Steric Energy Research Articles

Design, Synthesis and In Vitro Evaluation of 18β-Glycyrrhetinic Acid Derivatives for Anticancer Activity Against Human Breast Cancer Cell Line MCF-7

In the present work, QSAR model was derived by multiple linear regression method for the prediction of anticancer activity of 18β-glycyrrhetinic acid derivatives against the human breast cancer cell line MCF-7. The QSAR model for anti-proliferative activity against MCF-7 showed high correlation (r(2)=0.90 and rCV(2)=0.83) and indicated that chemical descriptors namely, dipole moment (debye), steric energy (kcal/mole), heat of formation (kcal/mole), ionization potential (eV), LogP, LUMO energy (eV) and shape index (basic kappa, order 3) correlate well with activity. The QSAR virtually predicted that active derivatives were first semi-synthesized and characterized on the basis of their (1)H and (13)C NMR spectroscopic data and then were in-vitro tested against MCF-7 cancer cell line. In particular, octylamide derivative of glycyrrhetinic acid GA-12 has marked cytotoxic activity against MCF-7 similar to that of standard anticancer drug paclitaxel. The biological assays of active derivative selected by virtual screening showed significant experimental activity.

Borontribromide-mediated C–C bond formation in cyclic ketones: a transition metal free approach

Borontribromide (BBr3) is a well-known demethylating agent. The current investigation was focused on a new application of borontribromide as a C–C bond forming agent in cyclic ketones. In this study, borontribromide mediated C–C bond formation reactions of tetralones, chromenone, thiochromenone and indanones were explored. A methoxy group containing ketones showed selective C–C bond formation reaction instead of demethylation of the methoxy group. MM2 steric energy calculations for the final products showed that the reaction favored the formation of exo- or endo-cyclic double bond containing products, depending upon their low MM2 steric energy in a specific frame structure, as observed in X-ray crystallography. A comprehensive crystallographic and pi-stacking analysis of product 10a demonstrated the formation of 10a as an enantiomeric mixture, and its centre of inversion was stabilized by a set of three unique pi–pi interactions.

Conformational Properties of 1-Halogenated-1-Silacyclohexanes, C5H10SiHX (X = Cl, Br, I): Gas Electron Diffraction, Low-Temperature NMR, Temperature-Dependent Raman Spectroscopy, and Quantum-Chemical Calculations

The molecular structures of axial and equatorial conformers of cyclo-C5H10SiHX (X = Cl, Br, I) as well as the thermodynamic equilibrium between these species was investigated by means of gas electron diffraction, dynamic nuclear magnetic resonance, temperature-dependent Raman spectroscopy, and quantum-chemical calculations applying CCSD(T), MP2, and DFT methods. According to the experimental and calculated results, all three compounds exist as a mixture of two chair conformers of the six-membered ring. The two chair forms of Cs symmetry differ in the axial or equatorial position of the X atom. In all cases, the axial conformer is preferred over the equatorial one. When the experimental uncertainties are taken into account, all of the experimental and theoretical results for the conformational energy (Eaxial – Eequatorial) fit into a remarkably narrow range of −0.50 ± 0.15 kcal mol–1. It was found by NBO analysis that the axial conformers are unfavorable in terms of steric energy and conjugation effects and that they are stabilized mainly by electrostatic interactions. The conformational energies for C6H11X and cyclo-C5H10SiHX (X = F, Cl, Br, I, At) were compared using CCSD(T) calculations. In both series, fluorine is predicted to have a lower conformational preference (cyclohexane equatorial, silacyclohexane axial) than Cl, Br, and I. It is predicted that astatine would behave very similarly to Cl, Br, and I within each series.

Numerical Simulations of Longitudinal Elastic Behavior of Single-Walled Carbon Nanotubes–Reinforced Polymer Nanocomposites

AbstractThe longitudinal elastic behavior of single-walled carbon nanotubes (SWCNTs) and SWCNT reinforced polymer nanocomposites are investigated. Finite-element (FE) models of SWCNTs and SWCNT reinforced polymer nanocomposites are developed utilizing a multiscale modeling technique along with molecular structural mechanics (MSM), which provides material properties at a molecular scale and establishes relations between the steric potential energy and classic structural mechanics. The mechanical behavior of SWCNT reinforced polymer nanocomposites is dictated by the mechanical behavior of the SWCNTs embedded in the polymer matrix. Furthermore, varying the radius and length of the SWCNTs affects the longitudinal elastic properties of the SWCNT reinforced polymer nanocomposites. Specifically, the simulation results demonstrated that longitudinal elastic properties of SWCNT reinforced polymer nanocomposites would vary due to different applied loading conditions, i.e., discrete and continuous.

Synthesis of some Thiadiazoline Derivatives from 2- Phenyl Chroman-4-one

2-Phenyl chroman-4-one 1(a-g) were synthesized by Pechmann condensation of proper phenol with cinnamic acid using poly phosphoric acid. Reactions of their derivatives with thiosemicarbazide were carried out using two methods, method A, using refluxing ethanol, gave low yield (17-20%). This method was modified to increase the yield using solvent free microwave irradiation technique, (method B), which improved the yield up to (30-40%). The treatment of these thiosemicabazones 2(a-g) with excess acetic anhydrid gave substituted thiadiazoline derivatives 3(a-g). The structures of these compounds was confirmed by IR, UV and NMR spectra in addition to their physical properties. On the other hand, the calculated values of the heat of formation and steric energy were established for compounds 2(a-g) and 3(a-g).

MM/QM study: Interactions of copper(II) and mercury(II) with food dyes in aqueous solutions

In this work we studied four azo dyes which are proposed for synthetic colorants in foods applications and named L 1 : Sunset Yellow, E110, L 2 : Tartrazin, E102, L 3 : Amaranth, E123, L 4 : Red Ponceau 4R, E124. In addition, electron density analysis has been carried out to highlight the possible strengths of interaction of these four azo dyes with metal ions. Density Functional Theory (DFT) was utilized, using the B3LYP functional and the 6-31G(d) basis set. This level of calculation was used to find the optimized molecular structure and to predict the molecular orbitals energies, dipole moment, Fukui function values f − k , locals nucleophilicity indexes N k and the chemical reactivity parameters that arise from Conceptual DFT. Also, the steric energies values from the four complexes were calculated with the EMO program using MM2 method. Complexes forms with mercury are easier to form and more stable than copper. These show that the mercury intoxication is faster than the copper, knowing that mercury is toxic even with low dose. For that, the men who carry amalgams, we advise may be avoid to eat food and drugs which contain azo dyes because there exists a high trend between these azo dyes and the metal ions which released by the amalgams.

Nature of the steric ΩS, ER and [formula omitted] substituent constants. Comparison with the aid of NBO and STERIC analysis

The nature of the major steric substituent constant scales for alkyl substituents, i.e. ΩS, ER and ES′ scales, was studied with the aid of the NBO and the natural steric (STERIC) analyses. Cyclohexyl esters R3CCOOC6H11 (R=alkyl or H) were used as the model compounds. Special emphasis was laid on the potential contribution of the polar component in these steric substituent parameters. In the light of our model the ΩS scale seems to be dominantly a steric substituent constant scale as is seen on the strengths of the good correlation between the ΩS constants of the CR3 group and the total steric exchange energy values ETSEE for the model compounds. However, the ΩS values also seem to include a minor electronic component due to the varying electrostatic effect via the Cα atom. On the other hand, ER and ES′ parameters largely hinge on the size dependent polar effect of the CR3 alkyl group. By way of our model this repulsive interaction can be quantified by descriptor ΔqOCO, the natural charge difference qC(CO)−ΣqO for the OC(O) functional group. ΔqOCO depends on the ETSEE values, on qCα and on the polarization coefficients of the oxygen hybrid in the NBO of the πCO bond. The size sensitivity of the kinetic ES′ constants can be connected to variation of the Bürgi–Dunitz angle in the transition state for the standard reaction used. A comparison is made for the qC(CO) or ΔqOCO values computed on the one hand with the NBO formalism and on the other hand with the Hirshfeld formalism. A practical novel substituent constant qC(CO) for the size of the alkyl groups is introduced.

Conformational analysis of retinoic acids: Effects of steric interactions on nonplanar conjugated polyenes

Retinoic acids and other vitamin A analogs contain a trimethylcyclohexenyl ring in conjugation with a polyene chain joined at carbon-6 (C6) and carbon-7 (C7). A MP2-SCS/cc-pVDZ//B3LYP/6-31G(d) 2-D potential energy surface was computed for all-trans retinoic acid, which had 6 minima (3 enantiomeric pairs). The global minima were distorted s-gauche enantiomers (τ6–7=±53°) with half-chair conformations of the ring. Distorted s-gauche enantiomers (τ6–7=±55°) with inverted half-chair ring conformations were 1.7kJ/mol above the global minima. The s-trans enantiomers (τ6–7=±164°) were 11.3kJ/mol above the global minima. Steric energies were computed by the method of Guo and Karplus to identify key structural elements in retinoic acids which determines their conformation. Small molecule crystal structures in the CCDC database with trimethylcyclohexenyl ring and exocyclic double bonds have ring-chain geometries near to one of the six energy minima of retinoic acids, except for retinaldehyde iminium cations.

On the utility of momentum space in the density functional theory description of the steric effect

This paper assesses the utility of momentum space in the density-based quantification of the steric effect proposed by Liu [J. Chem. Phys. 126, 244103 (2007)], which is based on a new energy partition scheme where the total electronic energy is decomposed into contributions from three independent effects: steric, electrostatic, and the fermionic quantum. The steric energy defined in this way is repulsive, exclusive, and extensive and intrinsically linked to Bader's quantum theory of atoms in molecules. In this work, the plausibility of defining and computing steric energies using momentum densities according to this scheme is confirmed from numerical tests. Moreover, we found that the correlation between the experimental scales of the steric energies and theoretical values computed from momentum densities is even better than the same correlation with theoretical estimations obtained from position densities.

Theoretical Investigation on the Steric Interaction in Colloidal Deposition

A theoretical investigation was conducted upon the steric interaction between a spherical particle and a flat plate. The effects of curvature on both the segment density distribution of polymer and on the steric interaction energy between a particle and a plate were examined. It was found that the conventional approach using Derjaguin approximation may overestimate the interaction energy, especially for very small particles. Based on the results obtained from applying the Flory-Krigbaum theory with the accurate geometry change during the interaction, simple approximate expressions of exponential form were proposed for both the osmotic (mixing) and elastic contributions to the steric interaction energy for a sphere-plate interaction. The proposed model was validated against a set of experimental results from a reported study employing atomic force microscopy. Also investigated was the steric interaction between a spherical particle coated with polymer and an uncoated flat surface. It was found that the steric interaction energy from the osmotic contribution is significantly higher than that from the elastic contribution and that steric interaction is considerably weaker when the polymer exists on only one of the interacting surfaces.

Complete basis set, hybrid-DFT study and NBO interpretation of conformational analysis of 2-methoxytetrahydropyran and its thiopyran and selenopyran analogues in relation to the anomeric effect

2-Methoxytetrahydropyran (1), -thiopyran (2) and -selenopyran (3) have been chosen as model compounds to investigate the origin of the anomeric effect (AE). The impacts of the hyperconjugation, electrostatic and steric interactions on the conformational preferences of compounds 1–3 have been analysed by means of complete basis set-4, hybrid-density functional theory (B3LYP/6-311+G**) based methods and natural bond orbital (NBO) interpretation. Both levels of theory showed that the axial conformations of compounds 1–3 are more stable than their equatorial conformations. The Gibbs free energy difference (G eq–G ax) values (i.e. ΔG eq–ax) between the axial and equatorial conformations increase from compound 1 to compound 2 but decrease from compound 2 to compound 3. Based on the NBO results obtained, the AE associated with the electron delocalisation [i.e. Σ(endo-AEeq + exo-AEeq) − Σ(endo-AEax + exo-AEax)] increase slightly from compound 1 to compound 2 but decrease from compound 2 to compound 3. Similar trend is also observed for the differences between the calculated total steric exchange energy values [i.e. Δ(TSEE)eq–ax]. On the other hand, the calculated differences between the dipole moment values of the axial and equatorial conformations [i.e. Δ(μeq–μax)] decrease from compound 1 to compound 3. These findings led to the proposal that the AE associated with the electron delocalisation (the hyperconjugation effect) is more significant for the explanation of the conformational preferences of compounds 1–3 than the electrostatic model. The correlations between the AE associated with the electron delocalisation, bond orders, TSEE, ΔG eq–ax, dipole–dipole interactions, structural parameters and conformational behaviours of compounds 1–3 have been investigated.

Conformational Studies of Dodecanolactone by Dynamic NMR Spectroscopy and Computational Methods

AbstractLow‐temperature carbon NMR spectra of dodecanolactone (1), the parent 13‐membered lactone, showed the presence of two conformations, with populations of 55.5 and 44.5 % at –164.2 °C. Populations were estimated at the coalescence temperature of –151.9 °C for the carbonyl carbon atoms, and rate constants of 172.1 and 141.1 s–1 were obtained by lineshape matching. The corresponding free‐energy barriers were 5.63 and 5.68 kcal/mol. A search of conformational space was made with Allinger's MM4 program, and the conformations found were numbered 1a–m in order of increasing steric energies. Ab initio calculations (HF/6‐311G* level) of chemical shifts and of free energies at –150 °C predict that the major conformation is 1b and the minor conformation is 1a.

Residue-Ligand Interaction Energy (ReLIE) on a Receptor-Dependent 3D-QSAR Analysis of S- and NH-DABOs as Non-Nucleoside Reverse Transcriptase Inhibitors

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by receptor-dependent (RD) three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to derive RD-3D-QSAR models. The descriptors in this new method are the steric and electrostatic interaction energies of the protein-ligand complexes (per residue) simulated by molecular dynamics, an approach named Residue-Ligand Interaction Energy (ReLIE). This study was performed using a training set of 59 compounds and the MKC-442/RT complex structure as reference. The ReLIE-3D-QSAR models were constructed and evaluated by genetic algorithm (GA) and partial least squares (PLS). In the best equations, at least one term is related to one of the amino acid residues of the p51 subunit: Asn136, Asn137, Glu138, and Thr139. This fact implies the importance of interchain interaction (p66-p51) in the equations that best describe the structure-activity relationship for this class of compounds. The best equation shows q2 = 0.660, SEcv = 0.500, r2 = 0.930, and SEE = 0.226. The external predictive ability of this best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, substituents capable of interactions with residues like Ile94, Lys101, Tyr181, and Tyr188 should be selected. Also, given the importance of the conserved Asn136, this residue could become an attractive target for the design of novel NNRTIs with improved potency and increased ability to avoid the development of drug-resistant viruses.

Complete basis set, hybrid-density functional theory study, and natural bond orbital interpretations of the conformational behavior of halocarbonyl, thiocarbonyl, and selenocarbonyl isocyanates

Complete basis set CBS-QB3, hybrid-density functional theory (B3LYP/Def2-TZVPP) based methods and NBO interpretation were used to investigate the impacts of the stereoelectronic effects and electrostatic and steric interactions on the conformational properties of halocarbonyl isocyanates (halo = F (1), Cl (2), and Br (3)), halothiocarbonyl isocyanates (halo = F (4), Cl (5), and Br (6)), and haloselenocarbonyl isocyanates(halo = F (7), Cl (8), and Br (9)). Both methods showed that the Z-conformations of compounds 1, 4, and 7 are more stable than their corresponding E conformations, but the stability of the E conformations, when compared with the corresponding Z conformations, increases from compound 1 to compound 3, compound 4 to compound 6, and also from compound 7 to compound 9. The NBO analysis showed that the generalized anomeric effect (GAE) is in favor of the Z conformations of compounds 1, 4, and 7. The GAE values calculated (i.e., GAEE–GAEZ) increase from compound 1 to compound 3, compound 4 to compound 6, and also from compound 7 to compound 9. On the other hand, there are none of the same trends between the calculated total dipole moment and the Gibbs free energy difference values between the E and Z conformations (i.e., ΔμE–Z and ΔGE–Z) of compounds 1–3, 4–6, and 7–9. Accordingly, the GAE succeeds in accounting for the increase of the E conformation stability from compound 1 to compound 3, compound 4 to compound 6, and also from compound 7 to compound 9. Therefore, the GAE associated with the electron delocalization, not the total dipole moment changes (i.e., ΔμE–Z), is a reasonable indicator of the total energy difference in compounds 1–3, 4–6, and 7–9. There is a direct correlation between the calculated GAE and Δ[r2–6(E) – r2–6(Z)] parameters. Importantly, there are interesting through-space electron delocalizations (LP2X6→π*C4–O5) that justify the increase of the E conformation stability from compound 1 to compound 3, compound 4 to compound 6, and also from compound 7 to compound 9, when compared with their corresponding Z conformations. The correlations between the GAE, bond orders, total steric exchange energies (TSEE), ΔGZ–E, ΔμE–Z, structural parameters, and conformational behaviors of compounds 1–9 were investigated.

Consensus Structure Elucidation Combining GC/EI-MS, Structure Generation, and Calculated Properties

This article explores consensus structure elucidation on the basis of GC/EI-MS, structure generation, and calculated properties for unknown compounds. Candidate structures were generated using the molecular formula and substructure information obtained from GC/EI-MS spectra. Calculated properties were then used to score candidates according to a consensus approach, rather than filtering or exclusion. Two mass spectral match calculations (MOLGEN-MS and MetFrag), retention behavior (Lee retention index/boiling point correlation, NIST Kovat's retention index), octanol-water partitioning behavior (log K(ow)), and finally steric energy calculations were used to select candidates. A simple consensus scoring function was developed and tested on two unknown spectra detected in a mutagenic subfraction of a water sample from the Elbe River using GC/EI-MS. The top candidates proposed using the consensus scoring technique were purchased and confirmed analytically using GC/EI-MS and LC/MS/MS. Although the compounds identified were not responsible for the sample mutagenicity, the structure-generation-based identification for GC/EI-MS using calculated properties and consensus scoring was demonstrated to be applicable to real-world unknowns and suggests that the development of a similar strategy for multidimensional high-resolution MS could improve the outcomes of environmental and metabolomics studies.

Structural Identification of a Novel Axially Chiral Binaphthyl Fluorene Based Salen Ligand in Solution Using Electronic Circular Dichroism: A Theoretical–Experimental Analysis

A novel axially chiral binaphthyl fluorene based salen ligand, AFX-155 [2,2'-(1E,1'E)-(R)-1,1'-binaphthyl-2,2'-diylbis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene)bis(4-((7-(diphenylamino)-9,9-dihexyl-9H-fluoren-2-l)ethynyl)phenol)], with potential applications in homogeneous catalysis, biophotonics, and sensing was synthesized. A full comparative theoretical-experimental analysis of the UV-vis and electronic circular dichroism (ECD) spectra of the 10 primary isomers, comprising stereoisomers and optical isomers, revealed the presence of the unique structure in tetrahydrofuran (THF) solution, the trans-R-intra//trans-R-extra. A proposed route of attack of the (R)-(+)-2,2'-diamino-1,1'-binapthalene onto a salicaldehyde 5-(2-(2-(diphenylamino)-9,9-dihexyl-9H-fluoren-7-yl)ethynyl)-2-hydroxybenzaldehyde followed by a consecutive attack of the resulting species onto another salicaldehyde, both via Burgi:Dunitz trajectory, validates the unambiguous formation of the established isomer. Steric hindrances seem to be the determinant factor that defines the 3D structural conformation of this particular stereoisomer of AFX-155 with triple axial chirality. The determination of every optimal structure and the dominant conformers of AFX-155 were calculated evaluating, in CONFLEX, their steric energies using force fields at MMFF94S (2006-11-24HGTEMP) level in gas phase. The geometry of the conformers was optimized in THF (using PCM) using Gaussian 09 at the DFT/B3LYP level of theory and 6-31G* basis set. The first 100 electronic excited states were calculated using the same level of theory and basis set.

From density functional steric analysis and molecular electrostatic potential to the estimation of etherification rate constant

This research extends our more recent work on the application of molecular electrostatic potential as an effective approach in describing the influence of substituent on etherification reaction rate constant of phenol derivatives. Here, in addition to electronic factor, the steric effects have also been considered for our purpose. To analyze steric effects on etherification rate constant, we use the novel energy partition scheme proposed recently by Liu [S. B. Liu,J. Chem. Phys. 2007,126, 244103], where the total electronic energy is decomposed into three independent components: steric, electrostatic, and fermionic quantum. In this scheme, the steric potential has also been introduced. We first derive a relationship on the basis of density functional theory to show that the etherification rate constant should be proportional to the electrostatic potential on the atomic sites. Then, a bilinear function of molecular electrostatic potential and steric energy or steric potential is proposed for estimation of etherification reaction rate constants. Taking the experimental kinetics data of 30 substituted phenols, the validity of the proposed approach has been verified in position and momentum spaces. It is worth noting that the remarkable good performance of the momentum densities, which for the first time used in calculations of steric energy for a reaction, has been observed. Finally, using the relationship between new energy partition scheme and information theory, applicability of the Shannon entropy as one of the information theoretic measures is also tested for our goal and considerable results were obtained. Copyright © 2012 John Wiley & Sons, Ltd.

Visualizing the Analogy between Competitive Adsorption and Colloid Stability to Restore Lung Surfactant Function

We investigated a model of acute respiratory distress syndrome in which the serum protein albumin adsorbs to an air-liquid interface and prevents the thermodynamically preferable adsorption of the clinical lung surfactant Survanta by inducing steric and electrostatic energy barriers analogous to those that prevent colloidal aggregation. Chitosan and polyethylene glycol (PEG), two polymers that traditionally have been used to aggregate colloids, both allow Survanta to quantitatively displace albumin from the interface, but through two distinct mechanisms. Direct visualization with confocal microscopy shows that the polycation chitosan coadsorbs to interfacial layers of both Survanta and albumin, and also colocalizes with the anionic domains of Survanta at the air-liquid interface, consistent with it eliminating the electrostatic repulsion by neutralizing the surface charges on albumin and Survanta. In contrast, the PEG distribution does not change during the displacement of albumin by Survanta, consistent with PEG inducing a depletion attraction sufficient to overcome the repulsive energy barrier toward adsorption.

Computer simulation of fatty acids

Fatty acids modified by sulfhydric collectors are investigated. Three-dimensional molecular models are constructed for these acids and the main computer parameters of the total steric energy are determined. Based on the computer design, new reagents are suggested and molecular models are constructed and the total steric energy is calculated for them.

Conformational stability and rotational energy barrier of RC60–C60R dimers: hyperconjugation versus steric effect

Open image in new window The conformational stability of 4, 4′ disubstituted HC60–C60R and RC60–C60R dimers were calculated at ONIOM approach (AM1:B3LYP/6-31+G**) and density functional theory (B3LYP/6-31G**). The new evidences for stability and rotational energy barriers of these dimers were obtained by natural bond orbital, natural steric and molecular orbital analyses. Based on B3LYP/6-31G** calculations, except for RC60–C60R (R = hydrogen, tert-butyl and trimethylsilyl) where gauche is the most stable conformer, trans is a global energy minimum. The greater stability of the gauche conformer of HC60–C60H over trans is the result of hyperconjugation, which dominates the instability caused by the steric effect. By increasing the size of the substituent of HC60–C60R dimers, the trans becomes sterically unstable but the hyperconjugation of bulky substituents dominates (the trans is global energy minimum). The hyperconjugation stability of RC60–C60R dimers dominates until R = iso-propyl (higher stability of trans). In the case of bulky tert-butyl and trimethylsilyl substituents, the steric energy of trans is large and overweighs the hyperconjugation effect. This favors gauche as the most stable conformer. The calculated rotational energy barrier for HC60–C60R and RC60–C60R dimers is less than 7.3 and more than 10 kcal/mol, respectively (depending on substitution).