Modeling and characterization of lenalidomide-loaded tripolyphosphate-crosslinked chitosan nanoparticles for anticancer drug delivery.

Tripolyphosphate-crosslinked chitosan (TPPCS) nanoparticles were employed in the encapsulation of lenalidomide (LND) using a straightforward ionic cross-linking approach. The primary objectives of this technique were to enhance the bioavailability of LND and mitigate inadequate or overloading of hydrophobic and sparingly soluble drug towards cancer cells. In this context, a quantum chemical model was employed to elucidate the characteristics of TPPCS nanoparticles, aiming to assess the efficiency of these nanocarriers for the anticancer drug LND. Fifteen configurations of TPPCS and LND (TPPCS /LND1-15) were optimized using B3LYP density functional level of theory and PCM model (H2O). AIM analysis revealed that the high drug loading capacity of TPPCS can be attributed to hydrogen bonds, as supported by the average binding energy (168 kJ mol-1). The encouraging theoretical results prompted us to fabricate this drug delivery system and characterize it using advanced analytical techniques. The encapsulation efficiency of LND within the TPPCS was remarkably high, reaching approximately 87 %. Cytotoxicity studies showed that TPPCS/LND nanoparticles are more effective than the LND drug. To sum up, TPPCS/LND nanoparticles improved bioavailability of poorly soluble LND through cancerous cell membrane. In light of this accomplishment, the novel drug delivery route enhances efficiency, allowing for lower therapy doses.

An applied quantum-chemical model for genipin-crosslinked chitosan (GCS) nanocarrier.

The genipin-crosslinked chitosan (GCS) nanocarrier has received a lot of attention due to its unique biological and chemical properties as an effective drug delivery system. GCS was modeled by considering two chitosan (CS) polymer sequences with six monomer units that are crosslinked by genipin. To investigate the characteristics of this model, we considered it as a nanocarrier of the anti-cancer drug cladribine (2CdA). Seven configurations of GCS and 2CdA (GCS/2CdA1-7) were optimized at M06-2X/6-31G(d,p) in aqueous solution. The average binding energy above 100 kJ mol-1 indicates a high drug loading amount. The high adsorption of the drug on GCS is due to the hydrogen bonds that were investigated by AIM analysis. Hydrogen bonds also allow the drug to be released more slowly. These results were confirmed by experimental evidence and the comparison of this model with the simple model of one polymer chain. Also, the mechanism of GCS formation was investigated by calculating the activation parameters, which indicates that solvent (H2O) molecules are explicitly involved in the formation of GCS.

Surface functionalization of chitosan with 5-nitroisatin.

Several possible configurations (CS/NI1-10) for the surface adsorption of 5-nitroisatin (NI) on the chitosan polymer (CS) were investigated using quantum mechanical methods in the gas and solution phases. The values of the binding energies indicate the energetic stability of these configurations. The solvation energies demonstrate that the solubility of NI and CS increases in the presence of each other. The role of hydrogen bonds in noncovalent surface functionalization was determined by AIM analysis. The mechanism of covalent surface functionalization and the explicit solvent effects (methanol) in this mechanism were investigated and it was determined that the covalent functionalization through Schiff base formation is possible. These findings, in addition to the biological applications of the chitosan Schiff bases and their complexes, led us to synthesize a new Schiff base from condensation reaction of CS and NI (CSB) together with its Ni(II) and Cu(II) complexes. The synthesized compounds were characterized by the elemental analysis, infrared spectroscopy (IR), thermogravimetry analysis (TGA) and differential scanning calorimetry (DSC). Also, optimized geometries, assignment of the IR vibrational bands as well as exploring of the frontier orbitals of the synthesized compounds have been calculated using density functional levels of theory.

Mn(II) complex of a vitamin B6 Schiff base as an exclusive apoptosis inducer in human MCF7 and HepG2 cancer cells: Synthesis, characterization, and biological studies.

Herein, a Mn(II) complex of the N,N'-dipyridoxyl(1,4-butanediamine) (═H2 L) Schiff base has been newly synthesized. The synthesized complex was characterized by several experimental methods. In addition, the density functional theory approaches were used for theoretical identification of the complex. A good agreement between the computed and experimental infrared frequencies demonstrates validity of the optimized geometry for the synthesized complex. In a N2 O2 manner, two azomethine nitrogens and two phenolate oxygens of the L2- ligand are coordinated to the Mn2+ metal ion. The biological studies indicate an efficient apoptotic and antioxidant activities of the synthesized [MnL(CH3 OH)2 ] complex on both of the HepG2 and MCF7 cancer cells. Since it has been suggested that the complex is an exclusive potent antitumor for treatment of the human breast and liver cancers.

Anticancer Activities of Cu(II) Complex-Schiff Base and Low-Frequency Electromagnetic Fields and the Interaction Between Cu(II) Complex-Schiff Base with Bovine Serum Albumin by Spectroscopy.

Cancer is the consequence of abnormal cell proliferation, which leads to the formation of abnormal mass. In this study, we aimed to determine the anticancer properties of Cu(II)-Schiff base complex and low-frequency electromagnetic field, and the interaction between BSA and Cu(II) complex. Firstly, Schiff base of the Cu(II) complex in the N,N'-dipyridoxyl(1,2 diaminobenzene) was originally synthesized. Following, the breast cancer was transplanted with the TUBO cells in vivo. Then, treatment of the cancerous mice was done by low-frequency electromagnetic field and the Cu(II)-Schiff base complex. In this project, antiproliferative activity on breast cancer cells was tested by TUBO cells using MTT assay and apoptosis properties were studied by flow cytometry. The interaction between the Cu(II)-Schiff base complex and bovine serum albumin (BSA) was checked by fluorescence and UV-vis absorbance spectroscopy. Tumor tissue investigation demonstrated that the low-frequency electromagnetic field and Cu(II)-Schiff base complex induce apoptosis and inhibit tumor growth. MTT results unveiled a cytotoxic impact on breast cancer cells. Flow cytometry analysis demonstrates that the anticancer effect of Cu(II)-Schiff base complex on breast cancer cells (MCF7) was associated with the cell cycle arrest. The results of fluorescence spectra and UV-vis absorption spectra showed that the conformation of bovine serum albumin has been changed in the presence of Cu(II)-Schiff base complex. Cu(II)-Schiff base complex and low-frequency electromagnetic field have anticancer properties. The spectroscopy method indicates the binding between Cu(II)-Schiff base complex and BSA.

Study of alpha-amylase and gold nanoparticles interaction at two different temperatures through molecular dynamics.

The interaction of alpha-amylase with gold nanoparticles was studied at the two different temperatures of 25 and 75 °C through molecular dynamics simulation. To this end, 3-nm diameter spherical gold nanoparticles were designed. According to root mean square deviation results, at a high temperature, enzyme stability decreased in the absence of nanoparticles and increased in the presence of nanoparticles. Root mean square fluctuation results obtained for alpha-amylase residues indicated that the flexibility of residues 150-160 was affected more by the temperature in the presence and absence of nanoparticles. In addition, loop and helix regions in the secondary structure were affected more by the temperature. Results of enzyme contact maps in the designed systems showed that, in the absence of nanoparticles, a great number of contacts between residues were removed at high temperatures. The radius of gyration showed that the contact between the residues of amylase were removed in the absence of nanoparticles due to the enzyme expansion. Also Molecular dynamics simulation of α-amylase was performed in the presence of fifty 3- to 7-carbon sugar molecules at 25 and 75 °C. The results showed that the structure of α-amylase beta sheets is not affected by sugars. Docking of 3- to 7-carbon sugars with amylase sampled from simulations revealed that the affinity of sugars to the enzyme decreased at high temperatures in the absence of nanoparticles, while the presence of nanoparticles increased the affinity. Docking also showed that van der Waals and hydrophobic interactions contributed more than hydrogen interactions to the sugars-amylase interactions.

The effect of different alcohols on the Asp23-Lys28 and Asp23-Ala42 salt bridges of the most effective peptide in Alzheimer's disease: Molecular dynamics viewpoints.

The beta-amyloid peptide Aß1-42 is the most effective peptide in the process of forming plaque and creating Alzheimer's. After the separation of Aß1-42 from APP membrane protein, the membrane surface is transmitted to the extracellular environment, which is a crowded environment. On the other hand, stability of salt bridges Asp23-Lys28 and Lys28-Ala42 is important for monomer toxicity and fibrillation formation. In this work, the effects of ethanol, propanol, butanol, pentanol, hexanol, heptanol and octanol on the Asp23-Lys28 and Lys28-Ala42 salt bridges of the Aß1-42 have been investigated by molecular dynamics simulation. The radial distribution function of the oxygen atoms of the water around the atoms Cγ-Asp23, Nξ-Lys28 and O-Ala42 was calculated in the presence of the alcohols. The results show that the peak height of the radial distribution function around the Cγ-Asp23 atom is larger than the other two atoms. Also, the numbering of water molecules in the interval corresponding to the first peak in the radial distribution function for all atoms involved in the two salt bridges Asp23-Lys28 and Lys28-Ala42 was calculated. The results show that the obtained coordinate numbers are within the range of experimental numbers reported for water. The results also show that the order of water molecules around the O-Ala42 is lower. The results of solvent accessible surface area of Aß1-42 show that the Lys28-Ala42 Salt bridge stability is more important for toxicity of monomer.

Treatment of the breast cancer by using low frequency electromagnetic fields and Mn(II) complex of a Schiff base derived from the pyridoxal.

The breast cancer is the most common type of cancer in women. In this project, the breast cancer was transplanted in vivo with the TUBO cells. Then, the cancerous mice were treated by radiation of low frequency electromagnetic fields and injection of the Mn(II) complex of the N,N'-dipyridoxyl(1,2-diaminobenzene) Schiff base. Three different concentrations of the Mn(II) complex were used. Cytotoxicity and morphological alterations caused by the Mn(II) complex in the TUBO breast cancer cell line have been evaluated. Apoptotic properties of the Mn(II) complex was studied using the flow cytometry. The Mn(II) complex has a cytotoxic effect on cancer cells. Also, both of the Mn(II) complex and low frequency electromagnetic field induced apoptosis, which was confirmed by flow cytometry. Both of them result in considerable changes in the treated tissues such as decrease of the tumor mass, induction of apoptosis and decrease in number of the blood vessels.

Does high pressure have any effect on the structure of alpha amylase and its ability to binding to the oligosaccharides having 3-7 residues? Molecular dynamics study.

Studies have shown that deletion of amino acids from the C-terminus of amylase do not alter its amylolytic activity. Although high pressure is used to modify the structure and function of this enzyme, the effects of high pressures on the structures of the wild-type and truncated amylases have not yet been understood at the molecular level. Using molecular dynamic simulations and docking, we studied the structures of wild-type and truncated Taka-amylases at high pressures (1000-4000 bar). To construct the truncated Taka-amylase, 50 and 100 C-terminal residues were removed in two separate steps. Results of simulation showed that, although the overall shape partly agglomerates with rise in pressure, high pressure fails to modify the structure of the barrel-like region of the ß-sheet in the wild-type and truncated enzymes. A comparison of contact graphs revealed that the changes at the N-terminus were less extensive than those at the C-terminus. Further analysis showed that 10 regions of the secondary structures changed due to pressure change in wild-type amylase, of which 6 regions were associated with the loops and 4 with helix, while the structure of ß-sheets remained unchanged. The docking of maltotriose, maltotetraose, maltopentaose, maltohexaose, and maltoheptaose with the averaged structures obtained from different simulations was conducted to characterize the influence of pressure on the activities of the wild-type and truncated enzymes. The results showed that maltoheptaose made hydrophobic contacts with residues Tyr238-Asp117-Tyr82-Leu166-Leu232-Tyr155 and hydrogen contacts with residues Asp233-Gly234-Asp206-Arg204-His296-Glu230. Similar results were obtained for other malto-oligosaccharides.

A DFT investigation of structure, spectroscopic properties and tautomerism of the anticonvulsant drug Lyrica.

The Lyrica (Pregabalin) is a novel anticonvulsant and neuropathic pain drug, which could exist as four possible conformers. Herein, employing density functional theory (DFT), and handling the solvent effects with the PCM model, the structural parameters, energetic behavior, natural bond orbital analysis (NBO), as well as tautomerism mechanization of the Lyrica are investigated. The L1 (-OH form) is the most stable conformer of the Lyrica, which can be tautomerized to the L5 (-NH form) tautomer. The tautomerism reaction includes an intramolecular-proton transfer, which affects considerably the structural parameters and atomic charges of the L1. The DFT-computed NMR chemical shifts and IR vibrational frequencies are good in agreement with the experimental values, confirming suitability of the optimized geometry for the Lyrica.

N,N'-dipyridoxyl Schiff bases: synthesis, experimental and theoretical characterization.

Three N,N'-dipyridoxyl Schiff bases (L1, L2 and L3) have been newly synthesized and characterized by IR, (1)H NMR, mass spectrometry and elemental analysis. Their optimized geometries together with the theoretical assignment of the vibrational frequencies and the (1)H NMR chemical shifts of them have been computed by using density functional theory (DFT) method. In the optimized structures of the Schiff bases, two pyridine rings are not in a same plane; however the substitutions are essentially in the same plane with the pyridine rings. Also, the benzene ring(s) in the bridge region is (are) not in the same plane with the pyridine rings and azomethine moieties. In all the species, engagement in intramolecular-hydrogen bonds causes to weakness of the phenolic O-H bonds. Consistency between the theoretical results and experimental evidence confirms suitability of the optimized geometries for the synthesized Schiff bases.

Synthesis, experimental and theoretical characterization of N,N'-dipyridoxyl (1,4-butanediamine) Schiff-base ligand and its Cu(II) complex.

A new N,N'-dipyridoxyl(1,4-butanediamine) [=H(2)BS] Schiff-base ligand and its Cu(II) salen complex, [Cu(BS)(H(2)O)(CH(3)OH)], were synthesized and characterized by IR, UV-vis, (1)H NMR, mass spectrometry and elemental analysis. Also, full optimization of the geometries, (1)H NMR chemical shifts (for the H(2)BS) and vibrational frequencies were calculated by using density functional theory (DFT) method. Structure of the H(2)BS ligand is not planar, i.e. two pyridine rings are not in the same plane. In the structure of the Cu complex, the Schiff-base ligand acts as a dianionic tetradentate ligand in N, N, O(-), O(-) manner. The coordinating atoms of BS(2-) occupy equatorial positions of the octahedral complex, where the H(2)O and CH(3)OH ligands locate at axial positions. The calculated results are in good agreement with the experimental data, confirming the suitability of the proposed and optimized structures for the H(2)BS ligand and its Cu complex.

Synthesis, experimental and theoretical characterization of tetra dentate N,N'-dipyridoxyl (1,3-propylenediamine) salen ligand and its Co(III) complex.

The new tetra dentate dianionic H2PS (N,N'-dipyridoxyl (1,3-propylenediamine)) Schiff-base ligand and its octahedral Co(III) salen complex [Co(PS)(H2O)(CH3OH)]+CH3COO(-) were synthesized, where coordinating atoms of H2PS (N,N,O(-),O(-)) occupied equatorial positions with H2O and CH3OH as axial ligands. The nature of the H2PS and its complex were determined by elemental and spectrochemical (IR, UV-vis, 1H NMR and Mass) analysis. Also, the fully optimized geometries and vibrational frequencies of them together with the 1H NMR chemical shifts of H2PS have been calculated using density functional theory (B3LYP) method. Obtained structural parameters are in good agreement with the experimental data reported for similar compounds. The calculated and experimental results confirmed the suggested structures for the ligand and complex.