Discovery of novel ocotillol derivatives modulating glucocorticoid receptor/NF-κB signaling for the treatment of sepsis.

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs.

Theoretical study on the activation of C-H bond in ethane by PdX+ (X = F, Cl, Br, H, and CH3) in the gas phase.

The mechanism of C-H bond activation of ethane was catalyzed by palladium halide cations (PdX+ (X = F, Cl, Br, H, and CH3)), which was investigated using density functional theory (DFT) at B3LYP level. The reaction mechanism was taken into account in triplet and singlet spin state potential energy surfaces. For PdF+, PdCl+, and PdBr+, the high spin states were the ground states, whereas the ground states were the low spin states in PdH+ and PdCH3+. The reaction of PdF+, PdCl+, and PdBr+ with ethane occurred via a typical "two-state reactivity" mechanism. In contrast, for PdH+ and PdCH3+, the overall reaction performed on the ground state PESs in a spin-conserving manner. The crossing points between two potential energy surfaces were observed and effectively decreased the activation barrier in PdX+/C2H6 (X = F, Cl, and Br). The minimum energy crossing points (MECP) were obtained used the algorithm in Harvey method. The natural valence electron configuration calculations were analyzed by natural bond orbital. The distribution and contribution of the front molecular orbital of the initial complexes could be further understand by the density of states. The feature of the bonding evolution in the main pathways was studied using topological analysis including localized orbital locator and atoms in molecules.

Enhancement of the Catalytic Activities of Heteronuclear Bimetallic Cations for the C-H Bond Activation of Cyclohexane.

Heterometallic cations NiCu+ and CoNi+ can easily induce triple dehydrogenation of cyclohexane with high yield, and monometallic cations Ni+ and Co+ only give rise to double dehydrogenation with low yield. Reaction mechanisms of the six C-H bond activations for cyclohexane are systematically investigated by comparing the difference between bimetallic cations and monometallic ones. Fragment molecular orbital analysis clearly indicates that charge transfer (CT) occurs from the occupied interacting orbital of the metallic cation to the σ*-antibonding orbital of the first, third, and fifth activated C-H bonds in transition states. The synergistic effects of heteronuclear bimetallic cations result in the destabilization of the occupied interacting orbital in bimetallic cations, which raise the reactivity of bimetallic cations and enhance the CT between catalysts and substrates. Contrary to the absence of the third dehydrogenation product in the mononuclear metallic cation catalytic reaction, a significant amount of the third dehydrogenation product is observed in the presence of heteronuclear cations (NiCu+ and CoNi+). π back-bonding between Ni of heteronuclear metallic cations and the substrate cyclohexadiene plays an essential role in lowering the energies of transition states, which accelerate the third dehydrogenation. The reasons why heteronuclear bimetallic cations are more reactive than monometallic ones are discussed in detail.

Theoretical investigation of auxiliary electronic acceptors in modifying D-D-π-A sensitizers for dye-sensitized solar cells.

In light of the performance of the SD2 pigments in DSSC, in order to expand the absorption spectral scope, decrease the energy difference between the highest occupied and the lowest unoccupied molecular orbitals, with SD2 dye molecular electron donor and electron acceptor as the fundamental framework, the indole fragment and thiophene derivative in the prototype dye molecule were replaced by the two π-bridges (labeled PA, PB, respectively) and the four auxiliary electron acceptors (labeled A1, A2, A3, A4, respectively). For the sake of characterizing dye molecules as thoroughly as possible in DSSC, the frontier orbital energy levels, ultraviolet absorption spectra, natural bond orbital analysis, intramolecular charge transfer, charge and hole reorganization energies, parameters influencing the short-circuit current density and the open-circuit photovoltage for these eight individual dye molecules are carried out to try to fully characterize the properties of these dye molecules. According to these computational results of physical quantities and based on the performance of these dye molecules in the above aspects, in this paper, six free molecular models were picked out to combine with titanium dioxide cluster to calculate their geometrical structures, frontier orbital distributions, electron excitation energies, ultraviolet absorption spectra and the composition of the electronic transitions in chloroform solvent with polarizable continuum model. The results of these calculations show that the PA-A2 and PB-A4 dye molecule has better properties in electron transfer and spectral absorption range before and after the adsorption on the titanium dioxide.

Rational molecular engineering of cyclopentadithiophene-bridged D-A-π-A sensitizers combining high photovoltaic efficiency with rapid dye adsorption.

Dye-sensitized solar cell (DSSC) is considered as a feasible route to the clean and renewable energy conversion technique. The commercial application requires further enhancements on photovoltaic efficiency and simplification on the device fabrication. For avoiding the unpreferable trade-off between photocurrent (JSC) and photovoltage (VOC), here we report the molecular engineering and comprehensive photovoltaic characterization of three cyclopentadithiophene-bridged D-A-π-A motif sensitizers with a change in donor group. We make a careful choice on the donor and conjugation bridge for synergistically increasing JSC and VOC. Comparing with the reference dye WS-2, the photovoltaic efficiency with the single component dye of WS-51 increases by 18%, among one of the rare examples in pure metal-free organic dyes exceeding 10% in combination with traditional iodine redox couples. Moreover, WS-51 exhibits several prominent merits on potentially scale-up industrial application: i) facile synthetic route to target molecule, ii) simple dipping procedure without requirement of co-sensitization, and iii) rapid dye adsorption capability.

Study of the competitive mechanisms of cyclohexane dehydrogenation by gas-phase Ni2(+) cationic dimer: one-face dehydrogenation versus flip dehydrogenation.

The mechanism of cyclohexane dehydrogenation catalyzed by the cationic dimer Ni2 (+) has been investigated at the B3LYP level of density functional theory. The first dehydrogenation occurs readily (it is exothermic by 30 kcal/mol), whereas the second and third dehydrogenations show weaker exothermicity than the first (23 and 21 kcal/mol, respectively). These three hydrogenations corresponding to the total dehydrogenation of one face of cyclohexane mainly proceed in the doublet state due to the presence of significant minimum-energy crossing points (MECPs). In addition, because the elimination of non-negligible amounts of [H2,2D2] and [2H2,D2] in this reaction was also observed in a previous experiment, we calculated a flip mechanism which would yield results that agree with those experimental results. This flip process includes two MECPs, meaning that the reaction mainly proceeds along the doublet potential energy surface but finishes in the quartet state. The rate-limiting step ((2)IM9 → (2)TS9/10 → (2)IM10) of the flip process is endothermic by 3 kcal/mol and the barrier to this step is 33 kcal/mol. Our calculations indicate that one-face dehydrogenation is a more favorable channel than the flip one. We excluded the possibility that eliminations of [H2,2D2] or [D2,2H2] could proceed through a mechanism involving Ni2 (+) dissociation, or that [H-D] scrambling could occur through (2)TS11/13 ((4)TS12/15), due to the large amounts of energy required. In the dissociation of (2)IM19, (2)[(H2)Ni2(C6H6)](+), a molecule of hydrogen first dissociates, leaving a final product of (2)[Ni2(C6H6)](+). Neither C6H6 nor (H2)Ni2 (+) can easily dissociate from (2)IM19 due to π backdonation.

Cosensitization of D-A-π-A quinoxaline organic dye: efficiently filling the absorption valley with high photovoltaic efficiency.

In the efficient cosensitization, the pure organic sensitizers with high molecular extinction coefficients and long wavelength response are highly preferable since the dye loading amount for each dye in cosensitization is decreased with respect to single dye sensitization. A D-A-π-A featured quinoxaline organic sensitizer IQ21 is specifically designed. The high conjugation building block of 4H-cyclopenta[2,1-b:3,4-b']dithiophene (CPDT) is introduced as the π bridge, instead of the traditional thiophene unit, especially in realizing high molecular extinction coefficients (up to 66 600 M(-1) cm(-1)) and extending the light response wavelength. With respect to the reference dye IQ4, the slightly lower efficiency of IQ21 (9.03%) arises from the decrease of VOC, which offsets the gain in JSC. While cosensitized with a smaller D-π-A dye S2, the efficiency in IQ21 is further improved to 10.41% (JSC = 19.8 mA cm(-2), VOC = 731 mV, FF = 0.72). The large improvement in efficiency is attributed to the well-matched molecular structures and loading amounts of both dyes in the cosensitization system. We also demonstrated that coabsorbent dye S2 can distinctly compensate the inherent drawbacks of IQ21, not only enhancing the response intensity of IPCE, making up the absorption defects around low wavelength region of IPCE, but also repressing the charge recombination rate to some extent.

Mechanism of the palladium-catalyzed hydrothiolation of alkynes to thioethers: a DFT study.

The mechanisms of the palladium-catalyzed hydrothiolation of alkynes with thiols were investigated using density functional theory at the B3LYP/6-31G(d, p) (SDD for Pd) level. Solvent effects on these reactions were explored using the polarizable continuum model (PCM) for the solvent tetrahydrofuran (THF). Markovnikov-type vinyl sulfides or cis-configured anti-Markovnikov-type products were formed by three possible pathways. Our calculation results suggested the following: (1) the first step of the cycle is a proton-transfer process from thiols onto the palladium atom to form a palladium-thiolate intermediate. The palladium-thiolate species is attacked on alkynes to obtain an elimination product, liberating the catalyst. (2) The higher activation energies for the alkyne into the palladium-thiolate bond indicate that this step is the rate-determining step. The Markovnikov-type vinyl sulfide product is favored. However, for the aromatic alkyne, the cis-configured anti-Markovnikov-type product is favored. (3) The activation energy would reduce when thiols are substituted with an aromatic group. Our calculated results are consistent with the experimental observations of Frech and colleagues for the palladium-catalyzed hydrothiolation of alkynes to thiols.

Effect of a long alkyl group on cyclopentadithiophene as a conjugated bridge for D-A-π-A organic sensitizers: IPCE, electron diffusion length, and charge recombination.

The option of using conjugated π-linkers is critical for rational molecular design toward an energy-level strategy for organic sensitizers. To further optimize photovoltaic performance, methyl- and octyl-substituted 4H-cyclopenta[2,1-b:3,4-b']dithiophene (CPDT) are introduced into D-A-π-A featured sensitizers. Along with CPDT, instead of thiophene as conjugated bridge, WS-39 and WS-43 exhibit an extended spectral response due to the excellent conjugation and coplanarity of CPDT. Specifically, we focused on the critical effect of length of the alkyl group linked to the bridging carbon atoms of CPDT on the photovoltaic performances. Octyl-substituted WS-39 shows a broader IPCE onset with an enhanced photovoltage relative to the analogue WS-5. In contrast, WS-43, with methyl substituted on the CPDT moiety, presents a relatively low quantum conversion efficiency within the whole spectral response region, along with low photocurrent density. WS-43 displays a distinctly low IPCE platform, predominately arising from the short electron diffusion length with significant electron loss during the electron transport. The relative movement of the conduction band edge (E(CB)) and charge transfer resistance as well as lifetime of injected electrons are studied in detail. Under standard AM 1.5 conditions, WS-39-based solar cells show a promising photovoltaic efficiency of 9.07% (J(SC) = 16.61 mA cm(-2), V(OC) = 770 mV, FF = 0.71). The octyl chains attached on CPDT can provide dual protection and exhibit a high propensity to prevent binding of the iodide-triiodide redox couple, producing an efficient shielding effect to retard the charge recombination and resulting in improvement of V(OC). Our research paves the way to explore more efficient sensitizers through ingenious molecular engineering.

Methane activation by MH+ (M = Os, Ir, and Pt) and comparisons to the congeners of MH+ (M = Fe, Co, Ni and Ru, Rh, Pd).

The mechanism of ligated-transition-metal- [MH(+) (M = Os, Ir, and Pt)] catalyzed methane activation has been computed at the B3LYP level of density functional theory. The B3LYP energies of important species on the potential energy surfaces were compared to CCSD(T) single-point energy calculations. Newer kinetic and dispersion-corrected methods such as M05-2X provide significantly better descriptions of the bonding interactions. The reactions take place more easily along the low-spin potential energy surface. The minimum-energy pathway proceeds as MH(+) + CH(4) → M(H)(2)(CH(3))(+) → TS → MH(CH(2))(H(2))(+) → MH(CH(2))(+) + H(2). The ground states are (5)Π, (4)Σ(-), and (1)Σ(+) for OsH(+), IrH(+), and PtH(+), respectively. The energy level differences of the reactants between the high- and low-spin states gradually become smaller from OsH(+) to PtH(+), being 30.66, 9.17, and 0.09 kcal/mol, respectively. The C-H bond can be readily activated by MH(+) (M = Os, Ir, and Pt) with a negligible barrier in the low-spin state; thus, OsH(+), IrH(+), and PtH(+) are likely to be excellent mediators for the activition of the C-H bond of methane. H(2) elimination is quite facile without barriers in the presence of excess reactants. The products of the reactions of MH(+) (M = Os, Ir, and Pt) + methane are all carbene complexes MH(CH(2))(+). The exothermicities of the reactions are 3.99, 15.66, and 12.14 kcal/mol, respectively. The results for MH(+) (M = Os, Ir, and Pt) are compared with those for the first- and second-row congeners, and the differences in behavior and mechanism are discussed.

Density functional study of S(N) 2 substitution reactions for CH(3) Cl + CX(1) X(2•-) (X(1) X(2) = HH, HF, HCl, HBr, HI, FF, ClCl, BrBr, and II).

A systematic investigation on the S(N) 2 displacement reactions of nine carbene radical anions toward the substrate CH(3) Cl has been theoretically carried out using the popular density functional theory functional BHandHLYP level with different basis sets 6-31+G (d, p)/relativistic effective core potential (RECP), 6-311++G (d, p)/RECP, and aug-cc-pVTZ/RECP. The studied models are CX(1) X(2•-) + CH(3) Cl → X(2) X(1) CH(3) C(•) + Cl(-) , with CX(1) X(2•-) = CH(2) (•-) , CHF(•-) , CHCl(•-) , CHBr(•-) , CHI(•-) , CF(2) (•-) , CCl(2) (•-) , CBr(2) (•-) , and CI(2) (•-) . The main results are proposed as follows: (a) Based on natural bond orbital (NBO), proton affinity (PA), and ionization energy (IE) analysis, reactant CH(2) (•-) should be a strongest base among the anion-containing species (CX(1) X(2•-) ) and so more favorable nucleophile. (b) Regardless of frontside attacking pathway or backside one, the S(N) 2 reaction starts at an identical precomplex whose formation with no barrier. (c) The back-S(N) 2 pathway is much more preferred than the front-S(N) 2 one in terms of the energy gaps [ΔE cent≠(front)-ΔE cent≠(back)], steric demand, NBO population analysis. Thus, the back-S(N) 2 reaction was discussed in detail. On the one hand, based on the energy barriers (ΔE cent≠ and ΔE ovr≠) analysis, we have strongly affirmed that the stabilization of back attacking transition states (b-TSs) presents increase in the order: b-TS-CI(2) < b-TS-CBr(2) < b-TS-CCl(2) < b-TS-CHI < b-TS-CHBr < b-TS-CHCl < b-TS-CF(2) < b-TS-CHF < b-TS-CH(2) . On the other hand, depended on discussions of the correlations of ΔE ovr≠ with influence factors (PA, IE, bond order, and ΔE def≠), we have explored how and to what extent they affect the reactions. Moreover, we have predicted that the less size of substitution (α-atom) required for the gas-phase reaction with α-nucleophile is related to the α-effect and estimated that the reaction with the stronger PA nucleophile, holding the lighter substituted atom, corresponds to the greater exothermicity given out from reactants to products.

CH4 activation by W atom in the gas phase: a case of two-state reactivity process.

Gas-phase methane activation by tungsten (W) atoms was studied at the density functional level of theory using the hybrid exchange correlation functional B3LYP. Four reaction profiles corresponding to the septet, quintet, triplet, and singlet multiplicities were investigated in order to ascertain the presence of some spin inversion during the methane activation. Methane activation mediated by W atoms was found to be a spin-forbidden process resulting from the crossing among the multistate energetic profiles. On the basis of the Hammond postulate, this is a typical two-state reactivity (TSR) reaction. The minimum energy crossing points lead to decrease in the barrier heights of TS01, TS12, TS23, and TS24 that correspond to the first, second, and third hydrogen transfer and the reductive elimination step of H(2), respectively. The spin-orbit coupling is calculated between electronic states of different multiplicities at the crossing points (MECPs) to estimate the intersystem crossing probabilities, and the probability of hopping from one surface to the other in the vicinity of the crossing region is calculated by the Landau-Zener type model.

Density functional theory studies of thermal activation of methane by MH+ (M = Ru, Rh, and Pd).

The dehydrogenation reaction mechanisms of methane catalyzed by a ligated transition metal MH(+) (M = Ru, Rh, and Pd) have been investigated theoretically. Activation of methane by MH(+) complexes is proposed to proceed in a one-step manner via one transition state: MH(+) + CH(4) --> MH(+)CH(4) --> [TS] --> (MCH(3)(+))H(2) -->MCH(3)(+) + H(2). Both high-spin and low-spin potential energy surfaces are characterized in detail. Our calculations indicate that the ground-states species have low electron spin and a dominant 4d(n) configuration for RuH(+), RhH(+), and PdH(+), and the whole reaction proceeds on the ground-states potential energy surfaces with a spin-allowed manner. The MH(+) (M = Ru, Rh, and Pd) complexes are expected from the general energy profiles of the reaction pathways to efficiently convert methane to metal methyl, thus RuH(+), RhH(+), and PdH(+) are likely to be excellent mediators for the activity of methane. In the reactions of MH(+) with methane, the H(2) elimination from the dihydrogen complex is quite facile without barriers. The exothermicities of the reactions are close for Ru, Rh, and Pd: 11.1, 1.2, and 5.2 kcal/mol, respectively.

Density functional theory study of the platinum-catalyzed cyclopropanation reaction with olefin.

A computational study of the platinum-catalyzed cyclopropanation reaction with olefin is presented. The model system is formed by an ethylene molecule and the active catalytic species, which forms from a CH2 fragment and the Cl2Pt(PH3)2 complex. The results show that the active catalytic species is not a metal-carbene of the type (PH3)2Cl2Pt=CH2 but two carbenoid complexes which can exist in almost two degenerate forms, namely (PH3)2Pt(CH2Cl)Cl (carbenoid A) and (PH3)Pt(CH2PH3)Cl2 (carbenoid B). The reaction proceeds through three pathways: methylene transfer, carbometalation for carbenoid A, and the reaction of a monophosphinic species for carbenoids (A and B). The most favored reaction channel is methylene transfer pathway for (PH3)Pt(CH2PH3)Cl2 (carbenoid B) species with a barrier of 31.32 kcal/mol in gas phase. The effects of dichloromethane, THF, and benzene solvent are investigated with PCM method. For carbenoid A, both methylene transfer and carbometalation pathway barriers to reaction become remarkably lower with the increasing polarity of solvent (from 43.25 and 52.50 kcal/mol for no solvent to 25.36 and 38.53 kcal/mol in the presence of the dichloromethane). In contrast, the reaction barriers for carbenoid B via the methylene transfer path hoist 6.30 kcal/mol, whereas the barriers do not change significantly for the reaction path of a monophosphinic species for carbenoids (A and B).

[Study on the fluorescence spectra of LaL3 with DNA].

A fluorescence method is presented for the determination of DNA. The method is based on the interaction of LaL3 [L = morin (2', 3, 4', 5, 7-Pentahydroxyflavone), 2'-OH group deprotonated] with DNA in NH3 x H2O-NH4Cl buffer of pH = 8.0, with lambdaex at 387 nm, and lambdaem at 535 nm. Enhanced fluorescence was observed for LaL3 in the presence of DNA and in the presence of buffer solution of 10%(psi) and ethanol of 10%(psi). The linear range of determination was between 0 and 15 microg x mL(-1) 1 for DNA. The method proved to be simple, easy and sensitive for the determination of DNA. The mechanism of enhancing and the reasons for the effects of acid were also discussed.