Synthesis of New Conjugates of Modified Podophyllotoxin and Stavudine

To find podophyllotoxin compounds with superior bioactivitiy and less toxicity, a series of novel conjugates of ring‐A‐modified 4‐epipodophyllotoxin and stavudine with amino acids as spacers were synthesized, i.e., the N‐[(2′,3′‐didehydro‐3′‐deoxythymidin‐5′‐O‐yl)carbonyl]‐substituted L ‐amino acid rel‐(3aR,4S,9R,9aR)‐1,3,3a,4,9,9a‐hexahydro‐6,7‐dimethoxy‐1‐oxo‐9‐(3,4,5‐trimethoxyphenyl)naphtho[2,3‐c]furan‐4‐yl esters 8a – 8f .     

Molecular dynamics simulations of the detoxification of paraoxon catalyzed by phosphotriesterase

Combined QM(PM3)/MM molecular dynamics simulations together with QM(DFT)/MM optimizations for key configurations have been performed to elucidate the enzymatic catalysis mechanism on the detoxification of paraoxon by phosphotriesterase (PTE). In the simulations, the PM3 parameters for the phosphorous atom were reoptimized. The equilibrated configuration of the enzyme/substrate complex showed that paraoxon can strongly bind to the more solvent‐exposed metal ion Zn_β, but the free energy profile along the binding path demonstrated that the binding is thermodynamically unfavorable. This explains why the crystal structures of PTE with substrate analogues often exhibit long distances between the phosphoral oxygen and Zn_β. The subsequent S_N2 reaction plays the key role in the whole process, but controversies exist over the identity of the nucleophilic species, which could be either a hydroxide ion terminally coordinated to Zn_α or the μ‐hydroxo bridge between the α‐ and β‐metals. Our simulations supported the latter and showed that the rate‐limiting step is the distortion of the bound paraoxon to approach the bridging hydroxide. After this preparation step, the bridging hydroxide ion attacks the phosphorous center and replaces the diethyl phosphate with a low barrier. Thus, a plausible way to engineer PTE with enhanced catalytic activity is to stabilize the deformed paraoxon. Conformational analyses indicate that Trp131 is the closest residue to the phosphoryl oxygen, and mutations to Arg or Gln or even Lys, which can shorten the hydrogen bond distance with the phosphoryl oxygen, could potentially lead to a mutant with enhanced activity for the detoxification of organophosphates. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Different Behaviors of Glutathione in Aqueous and DMSO Solutions: Molecular Dynamics Simulation and NMR Experimental Study

An all-atom molecular simulation and NMR experiments have been carried out to investigate the interactions and conformations of glutathione (GSH) in aqueous and DMSO solutions. The simulations started, from different initial conformations, are characterized by intramolecular distance, radius of gyration, root-mean-square deviation, and solvent-accessible surface. Interestingly, different behaviors are found in the two different solutions. GSH is highly flexible in an aqueous solution with transitions to the extended, semifolded, and folded states. However, once GSH reaches the folded state in DMSO, it remains there and becomes difficult to break down. The NMR results show agreement with the MD simulations. The water molecule is small. It is also a good proton donor and a good proton acceptor. Water molecules can easily break down the “folded” conformation. In DMSO solution, the stronger hydrogen bonds and the hydrophobic interactions are more important, which can make the GSH in the folded state stable. Variations in the distribution of conformations and the hydrogen-bonding network may play an important role in its function under physiological conditions.     

Evaluation of adiabatic runaway reaction of methyl ethyl ketone peroxide by DSC and VSP2

Methyl ethyl ketone peroxide (MEKPO) is generally applied to manufacturing in the polymerization processes. Due to thermal instability and high exothermic behaviors of MEKPO, if any operation is undertaken recklessly or some environmental effect is produced suddenly during the processes, fires and explosions may inevitably occur. In this study, thermal analysis was evaluated for MEKPO by differential scanning calorimetry (DSC) test. Vent sizing package 2 (VSP2) was used to analyze the thermal hazard of MEKPO under various stirring rates in a batch reactor. Thermokinetic and safety parameters, including exothermic onset temperature (T ₀), maximum temperature (T _max), maximum pressure (P _max), self-heating rate (dT dt ⁻¹), pressure rise rate (dP dt ⁻¹), and so on, were discovered to identify the safe handling situation. The stirring rates of reactor were confirmed to affect runaway and thermal hazard characteristics in the batch reactor. If the stirring rate was out of control, it could soon cause a thermal hazard in the reactor.     

Low-temperature tunneling and rotational dynamics of the ammonium cations in (NH4)2B12H12

Low-temperature neutron scattering spectra of diammonium dodecahydro-closo-dodecaborate [(NH(4))(2)B(12)H(12)] reveal two NH(4)(+) rotational tunneling peaks (e.g., 18.5 μeV and 37 μeV at 4 K), consistent with the tetrahedral symmetry and environment of the cations. The tunneling peaks persist between 4 K and 40 K. An estimate was made for the tunnel splitting of the first NH(4)(+) librational state from a fit of the observed ground-state tunnel splitting as a function of temperature. At temperatures of 50 K-70 K, classical neutron quasi-elastic scattering appears to dominate the spectra and is attributed to NH(4)(+) cation jump reorientation about the four C(3) axes defined by the N-H bonds. A reorientational activation energy of 8.1 ± 0.6 meV (0.79 ± 0.06 kJ/mol) is determined from the behavior of the quasi-elastic linewidths in this temperature regime. This activation energy is in accord with a change in NH(4)(+) dynamical behavior above 70 K. A low-temperature inelastic neutron scattering feature at 7.8 meV is assigned to a NH(4)(+) librational mode. At increased temperatures, this feature drops in intensity, having shifted entirely to higher energies by 200 K, suggesting the onset of quasi-free NH(4)(+) rotation. This is consistent with neutron-diffraction-based model refinements, which derive very large thermal ellipsoids for the ammonium-ion hydrogen atoms at room temperature in the direction of reorientation.     

Screening of inhibitors for oxidase mimics of Au@Pt nanorods by catalytic oxidation of OPD

Nanostructured materials are a new class of enzyme mimics, the inhibitors of which have not been studied. Herein, we demonstrate the screening of inhibitors for Au@Pt nanorod (NR) oxidase mimics. In addition, based on the enzyme inhibition reaction, determination of "poisoning" inhibitors is demonstrated.     

Catalytic asymmetric construction of spirocyclopentaneoxindoles by a combined Ru-catalyzed cross-metathesis/double Michael addition sequence

Biologically important and synthetically challenging spirocyclopentaneoxindoles with four contiguous stereocenters including one spiroquaternary stereocenter have been constructed in good yields (72-87%) with excellent diastereoselectivity (16:1→30:1 dr) and enantioselectivity (93→99% ee) by a combined Ru-catalyzed cross-metathesis/organocatalyzed asymmetric double-Michael addition sequence.     

Copper nitride nanocubes: size-controlled synthesis and application as cathode catalyst in alkaline fuel cells

Copper nitride nanocubes are synthesized in a facile one-phase process. The crystal size could be tuned easily by using different primary amines as capping agents. Such Pt-free nanocrystals exhibit electrocatalytic activity toward oxygen reduction and appear to be promising cathodic electrocatalysts in alkaline fuel cells.     

CH···π interactions do not contribute to hydrogen transfer catalysis by glycerol dehydratase

The role of the nonbonded CH···π interaction in the hydrogen abstraction from glycerol by the coenzyme B(12)-independent glycerol dehydratase (GDH) was examined using the QM/MM (ONIOM), MP2, and CCSD(T) methods. The studied CH···π interaction included the hydrogen atom of the -C(2)H(OH)- group of the glycerol substrate and the tyrosine-339 residue of the dehydratase. A contribution of this interaction to the stabilization of the transition state for the transfer of a hydrogen atom from the adjacent terminal C(1)H(2)(OH) group to cysteine 433 was determined by ab initio HF, MP2, and CCSD(T) calculations with the aug-cc-pvDZ basis set for the corresponding methane/benzene, methanol/phenol, and glycerol radical/phenol subsystems. The calculated CH···π distance, defined as the distance between the H atom and the center of the phenol ring, shortened from 2.62 to 2.52 ? upon going from the ground- to the transition-state of the GDH-catalyzed reaction. However, this shortening was not accompanied by the expected lowering of the CH···π interaction free energy. Instead, this interaction remained weak (about -1 kcal/mol) along the entire reaction coordinate. Additionally, the mutual orientation of the CH group and the phenol ring did not change significantly during the reaction. These results suggest that the phenol group of the tyrosine-339 does not contribute to lowering the activation barrier in the enzyme, but do not exclude the possibility that tyrosine 339 facilitates proper orientation of glycerol for the electrostatic catalysis, or inhibits side-reactions of the reactive glycerol radical intermediate.     

Coulomb explosion of nitrogen and oxygen molecules through non-Coulombic states

We have systematically studied Coulomb explosion of nitrogen and oxygen molecules in intense 8 and 24 fs laser pulses. In the experiment, we explicitly separated all explosion pathways through coincident measurements. The high resolution kinetic energy releases (KERs) and the exotic angular distributions of atomic ions provide direct evidence that Coulomb explosion occurs through non-Coulombic states. In the theory, we calculated dissociation potential energy curves (PECs) of nitrogen and oxygen molecules and their multicharged molecular ions using multiconfiguration second-order perturbation theory. The results indicate that Coulomb potentials are close to the accurate PECs of multicharged molecular ions only when the internuclear distance is larger than 3 ?. In comparison with the experimental observations and the theoretical calculations, we determined the internuclear distance when Coulombic explosion occurs. It is near the equilibrium distance of the neutral molecules in the case of 8 fs laser pulses and expands gradually with the increase of the charge state of the molecular ions in the case of 24 fs laser pulses.