Reactivity and Stability of (Hetero)Benzylic Alkenes via the Wittig Olefination Reaction.

Wittig olefination at hetero-benzylic positions for electron-deficient and electron-rich heterocycles has been studied. The electronic effects of some commonly used protective groups associated with the N-heterocycles were also investigated for alkenes obtained in the context of the widely employed Wittig olefination reaction. It was observed that hetero-benzylic positions of the pyridine, thiophene and furan derivatives were stable after Wittig olefination. Similarly, electron-withdrawing groups (EWGs) attached to N-heterocycles (indole and pyrrole derivatives) directly enhanced the stability of the benzylic position during and after Wittig olefination, resulting in the formation of stable alkenes. Conversely, electron-donating group (EDG)-associated N-heterocycles boosted the reactivity of benzylic alkene, leading to lower yields or decomposition of the olefination products.

Self-healing and self-cleaning clear coating.

Coatings exhibiting both self-cleaning and self-healing properties are envisioned for a wide range of applications. Herein we report a simple fabrication approach toward poly(urea-urethane) (PU) coatings having self-healing and self-cleaning properties. The self-cleaning component is a poly(dimethylsiloxane) (PDMS), which is affordable in cost and also has a lower environmental footprint relative to its fluorinated counterpart. The self-healing properties are imparted by dynamic urea bonds of the matrix. The obtained surfaces are evaluated for their anti-smudge properties such as water-, oil- and ink-repellency, as well as optical properties. The self-healing properties of these coatings are evaluated by making scores with a doctor blade and monitoring the healing under different conditions using optical microscopy. The resultant coatings are also investigated for their good mechanical properties. The surface chemical compositions are determined x-ray photoelectron spectroscopy, while atomic force microscopy is used for microstructural analysis of these coatings.

Molecular Recognition of Azelaic Acid and Related Molecules with DNA Polymerase I Investigated by Molecular Modeling Calculations.

Molecular recognition has central role on the development of rational drug design. Binding affinity and interactions are two key components which aid to understand the molecular recognition in drug-receptor complex and crucial for structure-based drug design in medicinal chemistry. Herein, we report the binding affinity and the nonbonding interactions of azelaic acid and related compounds with the receptor DNA polymerase I (2KFN). Quantum mechanical calculation was employed to optimize the modified drugs using B3LYP/6-31G(d,p) level of theory. Charge distribution, dipole moment and thermodynamic properties such as electronic energy, enthalpy and free energy of these optimized drugs are also explored to evaluate how modifications impact the drug properties. Molecular docking calculation was performed to evaluate the binding affinity and nonbonding interactions between designed molecules and the receptor protein. We notice that all modified drugs are thermodynamically more stable and some of them are more chemically reactive than the unmodified drug. Promise in enhancing hydrogen bonds is found in case of fluorine-directed modifications as well as in the addition of trifluoroacetyl group. Fluorine participates in forming fluorine bonds and also stimulates alkyl, pi-alkyl interactions in some drugs. Designed drugs revealed increased binding affinity toward 2KFN. A1, A2 and A3 showed binding affinities of -8.7, -8.6 and -7.9 kcal/mol, respectively against 2KFN compared to the binding affinity -6.7 kcal/mol of the parent drug. Significant interactions observed between the drugs and Thr358 and Asp355 residues of 2KFN. Moreover, designed drugs demonstrated improved pharmacokinetic properties. This study disclosed that 9-octadecenoic acid and drugs containing trifluoroacetyl and trifluoromethyl groups are the best 2KFN inhibitors. Overall, these results can be useful for the design of new potential candidates against DNA polymerase I.

Inhibition of DNA Topoisomerase Type IIα (TOP2A) by Mitoxantrone and Its Halogenated Derivatives: A Combined Density Functional and Molecular Docking Study.

In this study, mitoxantrone and its halogenated derivatives have been designed by density functional theory (DFT) to explore their structural and thermodynamical properties. The performance of these drugs was also evaluated to inhibit DNA topoisomerase type IIα (TOP2A) by molecular docking calculation. Noncovalent interactions play significant role in improving the performance of halogenated drugs. The combined quantum and molecular mechanics calculations revealed that CF3 containing drug shows better preference in inhibiting the TOP2A compared to other modified drugs.

Non-covalent interactions involving halogenated derivatives of capecitabine and thymidylate synthase: a computational approach.

Capecitabine, a fluoropyrimidine prodrug, has been a frequently chosen ligand for the last one and half decades to inhibit thymidylate synthase (TYMS) for treatment of colorectal cancer. TYMS is a key enzyme for de novo synthesis of deoxythymidine monophosphate and subsequent synthesis of DNA. Recent years have also seen the trait of modifying ligands using halogens and trifluoromethyl (-CF3) group to ensure enhanced drug performance. In this study, in silico modification of capecitabine with Cl, Br, I atoms and -CF3 group has been performed. Density functional theory has been employed to optimize the drug molecules and elucidate their thermodynamic and electrical properties such as Gibbs free energy, enthalpy, electronic energy, dipole moment and frontier orbital features (HOMO-LUMO gap, hardness and softness). Flexible and rigid molecular docking have been implemented between drugs and the receptor TYMS. Both inter- and intra-molecular non-covalent interactions involving the amino acid residues of TYMS and the drug molecules are explored in details. The drugs were superimposed on the resolved crystal structure (at 1.9 Å) of ZD1694/dUMP/TYMS system to shed light on similarity of the binding of capecitabine, and its modifiers, to that of ZD1694. Together, these results may provide more insights prior to synthesizing halogen-directed derivatives of capecitabine for anticancer treatment.

Amplified halogen bonding in a small space.

Weak, intermolecular forces are difficult to observe in solution because the molecular encounters are random, short-lived, and overwhelmed by the solvent. In confined spaces such as capsules and the active sites of enzymes or receptors, the encounters are prolonged, prearranged, and isolated from the medium. We report here the application of encapsulation techniques to directly observe halogen bonding. The small volume of the capsule amplifies the concentrations of both donor and acceptor, while the shape of the space permits their proper alignment. The extended lifetime of the encapsulation complex allows the weak interaction to be observed and characterized by conventional NMR methods under conditions in which the interaction would be negligible in bulk solvent.

Structure and energetics of gas phase halogen-bonding in mono-, bi-, and tri-dentate anion receptors as studied by BIRD.

Complexes of mono-, bi- (RB), and tridentate (RT) receptors with a range of anions (Cl(-), Br(-), I(-), NO3(-), H2PO4(-), HSO4(-), and tosylate (TsO(-))) have been studied in the gas phase by both experimental and theoretical methods. Temperature dependent blackbody infrared radiative dissociation (BIRD) experiments were performed on complexes of C8F17I with Br(-) and I(-), RB with I(-), NO3(-), HSO4(-), H2PO4(-), and TsO(-), and RT with I(-), HSO4(-) and TsO(-) and the observed Arrhenius parameters are reported here. Master equation modeling of the BIRD kinetics data was carried out to determine threshold dissociation energies. Geometry optimizations and thermochemistry calculations were performed using the B3LYP/6-31+G(d,p) level of theory. Additional single point energies were calculated using MP2/6-311++G(2d,p). Results were examined in terms of the binding order of various anions as well as the added binding strength from additional halogen bonding (XB) interactions. The relative binding energies of ions were generally consistent with the ordering previously reported from solution phase experiments; however, the relatively strong binding of H2PO4(-) to the bidentate receptor contrasted the solution phase observation of oxoanions having weaker interactions when compared to halides. An increase in the energy required to remove the same anion from the tridentate receptor when compared to the bidentate and monodentate receptors is explained as being due to the increase in halogen bonding interactions. The possibility of mixed halogen and hydrogen bonded complexes were considered.

Halogen bonding between anions and iodoperfluoroorganics: solution-phase thermodynamics and multidentate-receptor design.

The interactions of iodoperfluoroarenes and -alkanes with anions in organic solvent were studied. The data indicates that favorable halogen-bonding interactions exist between halide anions and the monodentate model compounds C(6)F(5)I and C(8)F(17)I. These data served as a basis for the development of preorganized multidentate receptors capable of high-affinity anion recognition. Several new receptor architectures were prepared, and the multidentate-iodoperfluorobenzoate-ester design, as described in a preliminary communication, was evaluated in more detail. Computation was employed to better interpret the structure-activity relationships arising from these studies. Investigations of the thermodynamics of anion binding (by van't Hoff analysis) and solvent effects reveal details of these halogen bonding interactions.

Halogen bonding in solution: thermodynamics and applications.

Halogen bonds are noncovalent interactions in which covalently bound halogens act as electrophilic species. The utility of halogen bonding for controlling self-assembly in the solid state is evident from a broad spectrum of applications in crystal engineering and materials science. Until recently, it has been less clear whether, and to what extent, halogen bonding could be employed to influence conformation, binding or reactivity in the solution phase. This tutorial review summarizes and interprets solution-phase thermodynamic data for halogen bonding interactions obtained over the past six decades and highlights emerging applications in molecular recognition, medicinal chemistry and catalysis.

Thermodynamics of halogen bonding in solution: substituent, structural, and solvent effects.

A detailed study of the thermodynamics of the halogen-bonding interaction in organic solution is presented. (19)F NMR titrations are used to determine association constants for the interactions of a variety of Lewis bases with fluorinated iodoalkanes and iodoarenes. Linear free energy relationships for the halogen bond donor ability of substituted iodoperfluoroarenes XC(6)F(4)I are described, demonstrating that both substituent constants (sigma) and calculated molecular electrostatic potential surfaces are useful for constructing such relationships. An electrostatic model is, however, limited in its ability to provide correlation with a more comprehensive data set in which both halogen bond donor and acceptor abilities are varied: the ability of computationally derived binding energies to accurately model such data is elucidated. Solvent effects also reveal limitations of a purely electrostatic depiction of halogen bonding and point to important differences between halogen bonding and hydrogen bonding.

Efficient synthesis of brussalexin A, a remarkable phytoalexin from Brussels sprouts.

The synthesis of brussalexin A, the first phytoalexin containing an allyl thiolcarbamate group, and its selective inhibitory activity against fungal plant pathogens is described.

Detection, characterization and identification of crucifer phytoalexins using high-performance liquid chromatography with diode array detection and electrospray ionization mass spectrometry.

We have analyzed 23 crucifer phytoalexins (e.g. brassinin, dioxibrassinin, cyclobrassinin, brassicanals A and C) by HPLC with diode array detection and electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS) using both negative and positive ion modes. Positive ion mode ESI-MS appeared more sensitive than negative ion mode ESI-MS in detecting this group of compounds. A new HPLC separation method, new LC-MS and LC-MS(2) data and proposed fragmentation pathways, LC retention times, and UV spectra for selected compounds are reported.

The phytoalexins from cauliflower, caulilexins A, B and C: isolation, structure determination, syntheses and antifungal activity.

Our continuous search for phytoalexins from crucifers led us to examine phytoalexin production in florets of cauliflower (Brassica oleracea var. botrytis) under abiotic (UV light) elicitation. Four known (isalexin, S-(-)-spirobrassinin, 1-methoxybrassitin, brassicanal C) and three new (caulilexins A-C) phytoalexins were isolated. The syntheses and antifungal activity of caulilexins A-C against the economically important pathogenic fungi Leptosphaeria maculans, Rhizoctonia solani and Sclerotinia sclerotiorum, and the first synthesis of brassicanal C are reported.