Wavelength-Dependent Ultraviolet Photodissociation of Protonated Tryptamine.

Ultraviolet photodissociation (UVPD) experiments of protonated tryptamine ([Tryp+H]+) have been implemented by a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer combined with a wavelength-tunable optical parametric oscillator (OPO) laser. UVPD mass spectra under different laser wavelengths have been obtained, in which the dependence of the yield of fragment ions on the laser wavelength was observed. The UVPD spectrum of [Tryp+H]+ has been obtained in the range of 210-310 nm. Besides the previously reported two competitive channels of H loss and NH3 loss, two important channels of losing CH2NH and CH2NH2 units were observed and further studied by UV-UV tandem mass spectrometry and theoretical calculations. Interestingly, results show that the pair of competitive channels of CH2NH loss and CH2NH2 loss are both from the McLafferty-type rearrangement caused by ππ* electronic excited states. After the excitation, the two different dissociation pathways produce two different ion-neutral complexes, respectively. The wavelength-dependent dissociation and the existing competitive channels shown in this study reflect the diversity of UVPD processes of such organic molecules.

Reductive Cleavage of Unactivated Carbon-Cyano Bonds under Ammonia-Free Birch Conditions.

A general protocol for the reductive cleavage of unactivated carbon-cyano bonds in aliphatic nitriles has been achieved under single-electron-transfer conditions using Na/15-crown-5/H2O. Electron is supplied by the electride derived from bench-stable sodium dispersions and recoverable 15-crown-5. H2O provides the proton source and suppresses the reduction of aromatic moieties. Compared with the Na/NH3 electride system generated under traditional Birch conditions, this ammonia-free electride system is more practical and features better reactivity and chemoselectivity for the decyanations of a broad range of aliphatic nitriles.

Chiral Differentiation of Non-Covalent Diastereomers Based on Multichannel Dissociation Induced by 213-nm Ultraviolet Photodissociation.

Here we present the implementation of 213-nm ultraviolet photodissociation (UVPD) in a FT-ICR mass spectrometer for chiral differentiation in the gas phase. The L/D amino acid-substituted serine octamer ions were selected as examples of diastereoisomers for chiral analysis. Several kinds of fragment ions were observed in these experiments, including fragment ions that are similar to the ones observed in corresponding collision-activated dissociation (CAD) experiments, fragment ions generated with different protonation sites by only destroying non-covalent bonds, and unique non-covalent cluster radical ions. The latter two kinds of fragment ions are found to be more sensitive to the chirality of the substituted units. Further experiments suggest that the formation of radical ions is mainly affected by chromophores on side chains of the substituted units and micro surroundings of the characterized non-covalent diastereoisomers. A comparing experiment performed by only changing the wavelength of UV laser to 266 nm shows that the 213-nm UV laser has the priority in the diversity of fragmentation pathways and potential of further application in chiral differentiation experiments.

A systematic study on the generation of multimetallic lanthanide fullerene ions by laser ablation mass spectrometry.

RATIONALE: Laser ablation masss spectromety has been previously proved to be a powerful tool for studying endohedro metallofullerene (EMF) ions. Our previous study showed the possiblity of forming multi-metallofullerene ions containg more than six metal atoms for La, Y and Lu. Thus, it is important to conduct a systematic study on the generation of multi-metallofullerenes and their distribuitons for all lanthanide elements. METHODS: Experiments were performed on a 7.0 T Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. Laser ablation mass spectra were obtained by laser irradiation on mixtures of graphene and MCl3 on a stainless steel plate, applying a 355 nm Nd:YAG laser with a typical energy of 2.5 mJ/pulse. Reaction test experiments were performed by introducing O2 into the FTICR cell with a pulse valve. RESULTS: Multi-metallofullerene ions Ce2-4C2m+, Pr2-4C2m+, Gd2-4C2m+, Nd3C2m+, Dy2-3C2m+, Tb2-7C2m+, Ho2-6C2m+ were observed in the mass spectra. For the metals Sm and Eu, no multi-metallofullerene ion was observed. No reaction with O2 was observed in the reaction experiments, verifying that these species had endohedral structures. For the observed series of multi-metallofullerene ions, tri-metallofullerene ions dominated their mass spectra. The results were further compared with previously generated EMF ions for La, Er, Tm, Yb and Lu. CONCLUSIONS: Endohedral lanthanide metallofullerene ions were generated by laser ablation of graphene and the corresponding metal salts MCl3 (M = Ce, Pr, Nd, Gd, Tb, Dy and Ho) and studied with a FTICR mass spectrometer. Typically, multi-metallofullerene ions of TbnC2m+2≤n≤780≤2m≤176 and Ho6C2m+2≤n≤674≤2m≤162 were observed. The results show that the formation of multi-EMF ions containing lanthanides that have +3 and + 4 oxidation states is easier than those containing +2 oxidation states in the process of laser ablation.

Gas phase UV spectrum of a Cu(II)-bis(benzene) sandwich complex: experiment and theory.

Photofragmentation with tunable UV radiation has been used to generate a spectrum for the copper-bis(benzene) complex, [Cu(C6H6)2](2+), in the gas phase. The ions were held in an ion trap where their temperature was reduced to ∼150 K, whereby the spectrum revealed two broad features at ∼38,200 and ∼45,700 cm(-1). Detailed calculations using density functional theory (DFT) show the complex can occupy three minimum energy structures with C2v and C2 (staggered and eclipsed) symmetries. Adiabatic time-dependent DFT (TDDFT) has been used to identify electronic transitions in [Cu(benzene)2](2+), and the calculations show these to fall into two groups that are in excellent agreement with the experimental data. However, the open-shell electronic configuration of Cu(2+) (d(9)) may give rise to excited states with double-excitation character, and the single-excitation adiabatic TDDFT treatment leads to extensive spin contamination. By quantifying the extent of spin contamination and allowing for the inclusion of a small percentage (∼10%), the theory can provide quantitative agreement with the experimental data.

Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: optimization of kinase selectivity and pharmacokinetics.

The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.

Conformation-resolved UV spectra of Pb(II) complexes: a gas phase study of the sandwich structures [Pb(toluene)2]2+ and [Pb(benzene)2]2+.

Toxic heavy metals, such as Pb(2+), have become important targets for the development of efficient receptors that are capable of recognizing their presence as environmental and biological pollutants, and an important part of that receptor-metal characterization process is the provision of spectral evidence that identifies the presence of a metal ion. From results reported here on a combined experimental and theoretical study it is shown that, when complexed with aromatic ligands, Pb(2+) is capable of yielding structured UV spectra, which: (i) exhibit discrete electronic transitions that include significant contributions from the metal ion; (ii) are very sensitive to the electronic properties of coordinating ligands; and (iii) are sensitive to subtle changes in coordination geometry. Two aromatic sandwich complexes, [Pb(benzene)2](2+) and [Pb(toluene)2](2+) have been prepared in the gas phase and their UV action spectra recorded from ions held and cooled in an ion trap. Whilst [Pb(benzene)2](2+) exhibits a spectrum with very little detail, that recorded for [Pb(toluene)2](2+) reveals a rich structure in the wavelength range 220-280 nm. Theory in the form of density functional theory (DFT) shows that both types of complex take the form of hemidirected structures, and that [Pb(toluene)2](2+) can adopt three distinct conformers depending upon the relative positions of the two methyl groups. Further calculations, using adiabatic time-dependent DFT to assign electronic transitions, provide evidence of individual [Pb(toluene)2](2+) conformers having been resolved in the experimental spectrum. Of particular significance for the development of methods for identifying Pb(2+) as an environmental or biological pollutant, is the observation that there are distinct ligand-to-metal charge transfer transitions in the UV that are sensitive to both the geometry and the electronic characteristics of molecules that accommodate the metal ion.

[The role of hypoxia inducible factor-1α and vascular endothelial growth factor in hypoxic pulmonary hypertension in patients with acute high altitude reaction of rescue workers in Yushu earthquake].

OBJECTIVE: To assess the effects of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) on hypoxic pulmonary hypertension(HPH) in patients with acute high altitude reaction(AHAR) and its change after return to lower altitude. METHODS: Ninety-six officers and soldier participating in rescue of Yushu megaseism on April 14th in 2010, leaving low altitude area (1 500 m) rapidly to high altitude area(3 700 m) to undertake strenuous physical work were enrolled for study. All of them were male, aged 18-35 years, and they were divided into three groups according to the symptomatic scores of AHAR: without AHAR(group B, n=25), mild to moderate AHAR (group C, n=47 ) and severe AHAR (group D, n=24). Mean pulmonary artery pressure (mPAP), levels in serum HIF-1α and VEGF were measured at high altitude area after a stay of 50 days, and also after their return to lower altitude area (1 500 m) for 12 hours and 15 days. Fifty healthy volunteers at low altitude area served as control (group A). RESULTS: Level of mPAP (mm Hg, 1 mm Hg=0.133 kPa), serum HIF-1α (pg/L) and VEGF (ng/L) in group B (24.23±1.56, 68.80±7.52 and 82.56±6.32) were significantly higher than those in group A (18.50±1.30, 50.95±3.33 and 65.78±4.03), respectively (all P<0.01). Moreover, the value of all the parameters increased with increase in severity of AHAR, the respective value in group C were 28.42±1.32, 88.10±9.20 and 104.82±10.36, and in group D were 34.70±2.94, 117.93±13.46 and 136.77±12.03, and there were significant differences in comparing two groups (all P<0.01). At high altitude area, AHAR total score was positively correlated with mPAP, serum HIF-1α and VEGF (r=0.672, 0.737 and 0.634, respectively, all P<0.01), mPAP was positively correlated with serum HIF-1α and VEGF (r=0.706, 0.638, both P<0.01). Compared with group A, level of mPAP (29.08±4.22), serum HIF-1α (91.16±20.58) and VEGF (107.11±10.32) were significantly increased in 96 officers and soldiers who stayed for 50 days at an altitude of 3 700 m (all P<0.01), and the values were significantly decreased after returning to lower altitude area for 12 hours(23.05±3.18, 70.99±8.22 and 78.65±6.47) and 15 days(18.96±1.75, 52.31±4.92 and 63.08±4.55). The values showed significant difference between 12 hours and 15 days stay at 1 500 m (all P<0.01). The values of the determined parameters 15 days after return to lower altitude area showed no difference compared with those of group A (all P>0.05). CONCLUSION: Strenuous physical work at high altitude area, AHAR becomes more serious, and it is accompanied by higher values of HIF-1α, VEGF and mPAP, indicating that HPH is closely associated with elevation of HIF-1α and VEGF. These changes are improved after returning to lower altitude area for 12 hours, and they recover to normal lever after 15 days.

Ultraviolet photofragmentation spectroscopy of alkaline earth dication complexes with pyridine and 4-picoline (4-methyl pyridine).

A detailed experimental and theoretical study has been undertaken of the UV photofragmentation spectroscopy of the alkaline earth metal dications Mg(2+), Ca(2+), and Sr(2+) complexed with pyridine and 4-methyl pyridine (4-picoline). The ion complexes have been prepared using the pick-up technique and held in an ion trap where their internal temperature has been reduced to <150 K. Exposure of the trapped ions to tunable UV laser radiation leads to the appearance of photofragments with intensities that show significant variation as a function of wavelength. For all three metal dications, the resultant spectra show evidence of resolved features. Time-dependent density functional theory (TDDFT) has been used to identify possible electronic transitions that might be present in the [M(pyridine)(4)](2+) complexes (M = Mg, Ca, and Sr) within the wavelength range studied. These calculations show that the spectra are dominated by strong π* ← π and weaker π* ← n transitions localized on the pyridine ligands. The calculations correctly identify those regions of the experimental spectra where UV transitions begin to occur in the complexes and also the wavelengths at which absorption maxima are reached; however, more subtle features of the spectra are difficult to assign with confidence.

[Effect of oxidative stress in development of acute high altitude response during the process of strong physical work at high altitude].

OBJECTIVE: To assess the effect of oxidative stress in development of acute high altitude response (AHAR) during the process of strong physical work at high altitude and its change after return to lower altitude. METHODS: Ninety-six officers and soldiers of rapid entering into high altitude (3 700 m) with strong physical work were analyzed, all subjects were male, aged 18-35 years. According to the symptomatic scores of AHAR were divided into 3 groups: severe AHAR (group A, n = 24), mild AHAR (group B, n = 47) and without AHAR (group C, n = 25). Levels in serum 8-iso prostaglandinF2alpha(8-iso-PGF2alpha), superoxide dismutase (SOD) and malonaldehyde (MDA) were measured at higher altitude stayed 50 d and after return to lower altitude (1 500 m) 12 h and 15 d, and 50 healthy volunteers (group D) at 1 500 m altitude served as controll. RESULTS: Levels of serum 8-iso-PGF2alpha and MDA [(9.53 +/- 0.47) microg/L, (8.91 +/- 0.39) micromol/L] were significantly higher in group A than those in group B [(8.34 +/- 0.42) microg/L, (7.31 +/- 0.32) micromol/L] , group C [(7.02 +/- 0.48) microg/L, (6.41 +/- 0.23) micromol/L] and group D [(5.13 +/- 0.56) microg/L, (5.48 +/- 0.33) micromol/L], (all P < 0.01), and serum SOD [(52.08 +/- 3.44) micro/ml] was significantly lower in group A than that in group B [62.27 +/- 2.54) micro/ml], group C [(71.99 +/- 3.35) micro/ml] and group D [(80.78 +/- 3.44) micro/ ml] (all P < 0.01), there were significant differences between group B and C, C and D (all P < 0.01). At altitude 3 700 m 50 d, AHAR scores was positively correlated with serum 8-iso-PGF2alpha and MDA (all P < 0.01), negatively correlated with SOD (P < 0.01). Serum 8-iso-PGF2alpha and MDA were negatively correlated with SOD (all P < 0.01). Levels of serum 8-iso-PGF2alpha and MDA were significantly higher at altitude of 3 700 m 50 d than those at altitude of 1 500 m 12 h,15 d in group D (all P < 0.01), and serum SOD was significantly lower than that at 1 500 m 12 h,15 d in group D (all P < 0.01), there were significantly difference between at 1 500 m 12 h and 15 d (all P < 0.01), there were no difference between at 15 d in group D (all P > 0.05). CONCLUSION: The more serious of oxidative stress and oxidative/antioxidative imbalance, the more serious of AHAR, oxidative stress and oxidative/antioxidative imbalance may be involved in the development of AHAR. The changes were obviously improved after return to lower altitude 12 h, and recovered to normal after 15 d.

A highly effective one-pot synthesis of quinolines from o-nitroarylcarbaldehydes.

A highly effective one-pot Friedländer quinoline synthesis using inexpensive reagents has been developed. o-Nitroarylcarbaldehydes were reduced to o-aminoarylcarbaldehydes with iron in the presence of catalytic HCl (aq.) and subsequently condensed in situ with aldehydes or ketones to form mono- or di-substituted quinolines in high yields (66-100%).

Synthesis and structure-activity relationship of N-alkyl Gly-boro-Pro inhibitors of DPP4, FAP, and DPP7.

The structure-activity relationship of various N-alkyl Gly-boro-Pro derivatives against three dipeptidyl peptidases (DPPs) was studied. In a series of N-cycloalkyl analogs, DPP4 and fibroblast activation protein-alpha (FAP) optimally preferred N-cycloheptyl whereas DPP7 tolerated even larger cycloalkyl rings. Gly alpha-carbon derivatization of N-cyclohexyl or N-(2-adamantyl) Gly-boro-Pro resulted in a significant decrease in potency against all the three DPPs.

Fishing for targets: novel approaches using small molecule baits.

New technologies for target identification have emerged in the past few years. Driven by the development of novel proteomic tools and advances in analytical techniques, three new approaches have been successfully applied to drug discovery efforts by determining targets and off-targets. Recent progress in labeling live cells with activity-based probes will further aide a deeper understanding of the interaction of small molecules with a complex biological system on a molecular level.: