Anticoagulant, Antiherpetic and Antibacterial Activities of Sulphated Polysaccharide from Indian Medicinal Plant Tridax procumbens L. (Asteraceae)

The sulphated polysaccharide from the widespread Tridax procumbens plant was studied for the anticoagulant, antiherpetic and antibacterial activity. The anticoagulant activity was determined by the activated partial thromboplastin time assay. The sulphated polysaccharide from T. procumbens represented potent anticoagulant reaching the efficacy to heparin and chondroitin sulphate. Moreover, the sulphated polysaccharide extracted from T. procumbens was found non-toxic on Vero cell lines up to the concentration of 200 μg/ml. Sulphated polysaccharide exhibited detectable antiviral effect towards HSV-1 with IC(50) value 100-150 μg/ml. Furthermore, sulphated polysaccharide from T. procumbens was highly inhibitory against the bacterial strains Vibrio alginolyticus and Vibrio harveyi isolated from oil sardine.     

Investigation of the solvent effect,molecular structure,electronic properties and adsorption mechanism of Tegafur anticancer drug on Graphene nanosheet surface as drug delivery system by molecular dynamics simulation and density functional approach

To understanding the adsorption mechanism and the induced effects of an anticancer drug, Tegafur molecule, on the surface of Graphene nanosheet (GNS) as a drug delivery system, we have performed density functional theory (DFT) and molecular dynamics (MD) methods. DFT calculations give valuable information on the structure, orientation, adsorption energy and charge transfer of nanosheet-molecule in the equilibrium GNS-Tegafur complexes in the gas phase as well as in the aqueous phase, i.e., water. The optimization of GNS-Tegafur geometries shows that drug molecule tends to adsorb via its six-membered aromatic ring to the hexagonal ring of Graphene nanosheet by π–π stacking interaction at the most stable physisorption configuration. Furthermore, the calculated solvation energy (E_sol) represented by a polarizable continuum model show the significant increase in the solubility of GNS after drug adsorption on its surface in the presence of H₂O solvent which leading to the possible applications of GNS in the drug delivery systems. MD simulation is also used to determine the effect of drug concentrations on dynamic properties of Tegafur adsorption on the GNS surfaces in the solution phase. Based on the obtained MD results, it is found that by increasing drug concentration, the van der Waals (vdW) interaction energy becomes more negative and the stabilities of the simulated complexes increase.     

Synthesis,pharmacological evaluation,and molecular modeling studies of novel isatin hybrids as potential anticancer agents

A novel series of isatin hybrids 5a-g was designed, synthesized, and characterized spectroscopically. The synthesized compounds were evaluated for their cytotoxic activity against the human breast cancer cell line (MCF-7) by in vitro MTT assay. Amongst the tested compounds, 5e compound bearing benzyl moiety at N₄ piperazine was found to be the most active with the promising IC₅₀ (12.47 µM). Moreover, the active compounds 5e and 5g were subjected to antitumor evaluation (in vivo) against Dalton’s ascitic lymphoma (DAL) cell line and the results suggested that the best active compound 5e can normalize the blood picture in comparison to the standard drug. An in silico molecular docking study using the crystal structure of Hsp90 protein described the role of significant protein–ligand interactions and revealed more insights into the binding mode. The drug-likeliness of the compounds was predicted based on Lipinski's rule of five and pharmacokinetic ADME parameters. Hence, the synthesized isatin hybrids could be novel starting point anticancer lead compounds demonstrating drug-like properties which can be explored further for anticancer drug discovery.     

Conformers,properties, and docking mechanism of the anticancer drug docetaxel: DFT and molecular dynamics studies

The conformational structures and properties of the anticancer drug docetaxel (DTX) are studied theoretically. A total of 3888 trial structures were initially generated by all combinations of internal single‐bond rotamers and screened with the B3LYP/3‐21G* method. A total of 31 unique conformers were further optimized at the B3LYP/6‐311G* method. Their relative energies, dipole moments, rotational constants, and harmonic vibrational frequencies were predicted. Single‐point relative energies were then determined at the M06‐L/6‐311G(2df,p) level. The UV spectrum of the lowest‐lying DTX conformer in methanol was investigated with the TD‐CAM‐B3LYP/6‐311 + G(2df,p) method. The 31 unique DTX structures are mainly docked at three different sites within β‐tubulin. Based on the results of molecular docking and double‐float MD simulations, the lowest‐lying DTX conformer consistently exhibits good docking performance with β‐tubulin. We identified the residues LYS299, ARG215, GLN294, LEU275, THR216, GLU290, PRO274, and THR276 on β‐tubulin as active sites forming a binding pocket responsible for locking DTX within β‐tubulin to make the combination more stable. The RMSD values show that the predicted complexes are favorable, and the SASA analysis shows that the hydrophilic properties of DTX are better than paclitaxel. © 2018 Wiley Periodicals, Inc.     

Effects of surface modifications on the physicochemical properties of iron oxide nanoparticles and their performance as anticancer drug carriers

Surface of iron oxide nanoparticles were modified with citric acid (CA), chitosan (CS) and folic acid conjugated chitosan (FA-g-CS), respectively. Their physicochemical properties, doxorubicin loading capacity, drug release patterns and in vitro cytotoxicity were comparatively studied.     

Electro-synthesis approach for some metal ion complexes derived from thiosemicarbazide; characterization,conformational, inhibitory simulation and Hirshfeld surface properties

Series of Co (II), Cu (II), Zn (II) and Sn (II) complexes derived from thiosemicarbazide ligand (HTSC), was synthesized by environmentally favorable method (electrochemical). All isolated complexes, were deliberately characterized by available analytical and spectral tools. The proposed molar ratio was 1:2 (M:L) as the only isolated one, beside the significant contribution for solvent molecules. The octahedral configuration was proposed for all complexes. Conformational analysis was implemented using advanced program to determine the best structural forms for complexes. Moreover, essential parameters were calculated to export important features for studied complexes. Meanwhile, Hirshfeld crystal surface properties, were interested to illustrate strength of packing interaction forces. Furthermore, distinction of site types inside the molecule and their H-donor or H-acceptor ability. Antimicrobial study was conducted against different microorganisms, to assert on the importance of new complexes in therapeutic field. Furthermore and to strengthen the study, the inhibition simulation was performed with respect to all complexes against selected pathogen proteins. Essential interaction data, were exported for each docking process, to classify inhibition efficiency. Co (II) and Cu (II) complexes were the complexes that played well in therapeutic simulation treatments against Bacillus subtilis (1bn8) and Candida albicans kinase (4c0t) proteins.     

Fluorescence spectral properties of the anticancer drug topotecan by steady-state and frequency domain fluorometry with one-photon and multi-photon excitation

Topotecan is an antitumor agent with activity against a variety of cancers. We examined the steady-state and time-resolved fluorescence spectral properties of topotecan with one- and two-photon excitation. Topotecan was found to display a high two-photon cross section near 20 GM for wavelengths within the fundamental output of a Ti:sapphire laser, 800-880 nm. In frozen solution the anisotropies of topotecan are near the theoretical maxima for one-photon and two-photon excitation with colinear electronic transitions. The intensity and anisotropy decays of topotecan fluorescence were found to be homogeneous (single exponentials) in phosphate-buffered saline and propylene glycol. The steady-state and time-resolved data indicate that topotecan binds to a double-helical DNA oligomer d(AT)10 resulting in increased anisotropies and multiexponential intensity and anisotropy decays. Subnanosecond components in the anisotropy decay of the DNA-topotecan complex suggest loose binding of the drug to DNA. Loose binding of topotecan to DNA is also revealed by accessibility of topotecan to collisional quenching by iodide.     

Synthesis,enzymes inhibitory properties and characterization of 2- (bis (4-aminophenyl) methyl) butan-1-ol compound: Quantum simulations,and in-silico molecular docking studies

In this study to be presented, the BAPMB molecule was synthesized and structurally characterized. All calculations were applied using the detailed DFT/B3LYP method with 6-311G (d, p) and SDD depended on the stable phase geometry of the molecule. Also, various HOMO-LUMO energy gaps, inter-orbital intramolecular interactions of the natural bond, and electro-static surface mapping actions were also realized. The molecule was characterized by NMR spectroscopic analysis. Besides, LC/MS data were acquired. In this analysis, fragment ions (m/z 168.9) of BAPMB were obtained as 137.8, 179.9, 198, 201.5, and 228.0 approximately. Also, molecular docking was performed while examining the exact binding site and binding mechanism of the ligand on the protein. In the study, glide scores in binding affinity with BAPMB – AChE, BAPMB – BChE, and BAPMB – GST, respectively; It was found to be −7.228 ​cal/mol, −7.205 ​cal/mol, −6.07 ​cal/mol and BAPMB - AChE was found to be more effective with receptor binding score. BAPMB was analyzed for its inhibition features counter AChE, BChE, and GST enzymes that exhibit effective inhibition. AChE, BChE, GST enzymes were powerfully inhibited by BAPMB. BChE showed excellent activity, particularly in comparison to standard tacrine. Eventually, AIM analysis was performed to search intermolecular interactions in the BAPMB compound.     

Photomutagenic properties of terfenadine as revealed by a stepwise photostability,phototoxicity and photomutagenicity testing approach

Administration of the second-generation antihistamine, terfenadine, is sometimes associated with photosensitivity and other skin reactions. To obtain information on its photoreactivity, we used a stepwise experimental approach involving tests for photostability, phototoxicity (PT) (mouse fibroblast cell line [3T3] neutral red uptake [NRU] test) and photomutagenicity (with standard Ames salmonella tester strains TA98, TA100 and TA102). Terfenadine was not phototoxic to cultured mammalian cells under the conditions used (i.e. 5000/161 mJ cm(-2) UVA-UVB). Natural sunlight and UV radiations caused considerable drug decomposition and formation of several photoproducts. Addition of the irradiated terfenadine solution (i.e. a mixture of photoproducts) to the tester did not significantly increase background mutation frequency. Irradiation of terfenadine coplated with the TA102 strain induced a clear-cut photomutagenic response, the magnitude of which was dependent upon the precursor compound concentration and the UV dose (212/7 to 339/11 mJ cm(-2) UVA-UVB). These findings demonstrate that in vitro terfenadine is photomutagenic in absence of PT. Further in vitro and in vivo studies are therefore needed to provide an adequate safety assessment of the photochemical genotoxicity--carcinogenicity potential of terfenadine. In the meantime, patients should be advised to avoid excessive exposure to sunlight.     

Synthesis, characterization and Stat3 inhibitory properties of the prototypical platinum(IV) anticancer drug, [PtCl3(NO2)(NH3)2] (CPA-7)

This paper describes a reinvestigation of the literature concerning the synthesis and structural characterization of the platinum(IV)-based anticancer drug known as CPA-7 and believed to be the compound fac-[PtCl3(NO2)(NH 3)2]. CPA-7 has previously been extensively investigated for its ability to control tumor cell growth by inhibition of Stat3 signaling, but very little information is available concerning its synthesis or spectroscopic properties. A reproducible synthetic route is shown to produce an active material which is characterized by IR and (1)H, (14)N, (15)N, and (195)Pt NMR spectroscopy, and single crystal X-ray crystallography. The freshly prepared drug is obtained as a single isomer which may in fact be fac- or mer-[PtCl3(NO2)(NH3)2], but recrystallization resulted in a disordered crystal containing approximately equal amounts of the two geometric isomers.     

In-silico profiling,design, molecular docking computation,and drug kinetic model evaluation of novel curcumin derivatives as potential anticancer agents

The alarming trend of leukemia cell lines that are multidrug-resistant has prompted scientists to scramble for effective new anticancer treatments. Therefore, it remains an intriguing scientific task to optimize curcumin by trying to introduce molecular alteration to its vital structure to improve the biological effect against the P388 cell line or get around resistance phenomena. Regardless of the wide range of medications that are now being studied, Prednisone remains the most important and efficient part of chemotherapy that the WHO recommends. This article discusses the QSAR-oriented model and in silico assessment of some potent curcumin derivatives' anticancer activity against the P388 cell line. The solidity and propensity for prediction of the model were ensured by using stringent validation procedures. The activity of these derivatives was shown to be unrelated to lipophilicity, while shorter N-N distances and short substituents result in quite bioactive molecules. This information was used to design potent molecules that demonstrate good quality as per the assessment based on the Lead-Like Soft rule is acceptable for drug-like molecules. Also, molecule d2 does not possess any toxic effects risk alerts, suggesting drug-adherent conduct. While Prednisone the reference drug has a toxicity risk alert in red, suggesting non-adherent conduct for Prednisone. Hence, the novel molecules are promising anticancer agents.     

New hints on the Ph-driven tautomeric equilibria of the topotecan anticancer drug in aqueous solutions from an integrated spectroscopic and quantum-mechanical approach

The equilibria between the different forms of the topotecan anticancer drug have been studied at moderately acidic and physiological pH by an integrated computational tool rooted in the density functional theory and its time-dependent extension together with the polarizable continuum model. The results allow an unbiased selection between the different possible tautomeric forms and provide invaluable complements to experimental data. The ultraviolet-visible topotecan spectrum, recorded at moderately acidic pH, is accurately reproduced only by TD-DFT computations including solvent effects. Comparison of the experimental and calculated bands of the UV-vis spectrum at physiological pH indicates the presence of an equilibrium among different forms that is tuned by the microenvironment embedding the drug. The quantitative agreement between TD-DFT/PCM computations and experiments allows the identification of unequivocal spectroscopic signatures for different forms of topotecan.     

A comprehensive approach to electro-orientation, electrodeformation, dielectrophoresis, and electrorotation of ellipsoidal particles and biological cells

Suspended cells may respond to AC polarization by orienting, deforming, moving or rotating. For modeling of ellipsoidal cells, a new dipole approach is proposed. Along each of the principal axis of the model, three finite elements of arbitrary but equal cross-sectional area for the interior, low conductive membrane shell and exterior are assumed. The length of the external medium elements is defined by influential radii which are related to the depolarizing factors. The model predicts the potential at the ellipsoid's surface leading to the induced dipole moment. The moment obtained is identical to the Laplace approach for homogeneous ellipsoids; in the single-shell case, it is slightly different. The reason is the constant shell thickness which overcomes the confocal thickness necessary for the Laplace solution. Expressions for electro-orientation, deformation, dielectrophoresis, and electrorotation are derived. In linearly and circularly polarized fields, different orientation spectra are predicted to occur. While in linearly polarized AC fields, particles are oriented along their axis of highest polarizability, in circularly polarized fields, the axis of lowest polarizability is oriented perpendicular to the plane of field rotation. Based on this finding, a new electro-orientation method is proposed. In dielectrophoresis and electrorotation, reorientations are predicted which lead to discontinuous spectra.     

A Virtual Active Compound Produced from the Negative Image of a Ligand-binding Pocket, and its Application to in-silico Drug Screening

We developed a new structure-based in-silico screening method using a negative image of a ligand-binding pocket and a multi-protein–compound interaction matrix. Based on the structure of the ligand pocket of the target protein, we designed a negative image, which consists of virtual atoms whose radii are close to those of carbon atoms. The virtual atoms fit the pocket ideally and achieve an optimal Coulomb interaction. A protein–compound docking program calculates the protein–compound interaction matrix for many proteins and many compounds including the negative image, which can be treated as a virtual compound. With specific attention to a vector of docking scores for a single compound with many proteins, we selected a compound whose score vector was similar to that of the negative image as a candidate hit compound. This method was applied to representative target proteins and showed high database enrichment with a relatively quick procedure.     

Determination of the chemical composition and antioxidant,anticancer, and antibacterial properties of essential oil of Pulicaria crispa from Saudi Arabia

Essential oils obtained from plants play critical roles in food and medicine. In this study, the phytochemical composition of Pulicaria crispa essential oil, and its antibacterial, antioxidant and anticancer properties were determined in vitro. The essential oil was extracted from the aerial parts of P. crispa through hydro-distillation using a Clevenger-type apparatus, and it was analyzed with GC-MS. The most dominant chemical constituents of the essential oil were sesquiterpenes (78.26%). The higher constituents were β-caryophyllene oxide (33.97%), modephene (23.34%), geranyl propionate (6.32%), geranyl isovalerate (6.74%), 4-cadinadiene (5%), humulene (4.05%), and β-caryophyllene (2.73%). The essential oil exhibited DPPH radical activity, and it exerted antibacterial effect against gram positive bacteria (Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. However, it had no antibacterial effect on gram negative bacteria (Pseudomonas aeruginosa, Shigella sonnei, Klebsiella pneumoniae and Escherichia coli). The P. crispa essential oil produced significant cytotoxic effects against Hep-G2, MCF-7, Coca-2, and HT-29 ?cells. The oil was most toxic to Hep-G2 cells, based on its IC₂₀ and IC₅₀ values. These results indicate that the essential oil from P. crispa has potent biological properties which can be useful in the food and pharmaceutical industries.     

Monitoring,and estimation of kinetic data,by piezoelectric impedance analysis,of the binding of the anticancer drug mitoxantrone to surface-immobilized DNA

A new method of monitoring drug binding to DNA, in real-time, by means of the piezoelectric quartz-crystal-impedance (PQCI) technique, is proposed. The method was used to monitor the binding of an anticancer drug, mitoxantrone (MX), to double-stranded calf-thymus DNA covalently immobilized on the thioglycollic acid-modified gold electrode surface of a quartz crystal. Optimum experimental conditions for the immobilization were established. The DNA-anchored piezoelectric sensor was in contact with MX solution. The time courses of the resonant frequency and the equivalent circuit characteristics of the sensor were also obtained during the study of DNA-drug binding. On the basis of the analysis of the multidimensional information provided by the PQCI technique the observed frequency decrease was mainly ascribed to the increase in the mass of the sensor surface resulting from the binding. The kinetics of the binding process were studied quantitatively by monitoring the frequency change with time and a piezoelectric response model for the binding was derived theoretically. The experimental data were fitted to the model and the binding and dissociation rate constants and the binding equilibrium constant were estimated to be 66.0+/-0.1 mol(-1) L s(-1), 1.4+/-0.1x10(-4) s(-1), and 4.71+/-0.07x10(5) mol(-1) L, respectively, at 37 degrees C.