The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats

The study was performed to evaluate whether magnesium sulfate could alter the degree of disruption of the blood-brain barrier (BBB) caused by hyperosmotic mannitol. Wistar adult female rats were infused with 25% mannitol into the left internal carotid artery. Each animal received intraperitoneally a 300 mg/kg loading dose of magnesium sulfate, dissolved in 0.9% saline, followed by a further 100 mg/kg dose. In the other group, intracarotid infusion of magnesium sulfate was performed at a dose of 150 mg/kg 10 min before mannitol administration. Evans blue (EB) dye was used as a marker of BBB disruption. The measured serum glucose and magnesium levels increased after mannitol and/or magnesium administration when compared with their initial values before treatment (P < 0.01). Water content of the left hemisphere was significantly increased by hyperosmotic mannitol (P < 0.01). The increased water content in the mannitol-perfused hemisphere was significantly decreased by magnesium treatment (P < 0.05). The content of EB dye in the mannitol-perfused hemisphere markedly increased when compared with the right hemisphere of the same brain (P < 0.01). The EB dye content in the mannitol-perfused hemisphere following both intraperitoneal and intraarterial administration of magnesium decreased when compared with mannitol alone (P < 0.01). We conclude that although magnesium sulfate administration by both intracarotid arterial and intraperitoneal routes attenuates BBB disruption caused by hyperosmolar mannitol, particularly intraperitoneal route of magnesium sulfate administration may provide a useful strategy to limit the transient osmotic opening of the BBB.     

Structural analysis,spectroscopic characterization and molecular docking studies of the cyclic heptapeptide

The theoretically possible stable conformer of the cyclic heptapeptide, that has significant anti-metastatic activity, was examined by conformational analysis followed by DFT calculations. Experimental infrared and Raman spectroscopy, together with theoretical DFT (6-31G (d,p) basis set)-based quantum chemical calculations, have been used to understand the structural and spectral characteristics of cyclo(Gly-Arg-Gly-Asp-Ser-Pro-Ala) {cyclo(GRGDSPA)}. A complete analysis of the vibrational spectrum has been reported on the basis of potential energy distribution (PED%) data of the vibrational modes. Finally, the calculation results were applied to simulate infrared and Raman spectra of the title compound. The simulated spectra satisfactorily coincide with the experimental spectra. In addition, molecular electrostatic potential and frontier molecular orbital analysis were investigated using theoretical calculations. The stability of the molecule, arising from hyperconjugative interaction and charge delocalization, has been analyzed using natural bond orbital analysis and a high E(2) value reveals the presence of strong interaction between donors and acceptors. Molecular docking studies with fibronectin were performed on cyclo(GRGDSPA) in order to understand its inhibitory nature. The results indicate that the docked ligand {cyclo(GRGDSPA)} forms a stable complex with human fibronectin and gives a binding affinity value of ?7.7 kcal/mol, which points out that cyclo(GRGDSPA) might exhibit inhibitory activity against the attachment of melanoma cells to human fibronectin.     

Synthesis,molecular docking and ADMET study of ionic liquid as anticancer inhibitors of DNA and COX-2, TOPII enzymes

Abstract

A new ionic liquid was synthesized by the reaction of caprolactam with salicylic acid (CL-SA) and characterized by analysis of spectroscopic and DSC data. The optimized geometry and the electrostatic potential map of CL-SA were calculated with DFT method using the wb97xd/6-31++G(d,p) level of theory. Molecular docking study of the CL-SA was carried out to clarify the probable binding modes between the title compound and DNA and COX-2 and TOPII enzymes. In silico ADMET study was also performed for predicting pharmacokinetic and toxicity profile of the synthesized ionic liquid which expressed good oral drug-like behavior and non-toxic nature. It was revealed that the compound has a potential to become a lead molecule in drug discovery process.

Communicated by Ramaswamy H. Sarma     

Antimicrobial,Antiproliferative Effects and Docking Studies of Methoxy Group Enriched Coumarin-Chalcone Hybrids

Methoxy group enriched eight coumarin-chalcone hybrid derivatives were synthesized. Antimicrobial/ antiproliferative activities were tested against eight human pathogenic microorganisms and four cancer cell lines (AGS, HepG2, MCF-7 and PC-3), respectively. Antimicrobial results showed that most of the compounds were almost more active than used standard antibiotics. Cytotoxicity results showed that 2,3,4-trimethoxyphenyl and thiophene containing structures have promising antiproliferative effects against AGS gastric cell lines with ∼5 μg/ml IC₅₀ values. At the same time, 2,4-dimethoxyphenyl bearing derivative exhibited the lowest IC₅₀ values against HepG2 (∼10 μg/ml) and PC-3 (∼5 μg/ml) cell lines. Particularly, the cell viabilities of MCF-7 cell lines were remarkably inhibited by all the compounds with lower IC₅₀ values. Therefore, molecular docking studies between hybrid ligands and quinone reductase-2 enzyme (regulates in MCF-7 cancer cells) were performed. The results demonstrated that all the derivatives can smoothly interact with interested enzyme in agreement with the experimental results. Finally, ADME parameters were studied to reveal drug-likeness potentials of the coumarin-chalcone hybrids.