based electrolytes have been proposed as environmentally friendly and low-cost alternatives for secondary zinc air batteries. Choline acetate [Ch]+ [OAc]- in protic (D2 O) and aprotic (DMSO-d6 ) solvents has been studied by means of concentration-dependent 1 H NMR, viscosity, and density measurements. The viscosities have been calculated on the basis of the Jones-Dole equation and showed that the dominant contribution originates from short-range ion-solvent interactions. Site-specific association affinities were assigned from NMR chemical shift titrations. In DMSO-d6 , the hydroxyl group of choline was found to have the smallest dissociation constant followed by the methyl group of acetate. The corresponding Gibbs energies at low concentration were found to be in agreement with a solvent-separated ion pair (2SIP) configuration, whereas at concentrations above 300 mM, a solvent-shared ion pair (SIP) configuration was assigned. For [Ch]+ [OAc]- in D2 O, association effects were found to be weaker, attributed to the high dielectric constant of the solvent. On time scales on the order of 100 ms, NMR linewidth perturbations indicated a change in the local rotational dynamics of the ions, attributed to short-range cation-solvent interactions and not to solvent viscosity. At 184 mM, ∼ 40 % of the cations in DMSO-d6 and ∼ 10 % in D2 O were found to exhibit short-range interactions, as indicated by the linewidth perturbations. It was found that at about 300 mM, the ions in DMSO-d6 exhibit a transition from free to collective translational dynamics on time scales on the order of 400 ms. In DMSO-d6 , both ions were found to be almost equally solvated, whereas in D2 O solvation of acetate was stronger, as indicated by the obtained effective hydrodynamic radii. For [Ch]+ [OAc]- in DMSO-d6 , the results suggest a solvent-shared ion association with weak H-bonding interactions for concentrations between 0.3-1 M. Overall, the extent of ion association in solvents such as DMSO is not expected to significantly limit charge transport and hinder the performance of choline-based electrolytes.
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