A Compound I Mimic Reveals the Transient Active Species of a Cytochrome P450 Enzyme: Insight into the Stereoselectivity of P450-Catalysed Oxidations

Catching the structure of cytochrome P450 enzymes in flagrante is crucial for the development of P450 biocatalysts, as most structures collected are found trapped in a precatalytic conformation. At the heart of P450 catalysis lies Cpd I, a short-lived, highly reactive intermediate, whose recalcitrant nature has thwarted most attempts at capturing catalytically relevant poses of P450s. We report the crystal structure of P450BM3 mimicking the state in the precise moment preceding epoxidation, which is in perfect agreement with the experimentally observed stereoselectivity. This structure was attained by incorporation of the stable Cpd I mimic oxomolybdenum mesoporphyrin IX into P450BM3 in the presence of styrene. The orientation of styrene to the Mo-oxo species in the crystal structures sheds light onto the dynamics involved in the rotation of styrene to present its vinyl group to Cpd I. This method serves as a powerful tool for predicting and modelling the stereoselectivity of P450 reactions.     

Intrinsic carrier doping in antiferromagnetically interacted supramolecular copper complexes with (pyrazino)tetrathiafulvalene (pyra-TTF) as the ligand, [CuIICl2(pyra-TTF)] and (pyra-TTF)2[CuI3Cl4(pyra-TTF)

New supramolecular copper complexes with pyrazinotetrathiafulvalene (pyra-TTF) as the ligand, [Cu(II)Cl2(pyra-TTF)] (1) and (pyra-TTF) 2[Cu(I)3Cl4(pyra-TTF)] (2), have been synthesized by the diffusion method. Complex 1 is a black block crystal with a three-dimensional (3-D) supramolecular network; the linear chain [-Cu(II)Cl2-(pyra-TTF)-] n extends along the b axis, where the coordinated pyra-TTF donors are stacked in a head-to-tail and ring-over-bond configuration to construct two-dimensional (2-D) sheets, and between the sheets, there are C...Cl(-) or H...Cl(-) contacts. Even though the electron spin resonance (ESR) measurement reveals the nearly Cu(II) state, complex 1 is a semiconductor with sigmaRT=1.0 x 10(-4) S cm(-1) and Ea=0.33 eV. The high-frequency conductivity measurement also confirmed the intrinsic slight carrier doping from Cu(II) to the pyra-TTF donor. This slight doping enhances not only the real and imaginary dielectric constants but also the antiferromagnetic interaction between Cu(II) spins following the 2-D Heisenberg model with 2J=-20 K. In contrast, complex 2 is a very thin black needle. This needle crystal has two crystallographically independent pyra-TTF molecules, which are coordinated and noncoordinated donors. The coordinated donors composed a supramolecular chain [Cu(I)3Cl4(pyra-TTF)(0)]n , whereas the noncoordinated donors formed conducting alpha'-type pyra-TTF(+0.5) sheets. This complex is semiconducting with sigmaRT=0.1 S cm(-1) and Ea=0.15 eV. Both complexes 1 and 2 demonstrate that the pyra-TTF molecule works not only as an oxidized donor by Cu(II) to construct conducting sheets but also as a ligand coordinated to a Cu cation to form supramolecuar chains.     

AlCl3-catalyzed tandem acetylation of hydroarylated [60]fullerenes

The AlCl3-catalyzed acetylation of 1,2-hydrophenylated [60]fullerenes, HC60-Ar, proceeded via a sequential manner involving the acetylation at the hydrogenated fullerene carbon, the following intramolecular cyclization with the adjacent aryl group, the facile loss of water, and the second acetylation of the generated indenylidene double bond. However, the similar reaction of the hydrobiphenylated analogue brought about the normal acetylation at the terminal aromatic ring prior to the same sequential reactions as did hydrophenylated fullerenes.     

Fibrous and helical calcite crystals induced by synthetic polypeptides containing o-phospho-L-serine and o-phospho-L-threonine

The modification of CaCO(3) crystal growth by synthetic L-Ser(PO(3)H(2)) and L-Thr(PO(3)H(2)) containing polypeptides is described. The amino acids Gly, L-Glu, L-Asp, L-Ser, L-Ala, and L-Lys induced rhombohedral calcite with a rough surface. Dipeptides, Xaa-L-Ser(PO(3)H(2)) (Xaa = Gly, L-Glu, L-Asp, L-Ser, L-Ala and L-Lys) induced vaterite crystals in the lower [Ca(2+)]. On the other hand, L-Ser(PO(3)H(2))-containing polypeptides formed spherical vaterite and fibrous calcite. The characteristic helical calcite was found in the presence of copoly[L-Ser(PO(3)H(2))(75)L-Asp(25)] or poly[L-Ser(PO(3)H(2))(3)-L-Asp]. Fibrous calcite, spherical vaterite, and helical calcite crystals were subjected to XRD and EDX analysis. XRD revealed the specific faces of these crystals. EDX spectra and surface analysis visualized the localization of the polypeptides and CaCO(3) components. Together with TEM and SAED data, we propose hypothetical growth mechanisms for the fibrous and helical calcite crystals.     

Long-range magnetic ordering of quasi-one-dimensional S=1/2 Heisenberg antiferromagnet Sr2Cu(PO4)2

Magnetic properties of quasi-one-dimensional S=1/2 Heisenberg antiferromagnet Sr₂Cu(PO₄)₂ were investigated by temperature and field dependence of AC susceptibility down to 0.03 K. A sharp peak was observed at on the temperature dependence of AC susceptibility indicating long-range magnetic ordering. Taking into account the exchange constant, (Hamiltonian =J∑S_iS_i+1), the ratio k_BT_N/J is 0.06%. Sr₂Cu(PO₄)₂ is, therefore, one of the best one-dimensional Heisenberg antiferromagnet known so far.     

1-D cobalt(II) spin transition compound with strong interchain interaction: [Co(pyterpy)Cl(2)].X

Cobalt(II) compounds [Co(pyterpy)Cl(2)].MeOH (1.(MeOH)) and [Co(pyterpy)Cl(2)].2H(2)O (1.(2H(2)O)) were synthesized. The compound 1.(MeOH) forms the quasi 3-D networks by making pi-pi stacking between the 1-D chains. The methanol molecules from 1.(MeOH) can be removed by heating, and substituted by absorption of water molecules. The MeOH molecules in 1.(MeOH) are removed by heating at 410 K, and they are substituted by water molecules to form 1.(2H(2)O). 1.(2H(2)O) exhibits a S = (3)/(2) (HS) left arrow over right arrow S = (1)/(2) (LS) spin transition with a thermal hysteresis. We have succeeded in constructing a guest dependent 1-D spin-crossover cobalt(II) compound.     

Enantioselective acylation of 1,2- and 1,3-diols catalyzed by aminophosphinite derivatives of (1S,2R)-1-amino-2-indanol

A phosphinite derivative that can be easily prepared in two steps from commercially available aminoindanol was found to be an effective catalyst for enantioselective acylation of diols. For the asymmetric desymmetrization of meso-1,2-diols, the corresponding monoester was obtained in up to 95% ee from the reaction in the presence of 5 mol % catalyst.     

Taste-masking effect of physical and organoleptic methods on peppermint-scented orally disintegrating tablet of famotidine based on suspension spray-coating method

Orally disintegrating tablets (ODTs) are useful for improving benefits for patients of various ages. Masking the unpleasant taste of a drug is an important factor in the compliance of patients who take ODTs. We evaluated the taste acceptability effects of various taste-masking methods on bitter famotidine ODTs as a clinical pharmacological study. The following methods were tested to compare taste-masking effects: physical masking by spray-coating famotidine with ethyl cellulose versus organoleptic masking with added sweetener and flavor. The ODT samples were prepared as single or combinations of each taste-masking method using a novel suspension spray-coating method including a placebo. A total of 31 healthy volunteers were enrolled in this randomized, double-blind study and asked to score their bitterness, sweetness and total palate impressions by 100?mm visual analogue scale (VAS). VAS scores were significantly improved by the physical and organoleptic methods as compared to without taste-masked ODTs. Furthermore, the combination of both taste-masking methods was most effective for improving palatability and VAS scores were similar to those of placebo ODTs. The results of this study suggest that different taste-masking mechanisms function cooperatively.     

Collective dynamics of sub- and supercritical methanol by inelastic X-ray scattering

Inelastic X-ray scattering experiments have been performed on methanol as a function of density from ambient to the supercritical state. Positive dispersion of the sound velocity, as compared to the hydrodynamic values, is 50% in the ambient condition and decreases to zero at 0.50 g cm⁻³ over the momentum transfer Q = 1–10 nm⁻¹ with lowering density; however, it increases again with a further decrease in density down to 0.20 g cm⁻³in the supercritical state only in the Q-range above 5 nm⁻¹. These results have been interpreted as the formation of small oligomers in the low-density supercritical methanol.     

Synthesis, reactivity, and properties of N-fused porphyrin manganese(I) tricarbonyl complexes

The reactions of N-fused tetraphenylporphyrin (NFTPP, 1a) and its 21-substituted derivatives, 21-Br-NFTPP (1b), 21-NO(2)-NFTPP (1c), and 21-Bz-NFTPP (1d), with Mn(CO)(5)Br gave the manganese(I) tricarbonyl complexes bearing N-fused tetraphenylporphyrinato ligands (2a-d), respectively, in 46-99% yields. The complexes were characterized by mass, IR, (1)H and (13)C NMR spectroscopy, and the final structural proof was evident from the X-ray crystallographic analysis for 2a. The crystals of 2a·CH(2)Cl(2) belong to the monoclinic space group P2(1)/n (#14), with a = 15.007(2) ?, b = 12.5455(19) ?, c = 21.150(3) ?, β = 102.227(4)°, and Z = 4. The lengths (?) of three manganese-nitrogen and three manganese-carbon bonds are inequivalent respectively [Mn-N(2), 2.007(2); Mn-N(23), 2.033(2); Mn-N(24), 1.988(3); and Mn-CO, 1.798(4), 1.804(4), 1.841(3)], reflecting the asymmetric structure of the NFp ligand. The aromatic substitution reactions of 2a, such as nitration, formylation, and chlorination, proceeded without a loss of center metal to give the corresponding 21-nitro (2c), 21-formyl (2e), and 21-chloro (2f) derivatives, regioselectively. In the electrochemical measurements of 2, one reversible oxidation and two reversible reduction waves were observed. The redox potentials of 2 indicate the narrow energy gaps between the highest occupied molecular orbital and the lowest unoccupied molecular orbital (HOMO-LUMO) being consistent with the electronic absorption spectra that display the absorption edges over 1000 nm. Protonation occurred at the inner core nitrogen of 2a upon the addition of acids, which is inferred from the (1)H NMR spectra as well as theoretical calculations. By a treatment with amine N-oxides, demetalation of 2 proceeded to afford the corresponding NFP free-bases (1).