Switching Ion Binding Selectivity of Thiacalix[4]arene Monocrowns at Liquid-Liquid and 2D-Confined Interfaces.

Understanding the interaction of ions with organic receptors in confined space is of fundamental importance and could advance nanoelectronics and sensor design. In this work, metal ion complexation of conformationally varied thiacalix[4]monocrowns bearing lower-rim hydroxy (type I), dodecyloxy (type II), or methoxy (type III) fragments was evaluated. At the liquid-liquid interface, alkylated thiacalixcrowns-5(6) selectively extract alkali metal ions according to the induced-fit concept, whereas crown-4 receptors were ineffective due to distortion of the crown-ether cavity, as predicted by quantum-chemical calculations. In type-I ligands, alkali-metal ion extraction by the solvent-accessible crown-ether cavity was prevented, which resulted in competitive Ag+ extraction by sulfide bridges. Surprisingly, amphiphilic type-I/II conjugates moderately extracted other metal ions, which was attributed to calixarene aggregation in salt aqueous phase and supported by dynamic light scattering measurements. Cation-monolayer interactions at the air-water interface were monitored by surface pressure/potential measurements and UV/visible reflection-absorption spectroscopy. Topology-varied selectivity was evidenced, towards Sr2+ (crown-4), K+ (crown-5), and Ag+ (crown-6) in type-I receptors and Na+ (crown-4), Ca2+ (crown-5), and Cs+ (crown-6) in type-II receptors. Nuclear magnetic resonance and electronic absorption spectroscopy revealed exocyclic coordination in type-I ligands and cation-π interactions in type-II ligands.

Phenotyping placental oxygenation in Lgals1 deficient mice using 19F MRI.

Placental hypoperfusion and hypoxia are key drivers in complications during fetal development such as fetal growth restriction and preeclampsia. In order to study the mechanisms of disease in mouse models, the development of quantitative biomarkers of placental hypoxia is a prerequisite. The goal of this exploratory study was to establish a technique to noninvasively characterize placental partial pressure of oxygen (PO2) in vivo in the Lgals1 (lectin, galactoside-binding, soluble, 1) deficient mouse model of preeclampsia using fluorine magnetic resonance imaging. We hypothesized a decrease in placental oxygenation in knockout mice. Wildtype and knockout animals received fluorescently labeled perfluoro-5-crown-15-ether nanoemulsion i.v. on day E14-15 during pregnancy. Placental PO2 was assessed via calibrated 19F MRI saturation recovery T1 mapping. A gas challenge with varying levels of oxygen in breathing air (30%, 60% and 100% O2) was used to validate that changes in oxygenation can be detected in freely breathing, anesthetized animals. At the end of the experiment, fluorophore-coupled lectin was injected i.v. to label the vasculature for histology. Differences in PO2 between breathing conditions and genotype were statistically analyzed with linear mixed-effects modeling. As expected, a significant increase in PO2 with increasing oxygen in breathing air was found. PO2 in Lgals1 knockout animals was decreased but this effect was only present at 30% oxygen in breathing air, not at 60% and 100%. Histological examinations showed crossing of the perfluorocarbon nanoemulsion to the fetal blood pool but the dominating contribution of 19F MR signal is estimated at > 70% from maternal plasma based on volume fraction measurements of previous studies. These results show for the first time that 19F MRI can characterize oxygenation in mouse models of placental malfunction.

Crown-ether-mediated crystal structures of the glycosyltransferase PaGT3 from Phytolacca americana.

Uridine diphosphate glycosyltransferases (UGTs) are ubiquitous enzymes that are involved in the glycosylation of small molecules. As glycosylation improves the water solubility and stability of hydrophobic compounds, interest in the use of UGTs for the synthesis of glycosides of poorly soluble compounds is increasing. While sugar-donor recognition in UGTs is conserved with the presence of a plant secondary product glycosyltransferase (PSPG) motif, the basis of the recognition of the sugar acceptor and the regioselectivity of the products is poorly understood owing to low sequence identity around the acceptor-binding region. PaGT3, a glycosyltransferase from the plant Phytolacca americana, can glycosylate a range of acceptors. To illustrate the structure-function relationship of PaGT3, its crystal structure was determined. The sugar-donor and sugar-acceptor binding pockets in PaGT3 were recognized by comparison of its structure with those of other UGTs. The key feature of PaGT3 was the presence of longer loop regions around the hydrophobic acceptor-binding pocket, which resulted in a flexible and wider acceptor binding pocket. In this study, PaGT3 crystals were grown by co-crystallization with 18-crown-6 ether or 15-crown-5 ether. The crown-ether molecule in the asymmetric unit was observed to form a complex with a metal ion, which was coordinated on two sides by the main-chain O atoms of Glu238 from two molecules of the protein. The crown ether-metal complex resembles a molecular glue that sticks two molecules of PaGT3 together to enhance crystal growth. Thus, this result provides an insight into the substrate-recognition strategy in PaGT3 for the study of glycosyltransferases. Additionally, it is shown that crown ether-metal ion complexes can be used as a molecular glue for the crystallization of proteins.

Lipidated Polyaza Crown Ethers as Membrane Anchors for DNA-Controlled Content Mixing between Liposomes.

The ability to manipulate and fuse nano-compartmentalized volumes addresses a demand for spatiotemporal control in the field of synthetic biology, for example in the bottom-up construction of (bio)chemical nanoreactors and for the interrogation of enzymatic reactions in confined space. Herein, we mix entrapped sub-attoliter volumes of liposomes (~135 nm diameter) via lipid bilayer fusion, facilitated by the hybridization of membrane-anchored lipidated oligonucleotides. We report on an improved synthesis of the membrane-anchor phosphoramidites that allows for a flexible choice of lipophilic moiety. Lipid-nucleic acid conjugates (LiNAs) with and without triethylene glycol spacers between anchor and the 17 nt binding sequence were synthesized and their fusogenic potential evaluated. A fluorescence-based content mixing assay was employed for kinetic monitoring of fusion of the bulk liposome populations at different temperatures. Data obtained at 50 °C indicated a quantitative conversion of the limiting liposome population into fused liposomes and an unprecedently high initial fusion rate was observed. For most conditions and designs only low leakage during fusion was observed. These results consolidate LiNA-mediated membrane fusion as a robust platform for programming compartmentalized chemical and enzymatic reactions.

Crown Ethers as Transthyretin Amyloidogenesis Inhibitors.

Transthyretin (TTR) is a tetrameric protein found in human serum and associated with amyloid diseases. Because the tetramer dissociation and misfolding of the monomer precede amyloid fibril formation, development of a small molecule that binds to TTR and stabilizes the TTR tetramer is an efficient strategy for the treatment of amyloidosis. Here, we report our discovery of the anti-TTR amyloidogenesis activities of crown ethers. X-ray crystallographic analysis, binding assay, and chemical cross-linking assay showed that 4'-carboxybenzo-18C6 (4) stabilized the TTR tetramer by binding to the allosteric sites on the molecular surface of the TTR tetramer. In addition, 4 synergistically increased the stabilization activity of diflunisal, one of the most potent TTR amyloidogenesis inhibitors. These experimental evidences establish that 4 is a valuable template compound as an allosteric inhibitor of TTR amyloidogenesis.

Validation of an LC-MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study.

In this study, a simple and sensitive LC-MS/MS method was developed and validated for simultaneous determination of icotinib and its four circulating metabolites in human plasma. The analytes were extracted with acetonitrile and separated on a C18 column using 2 mm ammonium acetate containing 0.2% formic acid and acetonitrile as mobile phase. The analytes were introduced into the mass spectrometer via an electrospray ionization source operated in positive ion mode. Precursor-to-product transitions were optimized to be m/z 392.2 → 304.1 for icotinib, m/z 424.1 → 278.2 for M1 and M2, m/z 408.2 → 320.1 for M3, m/z 410.2 → 322.1 for M4 and m/z 394.4 → 278.1 for IS. The assay showed good linearity over the concentration ranges of 0.1-600 ng/mL for icotinib and 0.1-200 ng/mL for metabolites, with correlation coefficients >0.994 (r > 0.994). The LLOQ was 0.1 ng/mL for each analyte. The intra- and inter-day precisions (RSD) were ≤12.98% while the accuracy (RE) ranged from -8.76 to 12.01%. No significant matrix effect was observed. The validated method was successfully applied for the pharmacokinetic study of icotinib and its four circulating metabolites in human plasma after oral administration of icotinib at a single dose of 125 mg.

Tyrosine kinase inhibitor-induced IL-6/STAT3 activation decreases sensitivity of EGFR-mutant non-small cell lung cancer to icotinib.

Tyrosine kinase Inhibitors (TKIs) of epidermal growth factor receptor (EGFR) has considerably benefited for non-small cell lung carcinomas (NSCLC) harbor mutations in EGFR. However, the factors attenuating EGFR-TKI efficiency are obstacles to inhibit the proliferation of EGFR-mutant NSCLC cells successfully. Clarifying the insensitivity mechanisms of EGFR-TKI would help to develop new treatment strategy. In this study, the sensitivity of EGFR-mutant NSCLC cell lines, PC9 and HCC827, to icotinib was detected. Similar with other EGFR-TKIs such as gefitinib and erlortinib in previous research, the proliferation of two cell lines was apparently inhibited. However, we surprisingly found that contrast with the suppression of EGFR-AKT/ERK pathway, STAT3 was significantly activated in PC9 cells with the treatment of icotinib, but not in HCC827 cells. Further study confirmed that icotinib concomitantly induced IL-6 secretion and src activation in PC9 cells. Moreover, with the treatment of IL-6 neutralizing antibody or src inhibitor, dasatinib, icotinib-induced phosphorylation of STAT3 was reduced, as well as the sensitivity of PC9 to icotinib was also partially increased. Our results suggest that Src/IL-6/STAT3 bypass pathway is activated to maintain cell survival when the EGFR pathway was inhibited by TKIs, even in some EGFR-mutant NSCLC cells sensitive to TKIs. This finding provides a groundwork for potential combinatorial treatment with TKIs and Src or STAT3 inhibitor to improve icotinib sensitivity.

Structure-Driven Selection of Adaptive Transmembrane Na+ Carriers or K+ Channels.

Self-assembled alkyl-ureido-benzo-15-crown-5-ethers are selective ionophores for K+ cations, which are preferred to Na+ cations. The transport mechanism is determined by the optimal coordination rather than classical dimensional compatibility between the crown ether hole and the cation diameter. Herein, we demonstrate that systematic changes of the structure lead to unexpected modifications in the cation-transport activity and suffice to produce adaptive selection. We show that the main contribution to performance arises from optimal constraints on the conformational freedom, which are determined by the binding macrocycles, the nature of the hydrogen-bonding groups, and the hydrophobic tails. Simple changes to the flexible 15-crown-5-ether lead to selective carriers for Na+ . Hydrophobic stabilization of the channels through mutual interactions between lipids and variable hydrophobic tails appears to be an important cause of increased activity. Oppositely, restricted translocation is achieved when constrained hydrogen-bonded macrocyclic relays are less dynamic in a pore superstructure.

Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction.

Icotinib is the first self-developed small molecule drug in China for targeted therapy of non-small cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction of icotinib were limited. By identifying metabolite generated in human liver microsomes and revealing the contributions of major cytochromes P450 (CYPs) in the formation of major metabolites, the aim of the present work was to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A liquid chromatography/UV/high-resolution mass spectrometer method was developed to characterize the icotinib metabolites. The formation of 6 major metabolites was studied in recombinant CYP isozymes and human liver microsomes with specific inhibitors to identify the CYPs responsible for icotinib metabolism. The metabolic pathways observed in vitro are consistent with those observed in human. Results demonstrated that the metabolites are predominantly catalyzed by CYP3A4 (77%∼87%), with a moderate contribution from CYP3A5 (5%∼15%) and CYP1A2 (3.7%∼7.5%). The contribution of CYP2C8, 2C9, 2C19, and 2D6 is insignificant. Based on our observations, to minimize drug-drug interaction risk in clinic, coprescription of icotinib with strong CYP3A inhibitors or inducers must be weighed. CYP1A2, a highly inducible enzyme in the smoking population, may also represent a determinant of pharmacokinetic and pharmacological variability of icotinib, especially in lung cancer patients with smoking history.

Lipase-catalyzed synthesis of sucrose monoester: Increased productivity by combining enzyme pretreatment and non-aqueous biphasic medium.

Sucrose monocaprate was synthesized by carrying out a lipase-catalyzed transesterification in a non-aqueous biphasic medium. Vinyl caprate was mechanically dispersed into a solution of sucrose in DMSO. The use of DMSO allowed increasing sucrose concentration up to 0.7M (in DMSO). The denaturing effect of DMSO on lipase was avoided by pretreatment of lipase by pH adjustment in the presence of crown ether. This pretreatment maintained a significant catalytic activity which led to 0.2M sucrose monoester within 1h at 50°C, which represented higher productivity than already reported. Detailed structural characterization revealed that only monoester was recovered and the 2-O-acylated sucrose monocaprate was the major isomer in the final product.

Allosteric activation of midazolam CYP3A5 hydroxylase activity by icotinib - Enhancement by ketoconazole.

Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4. When co-incubated with selective CYP3A4 inhibitor CYP3cide or monoclonal human CYP3A4 inhibitory antibody in HLM, the activation was extended to ∼60%, suggesting CYP3A5 might be the isozyme involved. Further, the relative activation was enhanced to ∼270% in rhCYP3A5 in the presence of ketoconazole. The activation was substrate and pathway dependent and observed only in the formation of 1'-OH-midazolam, and not 4-OH-midazolam, 6ß-OH-testosterone, or oxidized nifedipine. The activation requires the presence of cytochrome b5 and it is only observed in the liver microsomes of dogs, monkeys, and humans, but not in rats and mice. Kinetic analyses of 1'-OH-midazolam formation showed that ICO increased the Vmax values in HLM and rhCYP3A5 with no significant changes in Km values. By adding CYP3cide with ICO to the incubation, the Vmax values increased 2-fold over the CYP3cide control. Addition of ketoconazole with ICO alone or ICO plus CYP3cide resulted in an increase in Vmax values and decrease in Km values compared to their controls. This phenomenon may be attributed to a new mechanism of CYP3A5 heterotropic activation, which warrants further investigation.

Investigation on the protein-binding properties of icotinib by spectroscopic and molecular modeling method.

Icotinib is a highly-selective epidermal growth factor receptor tyrosine kinase inhibitor with preclinical and clinical activity in non-small cell lung cancer, which has been developed as a new targeted anti-tumor drug in China. In this work, the interaction of icotinib and human serum albumin (HSA) were studied by three-dimensional fluorescence spectra, ultraviolet spectra, circular dichroism (CD) spectra, molecular probe and molecular modeling methods. The results showed that icotinib binds to Sudlow's site I in subdomain IIA of HSA molecule, resulting in icotinib-HSA complexes formed at ground state. The number of binding sites, equilibrium constants, and thermodynamic parameters of the reaction were calculated at different temperatures. The negative enthalpy change (ΔH(θ)) and entropy change (ΔS(θ)) indicated that the structure of new complexes was stabilized by hydrogen bonds and van der Waals power. The distance between donor and acceptor was calculated according to Förster's non-radiation resonance energy transfer theory. The structural changes of HSA caused by icotinib binding were detected by synchronous spectra and circular dichroism (CD) spectra. Molecular modeling method was employed to unfold full details of the interaction at molecular level, most of which could be supported by experimental results. The study analyzed the probability that serum albumins act as carriers for this new anticarcinogen and provided fundamental information on the process of delivering icotinib to its target tissues, which might be helpful in understanding the mechanism of icotinib in cancer therapy.

Macrocyclic Gd(3+) complexes with pendant crown ethers designed for binding zwitterionic neurotransmitters.

A series of Gd(3+) complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1) between a positively charged and coordinatively unsaturated Gd(3+) chelate and the carboxylate group of the neurotransmitters and 2) between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln(3+) ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7 mM(-1) s(-1) at 60 MHz, 310 K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by (1) H relaxometric titrations of the Gd(3+) complexes and by luminescence measurements on the Eu(3+) and Tb(3+) analogues at pH 7.4. The remarkable relaxivity decrease (≈80 %) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu(3+) complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved.

Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease.

In this report, we reasoned that non-covalent modification of amyloid beta (Aß) by crown ethers could inhibit its aggregation. We demonstrated that PiB-C, a conjugate PiB and crown ether, could significantly reduce the aggregation in vitro. Additionally, two-photon imaging showed that PiB-C could efficiently label Aß plaques and CAAs in AD mice.

Therapeutic effects and adverse drug reactions are affected by icotinib exposure and CYP2C19 and EGFR genotypes in Chinese non-small cell lung cancer patients.

BACKGROUND: The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite' exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. MATERIALS AND METHODS: 274 NSCLC patients who accepted 125 mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in 672 nd (4th week) and 1,680 th hours (10th week), and plasma was used to quantify the concentration of icotinib and blood cells were sampled to check the genotypes. Clinical data were also collected at the same time, including EGFR genotypes. Plasma concentrations were assessed by HPLC-MS/MS and genotype by sequencing. All data were analyzed through SPSS 17.0 and SAS 9.2. RESULTS: CYP 2C19 genotypes affected bio-transformation from icotinib to M24 and M26, especially in poor-metabolisers. Higher icotinib concentrations (>1000 ng/mL) not only increased patient PFS and OS but also reduced tumor metastasis. Patients with mutant EGFR experienced a higher median PFS and OS (234 and 627 days), especially those with the 19del genotype demonstrating higher PR ratio. Patients who suffered grade II skin toxicity had a higher icotinib exposure than those with grade I skin toxicity or no adverse effects. Liver toxic reactions might occur in patients with greater M20 and M23 plasma concentrations. CONCLUSIONS: CYP2C19 polymorphisms significantly affect icotinib, M24 and M26 exposure. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations.

Structural and energetic effects in the molecular recognition of acetylated amino acids by 18-crown-6.

Absolute 18-crown-6 (18C6) binding affinities of four protonated acetylated amino acids (AcAAs) are determined using guided ion beam tandem mass spectrometry techniques. The AcAAs examined in this work include: N-terminal acetylated lysine (N(α)-AcLys), histidine (N(α)-AcHis), and arginine (N(α)-AcArg) as well as side chain acetylated lysine (N(ε)-AcLys). The kinetic-energy-dependent cross sections for collision-induced dissociation (CID) of the (AcAA)H(+)(18C6) complexes are analyzed using an empirical threshold law to extract absolute 0 and 298 K (AcAA)H(+)-18C6 bond dissociation energies (BDEs) after accounting for the effects of multiple collisions, kinetic and internal energy distributions of the reactants, and unimolecular dissociation lifetimes. Theoretical electronic structure calculations are performed to determine stable geometries and energetics for neutral and protonated 18C6 and the AcAAs as well as the proton bound complexes of these species, (AcAA)H(+)(18C6), at the B3LYP/6-311+G(2d,2p)//B3LYP/6-31 G* and M06/6-311+G(2d,2p)//B3LYP/6-31G* levels of theory. For all four (AcAA)H(+)(18C6) complexes, loss of neutral 18C6 corresponds to the most favorable dissociation pathway. At elevated energies, products arising from sequential dissociation of the primary CID product, H(+)(AcAA), are also observed. Protonated N(α)-AcLys exhibits a greater 18C6 binding affinity than other protonated N(α)-AcAAs, suggesting that the side chains of Lys residues are the preferred binding sites for 18C6 complexation to peptides and proteins. N(α)-AcLys exhibits a greater 18C6 binding affinity than N(ε)-AcLys, suggesting that binding of 18C6 to the side chain of Lys residues is more favorable than to the N-terminal amino group of Lys.

Quantization of bovine serum albumin by fluorescence enhancement effects and corresponding binding of macrocyclic host-protein assembly.

The present paper reports the investigations on the spectroscopic behavior of the binary complexes of the dye aurintricarboxylic acid (ATA) with protein bovine serum albumin (BSA) and 18-crown 6 (CW) (ATA·BSA, ATA·CW) and the ternary complex ATA·CW·BSA by using UV-vis steady state and time resolved fluorescence spectroscopy. The primary aim of the work is to determine the protein (BSA) quantization by fluorescence enhancement method and investigate the 'enhancer' activity of crown ether (CW) on it to increase the resolution. Steady state and time resolved fluorescence measurements demonstrated how fluorescence intensity of ATA could be used for the determination of the protein BSA in aqueous solution. The binding of dye (probe/fluorescent medicinal molecule) with protein and the denaturing effect in the polar environment of acetonitrile of the dye protein complex act as drug binding as well as drug release activity. Apart from its basic research point of view, the present study also possesses significant importance and applications in the field of medicinal chemistry.

Synthesis of N-(2-chloro purin-6-yl) aza-18-crown-6 and its interaction with human serum albumin.

The synthesis of novel purine nucleosides-linked azacrown ethers in the C6 position, N-(2-chloro purin-6-yl) aza-18-crown-6 (NCPAC), was described. This new nucleoside analogue can be prepared from a series of N9-modified nucleosides and the method allows for new and easy modification of the nucleosides. The interaction between NCPAC and human serum albumin (HSA) was studied using molecular docking and fluorescence techniques. Thermodynamics revealed that the interaction was entropy driven with predominantly hydrophobic forces. From the observed Föster's-type fluorescence resonance energy transfer, the donor (Trp 214 in HSA) to acceptor (NCPAC) distance was calculated to be 3.6 nm. The conformational changes of HSA due to the interaction were investigated qualitatively from synchronous fluorescence spectra. Molecular docking studies were performed to obtain information on the possible residues involved in the interaction process.

Metabolite characterization of a novel anti-cancer agent, icotinib, in humans through liquid chromatography/quadrupole time-of-flight tandem mass spectrometry.

Icotinib is a novel anti-cancer drug that has shown promising clinical efficacy and safety in patients with non-small-cell lung cancer (NSCLC). At this time, the metabolic fate of icotinib in humans is unknown. In the present study, a liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (LC/Q-TOF MS) method was established to characterize metabolites of icotinib in human plasma, urine and feces. In addition, nuclear magnetic resonance (NMR) detection was utilized to determine the connection between side-chain and quinazoline groups for some complex metabolites. In total, 29 human metabolites (21 isomer metabolites) were characterized, of which 23 metabolites are novel compared to the metabolites in rats. This metabolic study revealed that icotinib was extensively metabolized at the 12-crown-4 ether moiety (ring-opening and further oxidation), carbon 15 (hydroxylation) and an acetylene moiety (oxidation) to yield 19 oxidized metabolites and to further form 10 conjugates with sulfate acid or glucuronic acid. To our knowledge, this is the first report of the human metabolic profile of icotinib. Study results indicated that significant attention should be paid to the metabolic profiles of NSCLC patients during the development of icotinib.

How far can a sodium ion travel within a lipid bilayer?

Analogues of a synthetic ion channel made from a helical peptide were used to study the mechanism of cation translocation within bilayer membranes. Derivatives bearing two, three, four, and six crown ethers used as ion relays were synthesized, and their transport abilities across lipid bilayers were measured. The results showed that the maximum distance a sodium ion is permitted to travel between two binding sites within a lipid bilayer environment is 11 Å.