Synthesis and EPR studies of porphyrazines with bulky substituents

Magnesium porphyrazinate substituted with eight 4-tert-butylphenylthio-groups on the peripheral positions has been synthesized by cyclotetramerization of 1,2-bis(4-tert-butylphenylthio)maleonitrile in the presence of magnesium butanolate. The metal-free derivative was obtained by its treatment with trifluoroacetic acid and further reaction of this product with copper(II) acetate, zinc(II) acetate and cobalt(II) acetate led to the metal porphyrazinates (M = Cu, Zn, Co). These new compounds have been characterized by elemental analysis, together with FT-IR, ¹H NMR, UV–Vis spectral data. By using EPR technique, room temperature paramagnetic properties of Cu(II) doped porphyrazine sample as powder and solution forms were measured. The first-derivative EPR signals taken from as powder and solution forms shows that the sample is axially symmetric. The trend g_∥ > g_⊥ > 2 indicates that the unpaired electron is located mainly in the _dx2-y2${\mathrm{d}}_{x^2-y^2}$ orbital (²B₁ as ground state).     

Detection of Variation in Long-Term Micropropagated Mature Pistachio via DNA-Based Molecular Markers

Determination of genetic stability of in vitro-grown plantlets is needed for safe and large-scale production of mature trees. In this study, genetic variation of long-term micropropagated mature pistachio developed through direct shoot bud regeneration using apical buds (protocol A) and in vitro-derived leaves (protocol B) was assessed via DNA-based molecular markers. Randomly amplified polymorphic DNA (RAPD), inter-simple sequence repeat (ISSR), and amplified fragment length polymorphism (AFLP) were employed, and the obtained PIC values from RAPD (0.226), ISSR (0.220), and AFLP (0.241) showed that micropropagation of pistachio for different periods of time resulted in “reasonable polymorphism” among donor plant and its 18 clones. Mantel’s test showed a consistence polymorphism level between marker systems based on similarity matrices. In conclusion, this is the first study on occurrence of genetic variability in long-term micropropagated mature pistachio plantlets. The obtained results clearly indicated that different marker approaches used in this study are reliable for assessing tissue culture-induced variations in long-term cultured pistachio plantlets.     

A multi-objective genetic algorithm for a bi-objective facility location problem with partial coverage

In this study, we present a bi-objective facility location model that considers both partial coverage and service to uncovered demands. Due to limited number of facilities to be opened, some of the demand nodes may not be within full or partial coverage distance of a facility. However, a demand node that is not within the coverage distance of a facility should get service from the nearest facility within the shortest possible time. In this model, it is assumed that demand nodes within the predefined distance of opened facilities are fully covered, and after that distance the coverage level decreases linearly. The objectives are defined as the maximization of full and partial coverage, and the minimization of the maximum distance between uncovered demand nodes and their nearest facilities. We develop a new multi-objective genetic algorithm (MOGA) called modified SPEA-II (mSPEA-II). In this method, the fitness function of SPEA-II is modified and the crowding distance of NSGA-II is used. The performance of mSPEA-II is tested on randomly generated problems of different sizes. The results are compared with the solutions of the most well-known MOGAs, NSGA-II and SPEA-II. Computational experiments show that mSPEA-II outperforms both NSGA-II and SPEA-II.     

Large scale free energy calculations for blind predictions of protein–ligand binding: the D3R Grand Challenge 2015

We describe binding free energy calculations in the D3R Grand Challenge 2015 for blind prediction of the binding affinities of 180 ligands to Hsp90. The present D3R challenge was built around experimental datasets involving Heat shock protein (Hsp) 90, an ATP-dependent molecular chaperone which is an important anticancer drug target. The Hsp90 ATP binding site is known to be a challenging target for accurate calculations of ligand binding affinities because of the ligand-dependent conformational changes in the binding site, the presence of ordered waters and the broad chemical diversity of ligands that can bind at this site. Our primary focus here is to distinguish binders from nonbinders. Large scale absolute binding free energy calculations that cover over 3000 protein–ligand complexes were performed using the BEDAM method starting from docked structures generated by Glide docking. Although the ligand dataset in this study resembles an intermediate to late stage lead optimization project while the BEDAM method is mainly developed for early stage virtual screening of hit molecules, the BEDAM binding free energy scoring has resulted in a moderate enrichment of ligand screening against this challenging drug target. Results show that, using a statistical mechanics based free energy method like BEDAM starting from docked poses offers better enrichment than classical docking scoring functions and rescoring methods like Prime MM-GBSA for the Hsp90 data set in this blind challenge. Importantly, among the three methods tested here, only the mean value of the BEDAM binding free energy scores is able to separate the large group of binders from the small group of nonbinders with a gap of 2.4 kcal/mol. None of the three methods that we have tested provided accurate ranking of the affinities of the 147 active compounds. We discuss the possible sources of errors in the binding free energy calculations. The study suggests that BEDAM can be used strategically to discriminate binders from nonbinders in virtual screening and to more accurately predict the ligand binding modes prior to the more computationally expensive FEP calculations of binding affinity.     

Synthesis of 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitriles: in vitro anticancer activity against MCF-7, PC-3 and A2780 cancer cell lines

A series of 2-(2,3,4-trimethoxyphenyl)-1-(substituted-phenyl)acrylonitrile (2–9) were designed and synthesized to develop new cancer drugs. The structures of synthesized compounds 2–9 were described by using melting point, mass (MALDI-TOF-MS), FT-IR, elemental analysis, ¹H, ¹³C, ¹³C-APT and 2D NMR spectroscopy. The in vitro anticancer activities of 2–9 against human breast cancer (MCF-7), human prostate cancer (PC-3) and human ovarian cancer cells (A2780) were investigated by [3-(4,5-dimethylthiazol)-2-yl]-2,5-diphenyl-2H-tetrazolium bromide] (MTT) assay method. Additionally, the LogIC₅₀ values of these compounds on A2780, MCF-7 and PC-3 cell lines were calculated by using inhibition % values by the GraphPad Prism 6 program on a computer. The results indicated that these compounds have high anticancer activity against MCF-7, PC-3 and A2780 cell lines (especially A2780 cell lines, p < 0.05).     

Exact solutions of nonlinear Schrödinger equation by using symbolic computation

The (G′/G,1/G)‐expansion method and (1/G′)‐expansion method are interesting approaches to find new and more general exact solutions to the nonlinear evolution equations. In this paper, these methods are applied to construct new exact travelling wave solutions of nonlinear Schrödinger equation. The travelling wave solutions are expressed by hyperbolic functions, trigonometric functions and rational functions. It is shown that the proposed methods provide a powerful mathematical tool for solving nonlinear wave equations in mathematical physics and engineering. Copyright © 2015 John Wiley & Sons, Ltd.     

On the concept of exact solution for nonlinear differential equations of fractional‐order

In this article, the new exact travelling wave solutions of the nonlinear space‐time fractional Burger's, the nonlinear space‐time fractional Telegraph and the nonlinear space‐time fractional Fisher equations have been found. Based on a nonlinear fractional complex transformation, certain fractional partial differential equations can be turned into ordinary differential equations of integer order in the sense of the Jumarie's modified Riemann–Liouville derivative. The ‐expansion method is effective for constructing solutions to the nonlinear fractional equations, and it appears to be easier and more convenient by means of a symbolic computation system. Copyright © 2016 John Wiley & Sons, Ltd.     

Organic/inorganic interfaced field-effect transistor properties with a novel organic semiconducting material

A novel 1,3,4-oxadiazole-substituted benzo[b]triphenylene was synthesized by three-step synthetic procedure and OFET device design was successfully designed after theoretical calculations made using Gaussian software. For investigating the field-effect properties of designed organic electronic device, a SiO₂ (300 nm) was thermally grown on p-Si wafer at 1000 °C as a dielectric layer and gate, source and drain contacts have been deposited using Au metal with physical vapour deposition. 1,3,4-Oxadiazole-substituted benzo[b]triphenylene was spin coated on the source and drain electrodes of our device, forming organic/inorganic interfaced field-effect transistors. Surface morphology and thin film properties were investigated using AFM. All electrical measurements were done in air ambient. The device showed a typical p-type channel behaviour with increasing negative gate bias voltage values. Our results have surprisingly shown that the saturation regime of this device has high mobility (μ_FET), excellent on/off ratio (I_on/I_off), high transconductance (g_m) and a small threshold voltage (V_Th). The values of μ_FET, I_on/I_off, g_m and V_Th were found as 5.02 cm²/Vs, 0.7 × 10³, 5.64 μS/mm and 1.37 V, respectively. These values show that our novel organic material could be a potential candidate for organic electronic device applications in the future.     

Common system setup for the entire catalytic cycle of cytochrome P450(cam) in quantum mechanical/molecular mechanical studies

We describe a system setup that is applicable to all species in the catalytic cycle of cytochrome P450(cam). The chosen procedure starts from the X-ray coordinates of the ferrous dioxygen complex and follows a protocol that includes the careful assignment of protonation states, comparison between different conceivable hydration schemes, and system preparation through a series of classical minimizations and molecular dynamics (MD) simulations. The resulting setup was validated by quantum mechanical/molecular mechanical (QM/MM) calculations on the resting state, the pentacoordinated ferric and ferrous complexes, Compound I, the transition state and hydroxo intermediate of the C--H hydroxylation reaction, and the product complex. The present QM/MM results are generally consistent with those obtained previously with individual setups. Concerning hydration, we find that saturating the protein interior with water is detrimental and leads to higher structural flexibility and catalytically inefficient active-site geometries. The MD simulations favor a low water density around Asp251 that facilitates side chain rotation of protonated Asp251 during the conversion of Compound 0 to Compound I. The QM/MM results for the two preferred hydration schemes (labeled SE-1 and SE-4) are similar, indicating that slight differences in the solvation close to the active site are not critical as long as camphor and the crystallographic water molecules preserve their positions in the experimental X-ray structures.     

What is the active species of cytochrome P450 during camphor hydroxylation? QM/MM studies of different electronic states of compound I and of reduced and oxidized iron-oxo intermediates

We have investigated C-H hydroxylation of camphor by Compound I (Cpd I) of cytochrome P450cam in different electronic states and by its one-electron reduced and oxidized forms, using QM/MM calculations in the native protein/solvent environment. Cpd I species with five unpaired electrons (pentaradicaloids) are ca. 12 kcal/mol higher in energy than the ground state Cpd I species with three unpaired electrons (triradicaloids). The H-abstraction transition states of pentaradicaloids lie ca. 21 (9) kcal/mol above the triradicaloid (pentaradicaloid) reactants. Hydroxylation via pentaradicaloids is thus facile provided that they can react before relaxing to the ground-state triradicaloids. Excited states of Cpd I with an Fe(V)-oxo moiety lie more than 20 kcal/mol above the triradicaloid ground state in single-point gas-phase calculations, but these electronic configurations are not stable upon including the point-charge protein environment which causes SCF convergence to the triradicaloid ground state. One-electron reduced species (Cpd II) show sluggish reactivity compared with Cpd I in agreement with experimental model studies. One-electron oxidized species are more reactive than Cpd I but seem too high in energy to be accessible. The barriers to hydrogen abstraction for the various forms of Cpd I are generally not affected much by the chosen protonation states of the Asp297 and His355 residues near the propionate side chains of the heme or by the appearance of radical character at Asp297, His355, or the propionates.