Design,Synthesis, Docking,DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC₅₀ value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC₅₀ values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.     

Eosin photodegradation over TiO2 modified by γ-ray irradiation

TiO₂ thin films are elaborated by sol gel on glass substrates and irradiated with ⁶⁰Co γ-rays. The X-ray diffraction, UV-Visible spectroscopy and transport properties are investigated. The films are nominally non stochiometric and the conductivity occurs by thermally activated hopping of lattice polaron. The oxygen vacancies induced by γ-ray irradiation at lower dose (<10 kGy) generate mixed valences Ti⁴⁺/³⁺, thus altering the transport properties. The photo-electrochemical characterisation is undertaken to evaluate the photo catalytic performance. The Mott-Schottky plots are characteristic of n type conduction from which a flat band potential of ?0.62 V _SCE and a donor density of 5 × 10¹⁷ cm^?3 are determined for the most active film. The Nyquist plot exhibits a semi-circular arc whose center lies below the real axis, due to the constant phase element (CPE). The energy band diagram shows the potentiality of the films for the eosin photodegradation. 68% of initial concentration (10 mg L^?1) disappears after 2 h of exposure to the solar light. TiO₂ irradiated with gamma dose of 10 kGy shows the best efficiency, due to the resistance decrees and high electron mobility (25 cm² V^?1 s^?1). The eosin oxidation follows a first order kinetic with a rate constant of 6 × 10^?2 min^?1.     

Antileukemic α-pyrone derivatives from the endophytic fungus Alternaria phragmospora

Four new (1–4) and two known (5 and 6) α-pyrone derivatives have been isolated from Alternaria phragmospora, an endophytic fungus from Vinca rosea, leaves. The isolated compounds were chemically identified to be 5-butyl-4-methoxy-6-methyl-2H-pyran-2-one (1), 5-butyl-6-(hydroxymethyl)-4-methoxy-2H-pyran-2-one (2), 5-(1-hydroxybutyl)-4-methoxy-6-methyl-2H-pyran-2-one (3), 4-methoxy-6-methyl-5-(3-oxobutyl)-2H-pyran-2-one (4), 5-(2-hydroxyethyl)-4-methoxy-6-methyl-2H-pyran-2-one (5), and 5-[(2E)-but-2-en-1-yl]-4-methoxy-6-methyl-2H-pyran-2-one (6). Compounds 2 and 4 showed moderate antileukemic activities against HL60 cells with IC₅₀ values of 2.2 and 0.9 μM and against K562 cells with IC₅₀ values of 4.5 and 1.5 μM, respectively.     

Polyethylene Glycol Functionalized Graphene Oxide Nanoparticles Loaded with Nigella sativa Extract: A Smart Antibacterial Therapeutic Drug Delivery System

Flaky graphene oxide (GO) nanoparticles (NPs) were synthesized using Hummer’s method and then capped with polyethylene glycol (PEG) by an esterification reaction, then loaded with Nigella sativa (N. sativa) seed extract. Aiming to investigate their potential use as a smart drug delivery system against Staphylococcus aureus and Escherichia coli, the spectral and structural characteristics of GO-PEG NPs were comprehensively analyzed by XRD, AFM, TEM, FTIR, and UV- Vis. XRD patterns revealed that GO-PEG had different crystalline structures and defects, as well as a higher interlayer spacing. AFM results showed GONPs with the main grain size of 24.41 nm, while GONPs–PEG revealed graphene oxide aggregation with the main grain size of 287.04 nm after loading N. sativa seed extract, which was verified by TEM examination. A strong OH bond appeared in FTIR spectra. Furthermore, UV- Vis absorbance peaks at (275, 284, 324, and 327) nm seemed to be correlated with GONPs, GO–PEG, N. sativa seed extract, and GO –PEG- N. sativa extract. The drug delivery system was observed to destroy the bacteria by permeating the bacterial nucleic acid and cytoplasmic membrane, resulting in the loss of cell wall integrity, nucleic acid damage, and increased cell-wall permeability.     

Molecular Cage Assembly by Sn−O−Sn Bridging of Di-, Tri- and Tetranuclear Organotin Tectons: Extending the Spacing in Double Ladder Structures

Hydrolysis reactions of di- and trinuclear organotin halides yielded large novel cage compounds containing Sn−O−Sn bridges. The molecular structures of two octanuclear tetraorganodistannoxanes showing double-ladder motifs, viz., [{Me₃SiCH₂(Cl)SnCH₂YCH₂Sn(OH)CH₂SiMe₃}₂(μ-O)₂]₂ [ 1 , Y=p-(Me)₂SiC₆H₄-C₆H₄Si(Me)₂] and [{Me₃SiCH₂(I)SnCH₂YCH₂Sn(OH)CH₂SiMe₃}₂(μ-O)₂]₂ ⋅ 0.48 I₂ [ 2⋅ 0.48 I₂, Y=p-(Me)₂SiC₆H₄-C₆H₄Si(Me)₂], and the hexanuclear cage-compound 1,3,6-C₆H₃(p-C₆H₄Si(Me)₂CH₂Sn(R)₂OSn(R)₂CH₂Si(Me)₂C₆H₄-p)₃C₆H₃-1,3,6 ( 3 , R=CH₂SiMe₃) are reported. Of these, the co-crystal 2⋅ 0.48 I₂ exhibits the largest spacing of 16.7 Å reported to date for distannoxane-based double ladders. DFT calculations for the hexanuclear cage and a related octanuclear congener accompany the experimental work.     

2-Hydroxyestradiol Overcomes Mesenchymal Stem Cells-Mediated Platinum Chemoresistance in Ovarian Cancer Cells in an ERK-Independent Fashion

Ovarian cancer (OC) is the second most common type of gynecological malignancy. Platinum (Pt)-based chemotherapy is the standard of care for OC, but toxicity and acquired chemoresistance has proven challenging. Recently, we reported that sensitivity to platinum was significantly reduced in a co-culture of OC cells with MSC. To discover compounds capable of restoring platinum sensitivity, we screened a number of candidates and monitored ability to induce PARP cleavage. Moreover, we monitored platinum uptake and expression of ABC transporters in OC cells. Our results showed that 2-hydroxyestradiol (2HE2), a metabolite of estradiol, and dasatinib, an Abl/Src kinase inhibitor, were significantly effective in overcoming MSC-mediated platinum drug resistance. Dasatinib activity was dependent on ERK1/2 activation, whereas 2HE2 was independent of the activation of ERK1/2. MSC-mediated platinum drug resistance was accompanied by reduced intracellular platinum concentrations in OC cells. Moreover, MSC co-cultured with OC cells resulted in downregulation of the expression of cellular transporters required for platinum uptake and efflux. Exposure to 2HE2 and other modulators resulted in an increase in intracellular platinum concentrations. Thus, 2HE2 and dasatinib might act as sensitizers to restore platinum drug sensitivity to OC cells and thus to limit TME-mediated chemoresistance in OC.     

Effect of 1-Aminoanthracene (1-AMA) Binding on the Structure of Three Lipocalin Proteins,the Dimeric β Lactoglobulin,the Dimeric Odorant Binding Protein and the Monomeric α<Subscript>1</Subscript>-Acid Glycoprotein. Fluorescence Spectra and Lifetimes Studies

We studied effect of 1-aminoanthracene (1-AMA) binding on the structures of dimeric β lactoglobulin, dimeric odorant binding protein (OBP) and monomeric α₁-acid glycoprotein (lipocalin family proteins) by monitoring fluorescence excitation spectra and measuring fluorescence lifetimes of the tryptophan residues of the proteins. Results show that binding of 1-AMA to β lactoglobulin and OBP modifies their conformation even at low probe concentration compared to that of the proteins. Structural modification induces a red shift of the fluorescence excitation spectra maximum of tryptophan residues accompanied with an increase of the third fluorescence lifetime and a decrease of its pre-exponential factor. These effects were not observed for α₁-acid glycoprotein, probably as the result of carbohydrate presence. These data raise doubts concerning use of 1-AMA as a probe to study biological properties of β lactoglobulin and OBP.     

Spaces of analytic functions represented by Dirichlet series of two complex variables

We consider the space X of all analytic functionsf(s1 ,s2) = ∞∑aminexp(s1λm+s2μtn)of two complex variables s1 and s2, equipping it with the natural locally convex topology and using thegrowth parmeter, the order of f as defined recently by the authors. Under this topology X becomes aFrechet space. Apart from finding the characterization of continuous linear functiors, linear transforma-tion on X, we have obtained the necesary and sufficient conditions for a double sequence in X to be a properbases.     

A matrix formulation for the dynamic analysis of planar mechanisms using point coordinates and velocity transformation

This paper presents a matrix formulation for the dynamic analysis of planar mechanisms consisting of interconnected rigid bodies. The formulation initially uses the rectangular Cartesian coordinates of an equivalent constrained system of particles to define the configuration of the mechanical system. This results in a simple and straightforward procedure for generating the equations of motion. The equations of motion are then derived in terms of relative joint coordinates through the use of a velocity transformation matrix. The velocity transformation matrix relates the relative joint velocities to the Cartesian velocities. For the open-loop case, this process automatically eliminates all of the non-working constraint forces and leads to an efficient integration of the equations of motion. For the closed-loop case, suitable joints should be cut and few cut-joints constraint equations should be included for each closed loop. Two examples are used to demonstrate the generality and efficiency of the proposed method.