Development and Validation of High-Throughput Bioanalytical Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Quantification of Newly Synthesized Antitumor Carbonic Anhydrase Inhibitors in Human Plasma

In the present study, a sensitive and fully validated bioanalytical high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the quantitative determination of three newly synthesized carbonic anhydrases inhibitors (CAIs) with potential antitumor activity in human plasma. The analytes and the internal standard (IS) were extracted using 1.5 mL acetonitrile from only 450 µL aliquots of human plasma to achieve the desired protein precipitation. Chromatographic separations were achieved on Phenomenex Kinetex^® C₁₈ column (100 × 4.6 mm, 2.6 µm) using a binary gradient elution mode with a run time of less than 6 min. The mobile phase consisted of solvent (A): 0.1% formic acid in 50% methanol and solvent B: 0.1% formic acid in acetonitrile (30:70, v/v), pumped at a flow rate of 0.8 mL/min. Detection was employed using triple quadrupole tandem mass spectrometer (API 3500) equipped with an electrospray ionization (ESI) source in the positive ion mode. Multiple reaction monitoring (MRM) mode was selected for quantitation through monitoring the precursor-to-parent ion transition at m/z 291.9 → 173.0, m/z 396.9 → 225.1, m/z 388.9 → 217.0, and m/z 146.9 → 91.0 for AW-9a, WES-1, WES-2, and Coumarin (IS), respectively. Linearity was computed using the weighted least-squares linear regression method (1/x²) over a concentration range of 1–1000, 2.5–800, and 5–500 ng/mL for AW-9a, WES-1, and WES-2; respectively. The bioanalytical LC-MS/MS method was fully validated as per U.S. Food and Drug Administration (FDA) guidelines with all respect to linearity, accuracy, precision, carry-over, selectivity, dilution integrity, and stability. The proposed LC-MS/MS method was applied successfully for the determination of all investigated drugs in spiked human plasma with no significant matrix effect, which is a crucial cornerstone in further therapeutic drug monitoring of newly developed therapeutic agents.     

Medicinal Potential of Isoflavonoids: Polyphenols That May Cure Diabetes

In recent years, there is emerging evidence that isoflavonoids, either dietary or obtained from traditional medicinal plants, could play an important role as a supplementary drug in the management of type 2 diabetes mellitus (T2DM) due to their reported pronounced biological effects in relation to multiple metabolic factors associated with diabetes. Hence, in this regard, we have comprehensively reviewed the potential biological effects of isoflavonoids, particularly biochanin A, genistein, daidzein, glycitein, and formononetin on metabolic disorders and long-term complications induced by T2DM in order to understand whether they can be future candidates as a safe antidiabetic agent. Based on in-depth in vitro and in vivo studies evaluations, isoflavonoids have been found to activate gene expression through the stimulation of peroxisome proliferator-activated receptors (PPARs) (α, γ), modulate carbohydrate metabolism, regulate hyperglycemia, induce dyslipidemia, lessen insulin resistance, and modify adipocyte differentiation and tissue metabolism. Moreover, these natural compounds have also been found to attenuate oxidative stress through the oxidative signaling process and inflammatory mechanism. Hence, isoflavonoids have been envisioned to be able to prevent and slow down the progression of long-term diabetes complications including cardiovascular disease, nephropathy, neuropathy, and retinopathy. Further thoroughgoing investigations in human clinical studies are strongly recommended to obtain the optimum and specific dose and regimen required for supplementation with isoflavonoids and derivatives in diabetic patients.     

A simple microwave process for the preparation of cobalt oxide nanoparticles supported on carbon nanotubes for electrocatalytic applications

Journal of Solid State Electrochemistry - Cobalt oxide nanoparticles supported on multiwalled carbon nanotubes (CoOx/CNTs) were prepared by a facile and rapid solid-state synthesis using microwave...     

A new aliphatic ester of hydroxysalicylic acid from fermented Carica papaya L. preparation with a potential hair growth stimulating activity

Abstract

An aliphatic ester of hydroxysalicylic acid (6), reported for the first time from a natural source in addition to five known compounds were isolated from the fermented Carica papaya L. preparation, a commercialized functional food. The known compounds were identified as 5-hydroxymethylfurfuraldehyde (1), trans-caffeic acid (2), butyl 4-hydroxybenzoate (butylparaben) (3), lycopene (4), benzyl isothiocyanate (5). Compounds 1 and 3 were reported for the first time from Papaya fruits through this study. The new compound showed a moderate antioxidant activity and a potent hair growth stimulating activity in vitro.     

Stability of a general adaptive immunity virus dynamics model with multistages of infected cells and two routes of infection

This paper studies an (n+4)-dimensional nonlinear virus dynamics model that characterizes the interactions of the viruses, susceptible host cells, n-stages of infected cells, B cells and cytotoxic T lymphocyte (CTL) cells. Both viral and cellular infections have been incorporated into the model. The infected-susceptible and virus-susceptible infection rates as well as the generation and removal rates of all compartments are described by general nonlinear functions. Five threshold parameters are computed, which insure the existence of the equilibria of the model under consideration. A set of conditions on the general functions has been established, which is sufficient to investigate the global dynamics of the model. The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle's invariance principle. The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions.     

Acrolein and Copper as Competitive Effectors of α-Synuclein

Mounting evidence supports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by α-synuclein (αSyn) accumulation and aggregation in brain regions, also promoted by Cu²⁺. αSyn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper, and αSyn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on αSyn using an approach based on LC-MS/MS analysis. We also evaluated the influence of Cu²⁺ on the protein carbonylation and how the ACR modification impacts the Cu²⁺ binding and the production of Reactive Oxygen Species (ROS). Finally, we investigated the effects of ACR and Cu²⁺ ions on the αSyn aggregation by dynamic light scattering and fluorescence assays. Cu²⁺ regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu²⁺ and ACR inhibits αSyn aggregation both in the presence and in the absence of Cu²⁺.     

Facile one-pot,three-component synthesis of novel bis(heterocycles) incorporating thieno[2,3-b]thiophenes via Michael addition reaction

A synthesis of novel series of bis(2-amino-3-cyano-4H-chromene), bis(2-amino-3-cyanopyrano[3,2-c]chromene), bis(6-amino-5-cyano-1,4-dihydropyrano[2,3-c]pyrazole), and bis(2,7-diamino-3,4,6-tricyanopyrazolo[1,5-a]pyridine) derivatives linked to thieno[2,3-b]thiophene core via ether or ester linkages was reported. The formation of the target compounds presumably proceeds through a three component reaction of the appropriate bis(aldehyde) with 2 M of each of malononitrile and the corresponding active methylene compounds namely; dimedone, 4-hydroxycoumarine, 5-methyl-2,4-dihydro-3H-pyrazol-3-one, or cyanomethylpyrazole in dioxane at reflux in the presence of piperdine as a basic catalyst. The chemical structures of the new compounds were elucidated by several spectral tools.     

Synthesis of 5-oxo-5H-chromeno[3,4-c]pyridine-1-carbonitriles and features of their NMR spectra

Two different methods leading to 5-oxo-5H-chromeno[3,4-c]pyridine-1-carbonitriles were investigated. Reactions of 3-aminocrotonirile with substituted salicylaldehydes provided 5-oxo-5H-chromeno[3,4-c]pyridine-1-carbonitriles with the same substituent on positions 2 and 4 of the system. The reaction of 3-aminocrotonirile with variety of substituted 3-acetylcoumarins lead to 5-oxo-5H-chromeno[3,4-c]pyridine-1-carbonitriles with different substituents on positions 2 and 4. The structures of the products were confirmed by spectroscopic methods. The presence of nitrile moiety in the structures with fixed geometry caused the highly downfield shift of the aromatic proton at position 10 in ¹H NMR spectrum. The electronic factor of the substituents caused variation of this downfield shift.     

Effect of gemini surfactant additives on pour point depressant of crude oil

Efficiencies of cationic gemini surfactant additives in improving the pour point depressant of crude oil were investigated. The length of alkyl chain is a major factor affecting the improvement of the pour point depression. The adsorption behavior of these gemini surfactants at air/solution and oil/solution interfaces were investigated by measuring the surface tension and interfacial tension as functions of concentration. It is found that there is a good relation between surface properties especially interfacial tension of the gemini surfactants and their efficiency in depressing the pour point. Also, the surface parameters and free energies of micellization and adsorption confirm the decreasing and improving of pour point depression. Crystallization study in crude oil revealed the relationship between the structure and activity of gemini surfactant additives. It is found that the x-ray diffraction patterns of waxes with additives are remarkably different from those without additives. The mechanism of the depressants action has been suggested according the adsorption of each additive. Adsorption of the additive on the surface of the wax particles inhibits their growth and alters the crystal habits through micelle core. Pretreatment of the crude oil with pour point depressants has received the greatest acceptance due to its simplicity and economy.     

Critical Point of the 152Sm, 154Gd,and 156Dy Isotones

Physics of Atomic Nuclei - The even—even rare-earth nuclei in U(5)—SU(3) region at neutron number (N) = 90, have been systematically studied using the Bohr—Mottelson Model (BM),...