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Abstract: The design, synthesis and characterization of a series of 1-alkyl-4-[(5,6-dimethoxy-1-indanone-2-yl)methylene]pyridinium halide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors for the treatment of Alzheimer’s disease were reported. The strategy for this synthesis was based on aldol condensation reaction between 4-pyridinecarboxaldehyde with 5,6-dimethoxy-1-indanone in the presence of NaOH in EtOH-H2O solution as the first step and N-alkylation reaction of the produced 5,6-dimethoxy-2-[(pyridin-4-yl)methylene]-1-indanone with various alkyl halides (R–X) in the second step. This reaction was carried out under reflux temperature in polar aprotic solvents such as acetone or acetonitrile. 1H and 13C NMR and FTIR spectroscopy along with CHN analysis were used to confirm the structure of our synthesized compounds. Biological activities including acetylcholinesterase and butyrylcholinesterase (BuChE) inhibitions for synthesized compounds were tested using the Ellman method. The results were compared with donepezil and galantamine, and among the synthesized compounds, the highest inhibitory activity with BuChE IC50= 0.55 μM was observed. Graphic abstract:

Background: Cancer stem cells (CSCs) are of great diagnostic importance due to their involvement in tumorigenesis, therapeutic resistance, metastasis and relapse. Method: In this work, a sensitive electrochemical cytosensor was successfully established to detect HT-29 colorectal cancer stem cells based on a nanocomposite composed of mesoporous silica nanoparticles (MSNs) and platinum nanoparticles (PtNPs) using a simple and fast electrodeposition technique on a glassy carbon electrode (GCE). Results: According to SEM images, the PtNPs nanoparticles formed on the MSNs substrate are about 100 nm. As expected, high-rate porosity, increased surface-to-volume ratio, provides appropriate local electron transfer rate and suitable platform for the efficient formation of PtNPs. These features allow direct and stable binding of biotinylated monoclonal antibody of CD133to streptavidin (Strep) and the subsequent availability of active sites for CSCs identification. Differential pulse voltammetry (DPV) results show that close interaction of CD133+cells with monoclonal antibodies reduces charge transfer and electrical current, as confirmed by square wave voltammogram (SWV). Based on the recorded current versus number of CSCs, we noted that our developed system can sense CSCs from 5 to 20 cells/5 μL. Conclusions: As a proof of concept, the designed nanobiocomposite was able to specifically detect CD133+cells compared to whole HT-29 cells before magnetic activated cell sorting (MACS) process.

Background: Developing high-performance sensing frameworks for diagnosing anaplastic changes is the subject of debate. The lack of on-time diagnosis in patients with suspicious cancers can affect the prognosis and survival rate. As a correlate, the emergence of de novo strategies for developing transducing frameworks has an inevitable role in advanced biosensing. The combination of green chemistry procedures with eco-friendly and biocompatible materials is of high desirability in this context. The synthesis of new biocompatible and cost-effective nanomaterials to meet the emerging needs of rising demands appeals to new synthetic methodologies. Methods: Here, we applied the electrochemical synthesis method to the fabrication of biocompatible and subtly governed Molybdenum trioxide/poly taurine nano-bio films to monitor human epidermal growth factor receptor-2 (HER-2) in sera from breast cancer patients. Morphological and elemental assessments were performed using a scanning electron microscope, energy-dispersive X-Ray spectroscopy, and dot mapping analyses. In addition, HER-2 immunohistochemistry (IHC) staining was performed on tissue samples, and data were compared to the values obtained by Molybdenum trioxide/poly taurine nano-bio films. Results: We also noted our platform is eligible for feasible, rapid, and specific determination of HER-2 factor in human samples. The method had a lower limit of quantification of 0.000001 ng/mL and a linear dynamic range between 0.1 ng/mL and 0.000001 ng/mL. IHC imaging showed that the degree of anaplastic changes in breast samples (intensity of HER-2 factor) was closely associated with the intensity of signals obtained by our developed immunosensor. Conclusions: According to the obtained desirable coordination with pathological studies, the designed biosensor has excellent capability to use as a reliable diagnostic tool in clinical laboratories. Graphical Abstract:

Aldehyde oxidase (AOX) is an important molybdenum-containing enzyme with high similarity with xanthine oxidase (XO). AOX involved in the metabolism of a large array of aldehydes and N-heterocyclic compounds and its activity is highly substrate-dependent. The aim of this work was to study the effect of five important phenothiazine drugs on AOX activity using benzaldehyde and phenanthridine as aldehyde and N-heterocyclic substrates, respectively. The effect of trifluperazine, chlorpromazine, perphenazine, thioridazine and promethazine on rat liver AOX was measured spectrophotometrically. To predict the mode of interactions between the studied compounds and AOX, a combination of homology modeling and a molecular docking study was performed. All phenothiazines could inhibit AOX activity measured either by phenanthridine or benzaldehyde with almost no effect on XO activity. In the case of benzaldehyde oxidation, the lowest and highest half-maximal inhibitory concentration (IC50) values were obtained for promethazine (IC50= 0.9 µM), and trifluoperazine (IC50= 3.9 µM), respectively; whereas perphenazine (IC50= 4.3 µM), and trifluoperazine (IC50= 49.6 µM) showed the strongest and weakest inhibitory activity against AOX-catalyzed phenanthridine oxidation, respectively. The in silico findings revealed that the binding site of thioridazine is near the dimer interference, and that hydrophobic interactions are of great importance in all the tested phenothiazines. The five studied phenothiazine drugs showed dual inhibitory effects on AOX activity towards aldehydes and N-heterocycles as two major classes of enzyme substrates. Most of the interactions between the phenothiazine-related drugs and AOX in the binding pocket showed a hydrophobic nature.

Background: Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein found constitutively active in many types of human malignancies, is considered to be a promising target for cancer therapy. Objective: In this study for the first time, a simple and accurate method has been developed for the determination of a STAT3 dimerization inhibitor called stattic in aqueous and plasma samples. Methods: A reverse-phase high-performance liquid chromatography (RP-HPLC) composed of C18 column as stationary phase, and the mixture of acetonitrile (60%) and water (40%) as mobile phase with a UV detection at 215 nm were applied for quantification of stattic. The developed method was validated by Food and Drug Administration (FDA) guideline. Results: The method provided a linear range between 1-40 and 2.5-40 µg mL-1 for aqueous and plasma samples, respectively, with a correlation coefficient of 0.999. The accuracy (as recovery) of the developed method was found to be between 95-105% for aqueous medium and 85-115% for plasma samples. The precision (as relative standard deviation) for aqueous and plasma samples was less than 6% and 15%, respectively. The sensitivity of the developed method based on FDA guideline was 1 µg mL-1 for aqueous and 2.5 µg mL-1 for plasma samples. Conclusion: These results show that the established method is a fast and accurate quantification for stattic in aqueous and plasma samples.

ABSTRACTIntroduction:Given the rising trend in medicinal chemistry strategy to reduce cytochrome P450-dependent metabolism, aldehyde oxidase (AOX) has recently gained increased attention in drug discovery programs and the number of drug candidates that are metabolized by AOX is steadily growing.Areas covered:Despite the emerging importance of AOX in drug discovery, there are certain major recognized problems associated with AOX-mediated metabolism of drugs. Intra- and inter-species variations in AOX activity, the lack of reliable and predictive animal models using the common experimental animals, and failure in the predictions of in vivometabolic activity of AOX using traditional in vitromethods are among these issues that are covered in this article. A comprehensive review of computational human AOX (hAOX) related studies are also provided.Expert opinion:Following the recent progress in the stem cell field, the authors recommend the application of organoids technology as an effective tool to solve the fundamental problems associated with the evaluation of AOX in drug discovery. The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods.

Background: Recently, biosensors have become popular analytical tools for small analytes due to their high sensitivity and wide analytical range. In the present work, development of a novel biosensing method based on tungsten disulfide quantum dots (WS2QDs)-Au for rapidly and selectively detecting c-Met protein is introduced. As a proof of concept, M13 bacteriophage-based biosensors were used for the electrochemical detection of c-Met protein as a colon cancer biomarker. Method: The M13 bacteriophage (virus), as the biorecognition element, was immobilized on glassy carbon electrodes which were modified by WS2QDs-functionalized gold nanoparticles. The stepwise presence of the WS2QDs, gold nanoparticles, and immobilized phage on glassy carbon electrodes were confirmed by scanning electron microscope (SEM) and square wave voltammetry (SWV) technique. Results: The designed biosensor was applied to measure the amount of c-Met protein in standard solutions, and consequently the desirable detection limit of 1 pg was obtained. Finally, as a proof of concept, the developed platform was used for the evaluation of c-Met protein in serum samples of colon cancer-suffering patients and the results were compared with the results of the common Elisa kit. Conclusions: As an interesting part of this study, some concentrations of the c-Met protein in colon cancer serum samples which could not be determined by Elisa, were easily analyzed by the developed bioassay system. The developed bioassay system has great potential to application in biomedical laboratories. Graphical Abstract:

Molybdenum hydroxylases, aldehyde oxidase and xanthine oxidase, are metalloflavoproteins that catalyze both oxidation and reduction of a broad range of drugs and other xenobiotics indicating the importance of these enzymes in drug oxidation, detoxification and activation. Both enzymes are also involved in some physiological processes and also the metabolism of some endogenous compounds which may indicate their important roles in in vivoconditions. Superoxide radical and hydrogen peroxide produced during molybdenum hydroxylases-catalyzed reactions may be relevant in various disease conditions. Therefore, the interference with the function of molybdenum hydroxylases could be of great importance. Flavonoids are a large group of polyphenolic compounds that are able to interfere with xanthine oxidase and aldehyde oxidase function. As flavonoids are consumed in high content in our daily life, their potential to interfere with molybdenum hydroxylases could be a serious concern for consumer safety. However, the subject has not received enough attention and has usually been overshadowed by that of cytochrome P450 as the most important drug metabolizing enzyme system. The present review focuses on the different aspects of flavonoids interaction with molybdenum hydroxylases considering literature published mainly in the last 2 decades. The review also provides insight into some research areas that may offer a great potential for future studies.

Background: In this label-free bioassay, an electrochemiluminescence (ECL) immunosensor was developed for the quantification of breast cancer using HER-2 protein as a metastatic biomarker. Method: For this purpose, the ECL emitter, [Ru(bpy)3]2+, was embedded into biocompatible chitosan (CS) polymer. The prepared bio-composite offered high ECL reading due to the depletion of human epidermal growth factor receptor 2 (HER-2) protein. Reduced graphene oxide (rGO) was used as substrate to increase signal stability and achieve greater sensitivity. For this, rGO was initially placed electrochemically on the glassy carbon electrode (GCE) surface by cyclic voltammetry (CV) technique. Next, the prepared CS/[Ru(bpy)3]2+biopolymer solution was coated on a drop of the modified electrode such that the amine groups of CS and the carboxylic groups of rGO could covalently interact. Using EDC/NHS chemistry, monoclonal antibodies (Abs) of HER-2 were linked to CS/[Ru(bpy)3]2+/rGO/GCE via amide bonds between the carboxylic groups of Ab molecules and amine groups of CS. The electrochemical behavior of the electrode was studied using different electrochemical techniques such as electrochemical impedance spectroscopy (EIS), differential pulse voltammetry (DPV) and square wave voltammetry (SWV) and also ECL tests. Results: After passing all optimization steps, the lower limit of detection (LLOQ) and linear dynamic range (LDR) of HER-2 protein were practically obtained as 1 fM and 1 fM to 1 nM, individually. Importantly, the within and between laboratory precisions were performed and the suitable relative standard deviations (RSDs) were recorded as 3.1 and 3.5%, respectively. Conclusions: As a proof of concept, the designed immunosensor was desirably applied for the quantification of HER-2 protein in breast cancer suffering patients. As a result, the designed ECL-based immunosensor has the capability of being used as a conventional test method in biomedical laboratories for early detection of HER-2 protein in biological fluids. Graphic Abstract:

Although phenanthridine has been frequently used as a specific substrate for the assessment of aldehyde oxidase activity, the use of this method is questionable due to a lower limit of detection and its validity for kinetic studies. In the present study, a novel sensitive multivariate calibration method based on partial least squares (PLS) has been developed for the measurement of aldehyde oxidase activity using phenanthridine as a substrate. Phenanthridine and phenanthridinone binary mixtures were prepared in a dynamic linear range of 0.1–30.0 μM and the absorption spectra of the solutions were recorded in the range of 210–280 nm in Sorenson's phosphate buffer (pH 7.0) containing EDTA (0.1 mM). The optimized PLS calibration model was used to calculate the concentration of each chemical in the prediction set. Hepatic rat aldehyde oxidase was partially purified and the initial oxidation rates of different concentrations of phenanthridine were calculated using the PLS method. The values were used for calculating Michaelis–Menten constants from a Lineweaver–Burk double reciprocal plot of initial velocity against the substrate concentration. The limits of detection for phenanthridine and phenanthridinone were found to be 0.04±0.01 and 0.03±0.01 μM (mean±SD, n=5), respectively. Using this method, the Km value for the oxidation of phenanthridine was calculated as 1.72±0.09 μM (mean±SD, n=3). Thus, this study describes a novel spectrophotometric method that provides a suitable, sensitive and easily applicable means of measuring the kinetics of phenanthridine oxidation by aldehyde oxidase without the need for expensive instrumentation.

In spite of over 40 years of clinical use of 6-mercaptopurine, many aspects of complex pharmacology and metabolism of this drug remain unclear. It is thought that 6-mercaptopurine is oxidized to 6-thiouric acid through 6-thioxanthine or 8-oxo-6-mercaptopurine by one of two molybdenum hydroxylases, xanthine oxidase (XO), however, the role of other molybdenum hydroxylase, aldehyde oxidase (AO), in the oxidation of 6-mercaptopurine and possible interactions of AO substrates and inhibitors has not been investigated in more details. In the present study, the role of AO and XO in the oxidation of 6- mercaptopurine has been investigated. 6-Mercaptopurine was incubated with bovine milk xanthine oxidase or partially purified guinea pig liver molybdenum hydroxylase fractions in the absence and presence of XO and AO inhibitor/substrates, and the reactions were monitored by spectrophotometric and HPLC methods. According to the results obtained from the inhibition sudies, it is more likely that 6-mercaptopurine is oxidized to 6-thiouric acid via6-thioxanthine rather than 8-oxo-6-mercaptopurine. The first step which is the rate limiting step is catalized solely by XO, whereas both XO and AO are involved in the oxidation of 6-thioxanthine to 6-thiouric acid.

Unfortunately, the original article was published with error in author names. The author names are corrected here by this correction paper. The original article has been corrected.

The vegetable leafminer, Liriomyza sativae Blanchard, is a key pest of vegetable and ornamental crops worldwide and is mainly controlled by insecticides. The toxicity of fenpropathrin on adult flies of F1 generation of six Iranian populations of the pest was assessed using the residual glass vial method. The bioassay results showed significant differences in susceptibility to fenpropathrin among the populations tested. Resistance ratios ranged from 5.09 to 28.32. The resistant populations were reared in the greenhouse under fenpropathrin pressure for 14 mo and then susceptibility of both larvae and adults of these strains to fenpropathrin was evaluated. The resistance levels significantly increased in these populations. Further study demonstrated that diethyl maleate and triphenyl phosphate had no synergistic effects on fenpropathrin, however, this compound was significantly synergized by piperonyl butoxide in all tested populations. S,S,S-tributyl phosphorotrithioate also showed a slight synergism with fenpropathrin. Enzyme assays for general esterases, glutathione S-transferases and monooxygenases were performed on adults and larvae of L. sativae. The activity of glutathione s-transferase in different resistant and susceptible strains was not significantly different. The activity of esterases in resistant strains was higher than the susceptible strain. Monooxygenase levels also were higher in resistant strains compared with the susceptible strain. Synergism and biochemical assays revealed that esterases and monooxygenases have a major role in resistance of L. sativae to fenpropathrin.