Individual Isomers Research Articles

(Invited) Isomer Effects of Nanocarbons in Organic Solar Cells

Fullerene derivatives are excellent electron-accepting materials in bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. The spherical cage structure of fullerenes endows the small reorganization energy in electron transfer, thereby yielding superior electron-accepting and electron-transporting properties. A typical fullerene derivative is [6,6]-phenyl-C61-butyric acid methyl ester ([60]PCBM). Its [70]fullerene analogue ([70]PCBM) has been frequently employed in high-performance OPVs over [60]PCBM because of better light-harvesting ability in the visible region and solubility in common organic solvents arising from the rugby ball-shape with lower symmetry. High power conversion efficiencies (PCEs) of 8–11% have been achieved using [70]PCBM in combination with various low-bandgap conjugated polymers. However, the lower symmetric C70 cage possesses four distinct types of double bonds (α, β, γ, and δ), and mono-addition to C70 generally leads to a mixture of regioisomer products. In fact, [70]PCBM prepared by a conventional method using 4-benzoylbutyrate tosylhydrazone and C70 contains α-type (80-90%) and β-type (10-20%) isomers. Despite its prevalence use in OPV devices, [70]PCBM is usually used as the isomer mixture, which veils the device performances depending on the individual isomers of [70]PCBM. In this talk, I will give an overview of the isomer effects of nanocarbons on BHJ OPV devices. In particular, I will focus on the comprehensive regioisomer and diastereomer separation effect of the most prevalent electron-acceptor ([70]PCBM) on the structures and photovoltaic properties of the blend films with a high-performance conjugated polymer (i.e., PffBT4T-2OD). In spite of the strong tendency of PffBT4T-2OD to form a bicontinuous structure with fullerene derivatives, one of the diastereomers of the β-isomer (β1-[70]PCBM) showed an extraordinary cohesion nature in the blend film, deteriorating the OPV device performance. OPV devices based on the other isomers (i.e., α-[70]PCBM (8.4%) and β2-[70]PCBM (8.4%)) rival or slightly surpass the device with the as-synthesized isomer mixture (mix-[70]PCBM, 8.2%) because of the existence of the poor performance β1-[70]PCBM. The results demonstrate the large impact of the substituent position and direction on a C70 surface on the photovoltaic properties. [1] S. Kitaura, K. Kurotobi, M. Sato, Y. Takano, T. Umeyama, and H. Imahori, Chem. Commun., 48, 8550-8552 (2012). [2] R. Tao, T. Umeyama,K. Kurotobi, and H. Imahori, ACS Appl. Mater. Interface, 6, 17313-17322 (2014). [3] R. Tao, T. Umeyama, T. Higashino, T. Koganezawa, and H. Imahori, Chem. Commun., 51, 8199-8388 (2015). [4] R. Tao, T. Umeyama, T. Higashino, T. Koganezawa and H. Imahori, ACS Appl. Mater. Interfaces, 7, 16676-16685 (2015). [5] T. Umeyama, T. Miyata, A. C. Jakowetz, S. Shibata, K. Kurotobi, T. Higashino, T. Koganezawa, M. Tsujimoto, , S. Gélinas, W. Matsuda, S. Seki, R. H. Friend, and H. Imahori, Chem. Sci., 8, 181-188 (2017). [6] T. Umeyama, S. Shibata, T. Miyata, K. Igarashi, T. Koganezawa, and H. Imahori, RSC Advance, 7, 45697-45704 (2017). [7] T. Umeyama, K. Igarashi, D. Sakamaki, S. Seki, and H. Imahori, Chem. Commun., 54, 405-408 (2018).

On the origin of the difference between type A and type B skeletal isomerization of alkenes catalyzed by zeolites: The crucial input of ab initio molecular dynamics

Alkene skeletal isomerization elementary steps catalyzed by acid zeolites are key reactions in refining, petrochemistry and biomass conversion. We unravel the atomic-scale origin of the higher rate constant of type A isomerization (involving a direct alkyl transfer, without any change in the branching degree) than the one of type B isomerization (involving non-classical carbonium ions such as protonated cyclopropane (PCP), inducing a change in the branching degree) of C7 carbenium ions in chabazite. Accurate free energy barriers are calculated at 300 and 500 K for both reactions by means of molecular dynamics in combination with blue moon ensemble approach, whereas the static approach is shown to fail to describe these reactions. The slow transformation between individual rotational isomers, causing non-ergodic sampling of reactant state, largely overlooked in literature, is carefully addressed in the present work. At 500 K (representative of experimental conditions), free energy barriers of 83.4 kJ/mol and 15.0 kJ/mol are determined for type B and type A isomerization respectively. The much lower barrier for type A is thus recovered, and assigned to a loose transition state, with free rotation of the migrating alkyl group, while the transition state of type B isomerization is tighter, with such a rotation blocked, due to the simultaneous hydride shift taking place on the edge of the PCP.

Chlorogenic acid isomers directly interact with Keap 1-Nrf2 signaling in Caco-2 cells

Chlorogenic acid (CGA) exists as multiple isomers (e.g., 3-CQA, 4-CQA, 5-CQA, 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA) in foods such as coffee beverages, fruits and vegetables. This study aimed to investigate relative activities of these six different CGA isomers to modify redox biology in inflamed Caco-2 cells that involved Nrf2 signaling. Caco-2 cells were pre-treated with individual CGA isomers to assess the relative effectiveness to mitigate oxidative stress. Isomer-specific capacity of different CGA isomers for direct free radical scavenging activity and potential endogenous control of oxidative stress were determined using chemical assays and cell-based experiments, respectively. Molecular dynamics simulations of the CGA and Keap1-Nrf2 complex were performed to predict CGA structure-specific interactions. Results demonstrated that dicaffeoylquinic acid (diCQA including 3,4-diCQA, 3,5-diCQA, and 4,5-diCQA) isomers had greater (p < 0.05) affinity to ameliorate oxidative stress through direct free radical scavenging activity. This observation corresponded to greater (p < 0.05) capacity to activate Nrf2 signaling compared to caffeoylquinic acid (CQA including 3-CQA, 4-CQA, and 5-CQA) isomers in inflamed differentiated Caco-2 cells. Simulations revealed that differences between the ability of CQA and diCQA to interact with the Keap1-Nrf2 complex may be due to differences in relative orientation within this complex. The observed CGA isomer-specific affinity for CQA to activate Nrf2 signaling was confirmed by nuclear translocation of Nrf2 induced by CGA and greater (p < 0.05) upregulation of genes related to Nrf2 expression.

One-Pot Synthesis of N-2,4-Enyne Cyclic Amines

Stereoselective synthesis of N-2,4-enyne cyclic amines was performed by one-pot animation of individual isomers of 1,3-dichloropropene and the subsequent Pd-Cu-catalyzed cross-coupling of the formed vinyl chlorides with terminal alkynes.

Organic contamination of beached plastic pellets in the South Atlantic: Risk assessments can benefit by considering spatial gradients

Microplastics are important vectors for the transport and accumulation of persistent organic contaminants in coastal and marine environments. We determined the concentration of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) associated with microplastic pellets collected along a 39-km stretch of Brazil's South Atlantic coastline to understand the spatial dynamics and potential risk posed by these contaminants. Total PAH concentrations ranged from 1,454 to 6,002 ng g−1 and regularly exceeded the threshold effect level (TEL) for sediments defined by the United States Environmental Protection Agency. Sampling stations, spaced evenly along the coastline (i.e., 3-km intervals) exhibited a general north-to-south decline in the concentrations of some PAHs, but this spatial gradient was complicated by small-scale differences in the concentrations and composition of associated contaminants. Similarly, analysis of individual isomer ratios revealed further complexity driven by differences in the contribution of petrogenic versus pyrolytic inputs which pose different levels of risk to marine organisms. PCB concentrations ranged from 0.8 to 104.6 ng g−1 and were dominated by low chlorinated congeners likely to have originated from major industrial areas to the north. Overall, this study highlights the challenge of directly linking microplastic pollution with the potential toxicological effects of organic contaminants in coastal waters. We recommend that monitoring programs should explicitly consider both the origin (i.e., pellet sources and dispersal pathways) and nature of organic contamination (i.e., concentration and composition) when assessing the risks for biota and human health.

Pre-diagnostic serum concentrations of organochlorines and risk of acute myeloid leukemia: A nested case-control study in the Norwegian Janus Serum Bank Cohort

BackgroundEpidemiologic studies suggest an increased risk of leukemia among individuals occupationally exposed to some organochlorine (OC) compounds. Associations between serum OC pesticide and polychlorinated biphenyl (PCB) levels and risk of acute myeloid leukemia (AML), the most common subtype of acute leukemia in adult populations, have not been evaluated prospectively in the general population. ObjectiveWe evaluated the risk of AML in relation to pre-diagnostic serum levels of OC pesticides and PCBs in a case-control study nested within the Janus Serum Bank Cohort. MethodsJanus is a large population-based cohort containing biologic samples collected beginning in the early 1970s from ~318,000 individuals in Norway. Serum levels of 11 OC pesticides or their metabolites and 34 PCB congeners were measured in 56 AML cases and 288 controls. Conditional logistic regression was conducted to evaluate associations between lipid-adjusted serum OC levels and risk of AML. ResultsHigher serum levels of total chlordane/heptachlor metabolites were associated with AML risk (3rd vs. 1st tertile odds ratio (OR) = 2.26, 95% confidence interval (CI) = 0.91–5.63; ptrend = 0.11). Significant exposure-response associations were observed for levels of heptachlor epoxide (3rd vs. 1st tertile OR = 2.85, 95% CI = 1.05–7.73; ptrend = 0.02) and dieldrin (3rd vs. 1st tertile OR = 2.71, 95% CI = 1.07–6.83; ptrend = 0.03). No significant exposure-response associations with AML risk were observed for total DDT or individual isomers and derivatives. Higher serum levels of p,p′-DDT showed a non-significant increase in risk, but the exposure-response became attenuated when co-adjusting for heptachlor epoxide or dieldrin levels. Serum PCB levels were not significantly associated with AML risk. ConclusionsOur data suggest that higher serum levels of dieldrin and metabolites derived from chlordane/heptachlor are associated with risk of AML in the general Norwegian population, based on samples collected on average ~17 years before diagnosis. Further research in populations with historically high or recent exposure to DDT is warranted to assess the association with AML risk with body burden of specific DDT isomers and derivatives.

Characterization of glutathione conjugates derived from reactive metabolites of seven silymarin isomers

1. Silymarin refers to a class of flavonoid lignans occurring in the fruits and seeds of the Silybum manalttlm (L). Gaertn, and is widely used in dietary supplements.2. The main active ingredients of silymarin are silychristins A and B, silydianin, silybins A and B, and isosilybins A and B. However, the metabolism of silymarin has never been investigated. The major objectives of the present study were to investigate the metabolic pathways of silymarin isomers and to identify reactive metabolites.3. Fourteen glutathione (GSH) conjugates were detected in rat/human liver microsomes incubations containing NADPH, GSH and seven individual isomers. Seven GSH conjugates (M1-M7) resulted from demethylated silymarin. M8-M14 originated from hydroxylated silymarin. Moreover, we found that GSH was probably conjugated on either ring A or ring E of silymarin based on the mass spectrometric fragments. In addition, recombinant enzyme incubation experiments demonstrated that CYP3A4 was the predominant P450 responsible for the metabolism of silymarin.4. Several P450 enzymes were reportedly inactivated by some of bioactive constituents of silymarin to some extent. Our findings facilitate the understanding of mechanisms of the reported inactivation of P450 enzymes induced by silymarin.

Effects of ionization and proton-transfer on bond length alternation in favored and rare isomers of isocytosine

For favored and rare prototropic tautomers of isocytosine (iC), geometric consequences of ionization, one-electron loss (iC − e → iC+) and one-electron gain (iC + e → iC−), have been studied. Effects of protonation and deprotonation on geometry of neutral isocytosine (iC + H+ → iCH+ and iC − H+ → iC−H−) as well as of its charged radicals (iC− + H+ → iCH and (iC+ − H+ → iC−H) have also been examined for selected isomers. Bond length alternation for the ground states of individual isomers, investigated in two extreme environments at the B3LYP/6-311+G(d,p) and PCM(water)//B3LYP/6-311+G(d,p) levels, have been quantitatively described using the geometry-based HOMED (harmonic oscillator model of electron delocalization) index. Generally, one-electron loss, one-electron gain, and proton-transfer reactions change electron delocalization in isocytosine isomers, and consequently the HOMED values. However, the HOMED indices calculated for structures optimized at the DFT level vary analogously to those optimized with PCM. When compared to other pyrimidine bases, cytosine (C) and uracil (U), exhibiting analogous tautomeric equilibria, rotational and/or geometric isomerism of exo groups (NH2/NH and/or OH/O), linear trends can be distinguished between the HOMED values of negatively ionized isomers (iC−, C−, and U−). For positively ionized isomers (iC+, C+, and U+), relations between the HOMED indices seem to be more complex. This indicates some similarities in mechanisms of one-electron gain and some differences in mechanisms of one-electron loss for isomers of pyrimidine bases. Hence, the HOMED descriptor can be considered as some kind of ‘marker index’ for ionization mechanism in analogous series of tautomeric π-electron systems.

The sex pheromone of Legume Pod Borer, Maruca vitrata (Lepidoptera: Crambidae) Revisited

ABSTRACT Female produced sex pheromone of Maruca vitrata containing three components had been reported from countries in tropical Asia and sub-Saharan Africa. (E,E)-10,12-hexadecadienal as a major component, (E,E)-10,12-hexadecadienol and E-10-hexadecenal as minor components blended in the ratio of 100:5:5 was found to attract M. vitrata male moths in few countries in West Africa. However, this blend was found to have less or no effectiveness in trapping M. vitrata population in Asia, which triggered the need to refine the M. vitrata pheromone formulation. The isomers of major and minor pheromone compounds of M. vitrata were evaluated in this study. When subjected to Electroantennogram (EAG) analysis against male antennae, the isomer (Z,E)-10,12-hexadecadienal as a major component blended with the minor components (E,E)-10,12-hexadecadienol and (E)-10-hexadecenol in 100:10:5 was found to elicit better antennal response than the standard three component blend. GC-EAD profiles of the individual synthetic isomer components supported the EAG results. Additional experiments also confirmed the attraction of M. vitrata pheromone compounds and their isomers along with host plant volatiles in EAG and wind-tunnel experiments. Field experiments in India and Cambodia confirmed the effectiveness of improved M. vitrata pheromone lures in attracting the adult male moths in legume fields.

In Vivo Evaluation of Novel Geranylgeranyl Diphosphate Synthase Inhibitors

▪The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl diphosphate which is used in protein geranylgeranylation reactions. Our work has demonstrated that GGDPS inhibitors (GGDPSIs) represent a novel therapeutic strategy for multiple myeloma (MM) by disrupting Rab protein geranylgeranylation. Treatment of MM cells with GGDPSI results in disruption of monoclonal protein trafficking, leading to induction of the unfolded protein response pathway (UPR) and apoptosis. We have previously reported preclinical studies with a lead GGDPSI, VSW1198 (a mixture of homogeranyl/homoneryl triazole bisphosphonates), demonstrating the agent's metabolic stability, prolonged half-life (plasma elimination half-life of 47.7 (±7.4) hrs), systemic distribution and confirmed in vivo disruption of geranylgeranylation (Haney et al., Invest New Drugs, 2018). Additional structure-function efforts have led to the development of the α-methylated derivatives RAM2093 (homogeranyl) and RAM2061 (homoneryl). Intriguingly the addition of the α-methyl group abrogates the effects of the olefin stereochemistry on inhibitor potency such that the individual isomers display near identical ability to disrupt protein geranylgeranylation in enzyme and cell assays (Matthiesen et al., Bioorg Med Chem, 2018). As little is known regarding the impact of olefin stereochemistry on the pharmacokinetic (PK)/pharmacodynamic (PD) properties of drugs, we pursued additional in vitro and in vivo studies of RAM2093 and RAM2061 and investigated the efficacy of the GGDPSIs in a mouse MM xenograft model. In MM cell lines, qRT-PCR and western blot analysis showed that both isomers induce activation of UPR/apoptotic markers in a dose-dependent manner and with similar potency. Single dose testing in CD-1 mice identified a maximum tolerated dose of 0.5 mg/kg IV for RAM2061 and 0.3 mg/kg for RAM2093. Liver toxicity was the primary barrier to dose escalation with both compounds. Analysis of blood samples showed elevated liver transaminase levels with normal bilirubin/alkaline phosphatase levels and histopathological examination confirmed evidence of hepatocyte injury at higher doses. Multi-dose schedules of 0.1 mg/kg twice a week (two weeks on, one week off, two weeks on) for RAM2061 and RAM2093, as well as 0.2 mg/kg (RAM2061) and 0.15 mg/kg (RAM2093) weekly x four weeks were tested. All dosing schedules were tolerated with the exception of the twice-weekly schedule for RAM2093. Consistent with the findings from our single dose testing, both multi-dose schedules induced transient elevation of hepatic transaminases. No loss of weight was observed and creatinine and CBC results were within normal limits for both single and multi-dose injected animals. Importantly, western blot analysis of mouse tissues collected from both RAM2061 and RAM2093 multi-dose-treated mice showed accumulation of unmodified Rap1a in the liver, kidney and spleen, indicating in vivo disruption of protein geranylgeranylation was achieved. Furthermore, using MM.1S MM cell flank xenographs in NOD-SCID mice, we observed a significant reduction in tumor growth in mice treated with either VSW1198 or RAM2061 relative to vehicle control. Lastly, PK/biodistribution studies with RAM2093 and RAM2061 were performed following a single dose of 0.3 mg/kg IV. Both compounds were detectable in plasma and liver samples for up to seven days post-injection demonstrating prolonged half-life and tissue distribution. The full PK parameters for both compounds will be presented and studies measuring drug levels in other tissues are ongoing. Taken together, these data suggest that RAM2061 and RAM2093 have equivalent anti-MM activity in vitro, but that RAM2061 is better tolerated in vivo. Whether this is a consequence of different PK properties vs. differences in tissue uptake or metabolism will be determined. These studies also confirm the in vivo efficacy of our novel GGDPSIs and support further development of these agents for the treatment of MM. [Display omitted] DisclosuresHolstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Gas Chromatography-Mass Spectrometry (GC-MS) and Gas Chromatography-Infrared (GC-IR) Analyses of the Chloro-1- n-pentyl-3-(1-naphthoyl)-Indoles: Regioisomeric Cannabinoids.

The analytical differentiation of the indole ring regioisomeric chloro-1- n-pentyl-3-(1-naphthoyl)-indoles is described in this report. The regioisomeric chloroindole precursor compounds, N- n-pentyl chloroindole synthetic intermediates, and the target chloro-substituted naphthoylindoles showed the equivalent gas chromatographic elution order based on the position of chlorine substitution on the indole ring. The regioisomeric chloro-1- n-pentyl-3-(1-naphthoyl)-indoles yield electron ionization mass spectra having equivalent major fragments resulting from cleavage of the groups attached to the central indole nucleus. Fragment ions occur at m/z 127 and 155 for the naphthyl and naphthoyl cations common to all indoles having the naphthoyl group substituted at the indole-3 position. Fragments resulting from the loss of the naphthoyl and/or n-pentyl groups from the molecular radical cation yield the cations at m/z 318, 304, 248, and 178. The characteristic (M-17)+ fragment ion at m/z 358 resulting from the loss of OH radical is significant in the mass spectra of all these compounds with 1-naphthoyl groups substituted at the indole-3 position. The vapor phase infrared spectra provide a number of characteristic absorption bands to identify the individual isomers.

Protonation and Sequential Microsolvation of 5-Hydroxyindole: Infrared Photodissociation Spectra of 5HIH+–Ln with L = Ar and N2 (n ≤ 3)

Protonation and solvation of functionalized heterocyclic aromatic molecules, which often occur as biomolecular building blocks, are important processes in (bio-)organic biochemistry. Herein, we study the protonation and microsolvation mechanisms of 5-hydroxyindole (5HI, 1 H-indol-5-ol, C8H7NO), the chromophore of serotonin, produced by electron and and chemical ionization using infrared photodissociation (IRPD) spectroscopy of mass-selected cold 5HIH+-L n clusters (L = Ar/N2, n ≤ 3) and dispersion-corrected density functional theory calculations (B3LYP-D3/aug-cc-pVTZ). Isomer-selective OH and NH stretch frequencies in the spectral range 3000-3800 cm-1 reveal the coexistence of at least four protonated species: the most stable syn (cis) isomer protonated at the C3 position of indole, both syn- and anti-rotamers protonated at C4 of the phenol ring, and the drastically less stable O-protonated isomer (Δ E0 = 117.1 kJ/mol) stabilized by kinetic trapping. Manipulation of the IRPD conditions (fragmentation channels) facilitates the spectroscopic isolation of O-protonated species. Upon protonation, the acidity of the OH group increases in the order 5HIH+(C3), 5HIH+(C4), and 5HIH+(O), while the acidity of the NH group decreases along this series, strongly affecting the microsolvation motifs of the individual isomers. Comparison of 5HIH+-L to the corresponding neutral and radical cation clusters reveals the impact of both protonation and ionization on the interaction with nonpolar ligands. Furthermore, our results are compared to protonated phenol, for which similar gas-phase protonation mechanisms have been found. Comparison of 5HIH+-L with the corresponding clusters of protonated phenol illustrates the effects of functional substitution and addition of aromatic rings on intermolecular potential.

Mass spectrometric method for distinguishing isomers of dexamethasone via fragment mass ratio: An HRMS approach.

The major challenge in identifying dexamethasone, betamethasone, and paramethasone from a mixture of these corticosteroids is difficulty in achieving an efficient separation. In this study, we aimed to develop an efficient technique to identify these co-eluting isomers based on the mass spectral patterns of them and their corresponding phase II metabolites after electrospray ionization. Fragmentation pathways in tandem mass spectrometry revealed acceptable specificity within the groups of conjugates. The method was validated using individual isomers and mixtures at various compositions. The effects of concentration and collision energies on fragmentation patterns were also studied extensively. Matrix-fortified equine urine and plasma samples were also included so that matrix effects and interferences on fragmentation ratios could be elucidated. Preliminary results using biological samples demonstrated the suitability of this analytical strategy for direct measurement from their fragmentation patterns. Possible fragmentation pathways for each isomer were proposed.

Identification of halogenated polycyclic aromatic hydrocarbons in biological samples from Alberta Oil-Sands Region

Halogenated polycyclic aromatic hydrocarbons (HPAHs) were identified in biological samples from the Alberta Oil-Sands Region (AOSR) using gas chromatography coupled with high-resolution time-of-flight mass spectrometry (GC-HRTOF-MS) at a resolving power of 25,000. Knowledge of the electron ionization (EI) fragmentation behavior of individual HPAH isomers, achieved by injecting authentic standards in full-scan MS mode, was paramount in identifying a suite of HPAHs in samples from the AOSR. Confirmation of compounds in biological samples was based on the measured mass accuracy (±3 ppm) of 2 characteristic ions prominent in the EI mass spectra of each compound. Numerous compounds were detected in the high resolution total ion chromatogram in liver extracts of 4 biological species from the AOSR: river otter (Lontra Canadensis), northern pike (Esox lucius), lake whitefish (Coregonus clupeaformis) and snails (Gastropod sp.) many of which remain unidentified. Careful examination of the high-resolution accurate mass data suggests that dichloro-anthracene/phenanthrene, bromo-anthracene/phenanthrene and dibromo-fluorene were present in the biological samples. Lipid corrected concentrations of dichloro-PAHs were estimated to be 16.3 ± 11.4 (n = 4) and 5.5 (n = 1) ng/g in lake whitefish and river otter, respectively. Concentrations of mono-bromo-PAHs were an order of magnitude greater in snails (170.5 ng/g) than in northern pike (12.5 ng/g) while concentrations of dibromo-PAHs were 4 times greater in snails than in northern pike. The detection of these compounds in biota implies that these compounds are bioaccumulative. The liver-based biomagnification factor of the dichloro-PAH congener in the river otter/lake whitefish feeding relationship is much smaller than 1 implying that this compound does not biomagnify.

Isomers of halodrol: synthesis and partial reduction to form A-ring of a long-term metabolite of dehydrochloromethyltestosterone (oral turinabol)

A new synthetic route to individual isomers of 4-chloro-17α-methylandrost-1,4-diene-3,17β-diol (halodrol, CDMA) based on reduction of the carbonyl group in dehydrochloromethyltestosterone (oral turinabol, DHCMT), followed by separation of epimers by fractional crystallisation from dichloromethane is presented. Reduction of the disubstituted double bond of the diene system in 3α-hydroxy isomer of halodrol afforded 4-chloro-17α-methyl-androst-4-ene-3α,17β-diol contained A-ring corresponding to 4-chloro-17β-hydroxymethyl-17α-methyl-18-norandrosta-4,13-dien-3α-ol (M4), which is one of the long-term metabolites of oral turinabol.

The isolation and electrochemical property of Tb2C90 (I, II) isomers

ABSTRACTSoot containing Tb2C90 was synthesized in a modified Krätschmer-Huffman generator by vaporizing the composite graphite rods containing a mixture of Tb4O7 and graphite powder at an atmosphere of 300 torr He. The as-produced soot was collected and refluxed in 1,2,4-trichlorobenzene (TCB) for 12 h. After filtration and distillation to remove TCB, the product was immediately dissolved in toluene, and then subjected to HPLC separation to obtain the two individual isomers of Tb2C90 (I, II), which were confirmed by matrix-assisted laser desorption time-of-flight mass spectrometry and analytical HPLC. According to its UV-Vis-NIR absorption spectrum, the molecular structure of Tb2C90 (II) was estimated to be Tb2C2@Cs(hept)-C88, in which four electrons are transferred from endohedral Tb2C2 carbide cluster to the Cs(hept)-C88 carbon cage. The electrochemical properties of Tb2C90 (I, II) isomers was investigated by cyclic voltammetry. It is found that the first reduction of Tb2C90 (II) is close to that of Tb2C90 (I), whereas its first oxidation potential is larger than that of Tb2C90 (I). Hence, is a better electron acceptor than Tb2C90 (I). Moreover, the electrochemical potential gap of Tb2C90 (II) is larger than that of Tb2C90 (I), which is correlated with the thermodynamic stability and relative abundance of the two isolated Tb2C90 isomers. Through comparative study of Tb2C2@Cs(hept)-C88 and Sc2C2@Cs(hept)-C88, it is concluded that the endohedral dimetallo-carbide cluster has greater effect on the oxidation properties than reduction properties of dimetallo-carbide clusterfullerenes.

GC-MS and GC-IR Analyses of the Methoxy-1-n-pentyl-3-(1-naphthoyl)-indoles: Regioisomeric Designer Cannabinoids.

The indole ring regioisomeric methoxy-1-n-pentyl-3-(1-naphthoyl)-indoles represent indole ring-substituted analogs of the synthetic cannabinoid JWH-018. The electron ionization mass spectra show equivalent regioisomeric major fragments resulting from cleavage of the groups attached to the central indole nucleus. The characteristic (M-17)+ fragment ion at m/z 354 resulting from the loss of OH group is significant in the mass spectra of all four compounds. Fragmentation of the naphthoyl and/or pentyl groups yields the cations at m/z 314, 300, 244 and 216. The vapor-phase infrared spectra provide a number of characteristic absorption bands to identify the individual isomers. Gas chromatographic separations on a capillary column containing a film of trifluoropropylmethyl polysiloxane (Rtx-200) provided excellent resolution of these compounds, their precursor indoles and intermediate pentylindoles. The elution order appears related to the degree of crowding of indole ring substituents.

Chemoenzymatic Synthesis of N-glycan Positional Isomers and Evidence for Branch Selective Binding by Monoclonal Antibodies and Human C-type Lectin Receptors.

Here, we describe a strategy for the rapid preparation of pure positional isomers of complex N-glycans to complement an existing array comprising a larger number of N-glycans and smaller glycan structures. The expanded array was then employed to study context-dependent binding of structural glycan fragments by monoclonal antibodies and C-type lectins. A partial enzymatic elongation of semiprotected core structures was combined with the protecting-group-aided separation of positional isomers by preparative HPLC. This methodology, which avoids the laborious chemical differentiation of antennae, was employed for the preparation of eight biantennary N-glycans with Galβ1,4GlcNAc (LN), GalNAcβ1,4GlcNAc (LDN), and GalNAcβ1,4[Fucα1,3]GlcNAc (LDNF) motifs presented on either one or both antennae. Screening of the binding specificities of three anti-LeX monoclonal IgM antibodies raised against S. mansoni glycans and three C-type lectin receptors of the innate immune system, namely DC-SIGN, DC-SIGNR, and LSECtin, revealed a surprising context-dependent fine specificity for the recognition of the glycan motifs. Moreover, we observed a striking selection of one individual positional isomer over the other by the C-type lectins tested, underscoring the biological relevance of the structural context of glycan elements in molecular recognition.

Differentiating Positional Isomers of Nucleoside Modifications by Higher-Energy Collisional Dissociation Mass Spectrometry (HCD MS).

The analytical identification of positional isomers (e.g., 3-, N4-, 5-methylcytidine) within the > 160 different post-transcriptional modifications found in RNA can be challenging. Conventional liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) approaches rely on chromatographic separation for accurate identification because the collision-induced dissociation (CID) mass spectra of these isomers nearly exclusively yield identical nucleobase ions (BH2+) from the same molecular ion (MH+). Here, we have explored higher-energy collisional dissociation (HCD) as an alternative fragmentation technique to generate more informative product ions that can be used to differentiate positional isomers. LC-MS/MS of modified nucleosides characterized using HCD led to the creation of structure- and HCD energy-specific fragmentation patterns that generated unique fingerprints, which can be used to identify individual positional isomers even when they cannot be separated chromatographically. While particularly useful for identifying positional isomers, the fingerprinting capabilities enabled by HCD also offer the potential to generate HPLC-independent spectral libraries for the rapid analysis of modified ribonucleosides. Graphical Abstract ᅟ.

Chemistry of 2,4,6-Tri-tert-butylanilides Possessing Isolable Rotational Isomer

Amide C-N bond in 2,6-di-tert-butylanilides has a high rotational barrier and the individual amide rotational isomers can be isolated at ambient temperature. These anilides have been reported by Chupp et al. in 1967, but no systematic study with anilide substrates other than α-haloacetoanilides, or the stereoselective synthesis of anilide rotamers have been reported. In addition, the structural properties of these anilides have not been investigated in detail. We succeeded in the highly selective stereodivergent synthesis of Z- and E-rotamers of various N-allyl-2,4,6-tri-tert-butylanilides through Pd(0) and Pd(II) catalyzed N-allylation of O-allyl-N-(2,4,6-tri-tert-butylphenyl)imidates. Moreover, the relative thermodynamic stabilities of the obtained anilide rotamers were clarified. Specific reactivity of 2,4,6-tri-tert-butylanilide derivatives was also found. For examples, in intramolecular Diels-Alder reaction of N-ally 2-furoyl amides, 2,4,6-tri-tert-butylphenyl group on the nitrogen atom remarkably accelerated the reaction. Although the reaction of ordinal anilide anion with alkyl halide gives N-alkylation product, the alkylation with 2,4,6-tri-tert-butylanilide anion preferentially proceeded on the oxygen atom to give O-alkyl imidate. O-Benzyl imidate, which was obtained by the reaction with benzyl bromide, was used as bezylation reagent of alcohols and carboxylic acids. In contrast to rotational rigidity of 2,4,6-tri-tert-butylanilide, in the anilide enolates, interconversion between the rotamers readily occurs at ambient temperature, and their reaction with electrophiles gave rotamer mixtures of the products in a ratio that depends on the reactivity of the electrophiles. Furthermore, as an application of this isomerization reaction, switching between the anilide rotamers was achieved.