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The roots of Angelica sinensis(Oliv.) Diels (Dang Gui; Apiaceae) have a long history in traditional Chinese medicine as a remedy for women’s disorders and are often called “lady’s ginseng”. Currently, extracts of A. sinensisare commonly included in numerous dietary supplements used for women’s health and as antiaging products. In the present study, we examined the potential chemopreventive activity of A. sinensisextracts by measuring the relative ability to induce the detoxification enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1). The lipophilic partitions showed strong NQO1 induction with concentrations to double the enzyme activity (CD) of 5.5 ± 0.7 (petroleum ether) and 3.9 ± 0.5 μg/mL (chloroform). Fractionation led to the isolation of phenolic esters and alkylphthalides, especially Z-ligustilide, the main lipophilic compound, which showed strong NQO1 inducing properties (CD = 6.9 ± 1.9 μM). Transcription of many detoxifying enzymes is regulated through the antioxidant response element (ARE) and its transcription factor Nrf2, which is repressed under basal conditions by Keap1. However, exposure to electrophilic inducers that alkylate Keap1 results in higher concentrations of free Nrf2 and ARE activation. The ARE reporter activity was therefore analyzed in HepG2-ARE-C8 cells after incubation with lipophilic extracts of A. sinensisor ligustilide for 24 h. Under these conditions, both the extract and the ligustilide increased ARE-luciferase reporter activity in a dose-dependent manner. Incubation of ligustilide with GSH and subsequent LC-MS-MS analysis revealed that ligustilide as well as oxidized ligustilide species covalently modified GSH. In addition, using MALDI-TOF mass spectrometry and LC-MS-MS, it was demonstrated that the lipophilic extracts, ligustilide, and monooxygenated ligustilide alkylated important cysteine residues in human Keap1 protein, thus activating Nrf2 and transcription of ARE regulated genes. These observations suggest that A. sinensisdietary supplements standardized to ligustilide have potential as chemopreventive agents through induction of detoxification enzymes. [ABSTRACT FROM AUTHOR]

Molecular chains of two-coordinate carbon atoms (cumulenes) have long been targeted, due to interest in the electronic structure and applications of extended π-systems, and their relationship to the carbon allotrope, carbyne. While formal (isoelectronic) B═N for C═C substitution has been employed in two-dimensional (2-D) materials, unsaturated one-dimensional all-inorganic "molecular wires" are unknown. Here, we report high-yielding synthetic approaches to heterocumulenes containing a five-atom BNBNB chain, the geometric structure of which can be modified by choice of end group. The diamido-capped system is bent at the 2-/4-positions, and natural resonance theory calculations reveal significant contributions from B═N(:)-B≡N-B resonance forms featuring a lone pair at N (consistent with observed N-centered nucleophilicity). Molecular modification to generate a linear system best described by a B═N═B═N═B resonance structure involves chemical transformation of the capping groups (using B(C 5 F 5 ) 3 ) to enhance their π-acidity and conjugate the N-lone pairs.

Conjugation between three-dimensional (3D) carboranes and the attached substituents is commonly believed to be very weak. In this paper, we report that reducing 1,12-bis(BMes 2 )- p -carborane ( B 2 p Cab ) with one electron gives a radical anion with a centrosymmetric semiquinoidal structure. This radical anion shows extensive electron delocalization between the two boron centers over the p -carborane bridge due to the overlap of carborane lowest unoccupied molecular orbital (LUMO) and the BMes 2 LUMO. Unlike dianions of other C 2 B 10 H 12 carboranes, which rearrange to a nido -form, two-electron reduction of B 2 p Cab leads to a rearrangement into a basket-shaped intermediate.

The 1,3-addition of 1,2-diaryl-1,2-dibromodiboranes (B 2 Br 2 Ar 2 ) to trans -[W(N 2 ) 2 (dppe) 2 ] (dppe = κ 2 -(Ph 2 PCH 2 ) 2 ), which is accompanied by a Br-Ar substituent exchange between the two boron atoms, is followed by a spontaneous rearrangement of the resulting tungsten diboranyldiazenido complex to a 2-aza-1,3-diboraallenylimido complex displaying a linear, cumulenic B=N=B moiety. This rearrangement involves the splitting of both the B-B and N=N bonds of the N 2 B 2 ligand, formal insertion of a BAr boranediyl moiety into the N=N bond, and coordination of the remaining BArBr boryl moiety to the terminal nitrogen atom. Density functional theory calculations show that the reaction proceeds via a cyclic NB 2 intermediate, followed by dissociation into a tungsten nitrido complex and a linear boryliminoborane, which recombine by adduct formation between the nitrido ligand and the electron-deficient iminoborane boron atom. The linear B=N=B moiety also undergoes facile 1,2-addition of Brønsted acids (HY = HOPh, HSPh, and H 2 NPh) with concomitant Y-Br substituent exchange at the terminal boron atom, yielding cationic (borylamino)borylimido tungsten complexes.

A cyclic alkyl(amino)carbene (CAAC)-stabilized 1,4-diborabenzene (DBB, 1 ) reacts with the group 10 precursor [Ni(CO) 4 ] to yield the DBB pogo-stick complex [(η 6 -DBB)Ni(CO)] ( 2 ) as a dark-green crystalline solid. The IR-spectroscopic and X-ray crystallographic data of 2 highlight the strong π-donor properties of the DBB ligand. The reaction of 1 with [M(nbe) 2 ] (M = Pd, Pt; nbe = norbornene) yields the unique zerovalent heavier group 10 arene pogo-stick complexes [(η 6 -DBB)M(nbe)] ( 3-M ), isolated as dark-purple and black crystalline solids, respectively. 3-Pd and 3-Pt show strong near-IR (NIR) absorptions at 835 and 904 nm, respectively. Time-dependent density functional theory (TD-DFT) calculations show that these result from the S 0 →S 1 excitation, which corresponds to a transfer of electron density from a metal d orbital aligned with the z direction (d xz or d yz ) to a d orbital located in the xy plane (d xy or d x 2 -y 2 ), with the redshift for 3-Pt resulting from the higher spin-orbit coupling (SOC). In complex 2 , electron donation from the nickel center into the carbonyl 2π* orbital destabilizes the DBB···Ni interaction, resulting in an absorption at a higher energy. Complexes 2 and 3-M react with [Fe(CO) 5 ] to yield the doubly CO-bridged M(0)→Fe(0) (M = Ni, Pd, Pt) metal-only Lewis pairs (MOLPs) 4-M as black (M = Ni, Pt) and dark-turquoise (M = Pd) crystalline solids. Furthermore, 3-Pt undergoes oxidative Sn-H addition with Ph 3 SnH to yield the corresponding Pt(II) stannyl hydride, [(η 6 -DBB)PtH(SnPh 3 )] ( 5 ).

This combined experimental and theoretical study examines the influence of acene elongation, boron atom position, and acene substitution pattern on the structure and electronics of cyclic alkyl(amino)carbene (CAAC)-stabilized diboraacenes and presents the first syntheses of neutral diboranaphthalene (DBN) and diborapentacene (DBP). Whereas 2,3-diethyl-substituted 1,4-(CAAC) 2 - Et2 DBN is isolated as a mixture of a planar (structurally characterized) NMR-active conformer and a presumably bent EPR-active conformer, 6,13-(CAAC) 2 -DBP resembles 9,10-(CAAC) 2 -DBA (DBA = diboraanthracene), with a highly puckered 6,13-DBP core and a typical biradical EPR signal. Both species are easily reduced to their puckered dianions. DFT calculations confirm that 6,13-(CAAC) 2 -DBP is only stable in its bent conformation, whereas 1,4-(CAAC) 2 - Et2 DBN exists as both flat closed-shell and bent open-shell biradical conformers, which interchange by thermally activated ethyl and CAAC rotation/diboraacene bending processes. An in-depth computational study of the series of unsubstituted, CAAC-stabilized, symmetrically diboron-doped acenes from 1,4-(CAAC) 2 -DBN to 6,13-(CAAC) 2 -DBP was carried out. The results show interesting trends dependent on the position of the boron atoms within the acene framework as well as on the relative orientation of the CAAC ligands, which enable fine-tuning of the electronic and structural features.

The stepwise reduction of a doubly cyclic alkyl(amino)carbene (CAAC)-stabilized 2,3-bis(dibromoboryl)naphthalene enables the isolation of the corresponding mono- and bis(boryl) radicals (one- and two-electron reduction), a 2π-aromatic 1,2-diborete (four-electron reduction), which shows biradical character in the solid-state EPR spectrum, and its cyclic bis(alkylidene)diboron dianion (six-electron reduction). The X-ray crystallographic analysis of the diborete shows a highly strained and twisted four-membered ring with a formal cis -diborene motif featuring a very elongated B-B double bond. Calculations based on DFT and multireference approaches reveal that the diborete possesses an open-shell singlet biradicaloid ground state, which is slightly energetically preferred to its EPR-active triplet-state congener. The addition of CO to the diborete resulted in B-B bond splitting and the formation of the corresponding closed-shell singlet, doubly Lewis base-stabilized bis(borylene), whereas a twofold γ insertion of phenyl azide generates a 1,3-bis(diazenyl)-1,3,2,4-diazadiboretidine.

The new chemical class N -hetaryl-[2(1 H )-pyridinylidene]cyanamides were inspired by the long known five-ring structure 2-chloro-5-[2-(nitro-methylene)-1-imidazolidinyl]-pyridine (Shell) and the current development candidate flupyrimin (Meiji Seika Pharma) via scaffold hopping and the concept for designing "shortened structures" by omitting the "methylene link" as a structural feature. The most active N -hetaryl-[2(1 H )-pyridinylidene]cyanamides can be synthesized on a technical scale by a simple manufacturing procedure. As full nicotinic acetylcholine receptor ( n AChR) agonists, the compounds bind with low affinity at the orthosteric binding site of n AChR. In molecular modeling studies, structural differences are visible in the superposition of active N -[6'-(trifluoromethyl)[1(2 H ),3'-bipyridin]-2-ylidene]cyanamide onto imidacloprid (IMD) and sulfoxaflor (SXF) in bound conformation. On the basis of their physicochemical properties, the most active xylem systemic candidates offer excellent aphicidal activity in vegetables and cotton, when applied as a foliar spray, by soil drench application, or, in particular, as seed dressing for seed treatment uses. Selected candidates show good plant compatibility and reveal a better risk profile with respect to bee pollinators than the majority of currently registered n AChR competitive modulators for seed treatment uses. Applied as a seed dressing in greenhouse profiling, good to excellent control of different aphid species has been observed. In field trials, an interesting level of activity potential against cereal grain aphids (inclusive virus vector control), corn rootworm, and wireworm could be demonstrated. According to molecular modeling investigations (Fukui functions, dipole moments, and electrostatic potentials), there is a broad scope for structure optimization of the chemical class leading to proposals for novel bicyclic insecticides.

The reactions of organic azides with diaryl(dihalo)diboranes(4) were explored, resulting in the observation of a number of surprising reactivity patterns. The reaction of phenyl azide with 1,2-diaryl-1,2-dihalodiboranes(4) resulted in the formation of five-membered rings comprising diboryl-triazenes with retention of the boron-boron bond, while the reaction of the peculiar 1,1-di(9-anthryl)-2,2-difluorodiborane(4) with phenyl azide yielded a six-membered ring bearing a diboryl-triazene, whereby the B-B bond was ruptured by the insertion of an arylnitrene-like reactive intermediate. Both types of heterocycles feature unprecedented connectivity patterns and are very rare examples of boryl triazenes beyond the more common 1,2,3-triazolatoboranes. They are also the product of a unique type of aryl migration from a boron center to the phenyl azide γ-nitrogen center. Lastly, the substitution of 1,2-diaryl-1,2-dihalodiboranes(4) with azide groups, using trimethylsilyl azide as the transfer reagent, yielded boryl-tetrazaboroles and diboryldiazadiboretidines (as side-products), invoking the intermediacy of the first N-boryl-substituted iminoboranes, which are BN isosteres of monoborylated alkynes. The synthetic results are complemented with mechanistic proposals derived from quantum-chemical calculations.

The recently disclosed next generation of reversible, selective, and potent MetAP-2 inhibitors introduced a cyclic tartronic diamide scaffold. However, the lead compound 1a suffered from enterohepatic circulation, preventing further development. Nevertheless, 1a served as a starting point for further optimization. Maintaining potent antiproliferation activity, while improving other compound properties, enabled the generation of an attractive array of new MetAP-2 inhibitors. The most promising derivatives were identified by a multiparameter analysis of the compound properties. Essential for the efficient selection of candidates with in vivo activity was the identification of molecules with a long residence time on the target protein, high permeability, and low efflux ratio not only in Caco-2 but also in the MDR-MDCK cell line. Orally bioavailable, potent, and reversible MetAP-2 inhibitors impede the growth of primary endothelial cells and demonstrated antitumoral activity in mouse models. This assessment led to the nomination of the clinical development compound M8891 , which is currently in phase I clinical testing in oncology patients.

To map qualitative and quantitative metabolome alterations when Penicillium roqueforti is grown in an environment where l-tyrosine levels are perturbed, the recently established differential off-line LC-NMR (DOLC-NMR) approach was successfully applied in connection with an absolute metabolite quantitation using a quantitative 1 H NMR protocol following the ERETIC 2 (Electronic REference To access In vivo Concentrations) methodology. Among the 23 influenced metabolites, amino acid degradation products like 2-(4-hydroxyphenyl)acetic acid and 2-(3,4-dihydroxyphenyl)acetic acid underwent a tremendous upregulation in the amino acid perturbed approach. Moreover, the output of secondary metabolites like andrastin A, eremofortin B, and the tetrapeptide d-Phe-l-Val-d-Val-l-Tyr was affected in the case of the presence or absence of the added aromatic amino acid. Furthermore, the isolated secondary metabolites of P. roqueforti have been quantified for the first time in five divergent Penicillium isolates by means of a validated LC-ECHO-MS/MS method. This technique is used to compensate the effect of co-extracted matrix compounds during the analysis and to utilize quasi-internal standards to quantify all metabolites of interest accurately. This screening outlined the great variety between the different fungi of the same species. The metabolite spectra of wild-type fungi included more toxic intermediates compared to a selected fungi used as a starter culture for blue-mold cheese production. In addition, these secondary metabolites were quantified in commercially available white- and blue-mold cheese samples. The main differences between the analyte profiles of white and blue cheeses were linked to the impact of the used starter culture. Specific metabolites detected from P. roqueforti like andrastin A and B or roquefortine C could not be detected in white cheese. Among the blue cheese samples, different metabolite pattern could be observed regarding various P. roqueforti starter cultures.

The reaction of the tetrahalodiboranes(4) B 2 F 4 , B 2 Cl 4 , and B 2 Br 4 with a Lewis basic platinum(0) complex led to the isolation of the cis-bis(difluoroboryl) complex cis-[(Cy 3 P) 2 Pt(BF 2 ) 2 ] (1) and the novel borylborato complexes trans-[(Cy 3 P) 2 Pt{B(X)-BX 3 }] (2, X = Cl; 3, X = Br), respectively. The trans influence of the borylborato group was found to be one of the strongest ever observed experimentally. Furthermore, the reactivity of little-explored diaryldifluorodiboranes(4) F 2 B-BMes 2 and the new derivative F 2 B-BAn 2 (An = 9-anthryl) toward a range of platinum(0) complexes was investigated. Reactions with relatively nonbulky platinum(0) complexes led to the formation of unsymmetrical cis-bis(boryl) complexes cis-[(R 3 P) 2 Pt(BF 2 )(BMes 2 )] (6, R = Me; 7, R = Et) as well as the first example of a fourfold-unsymmetrical bis(boryl) complex, [(Me 3 P)(Cy 3 P)Pt(BF 2 )(BMes 2 )] (12). The use of a more bulky Pt complex provided access to the unprecedented dinuclear bis(boryl) complexes [{( iPr 3 P)Pt} 2 (μ-BF 2 )(μ-BAr 2 )] (8, Ar = Mes; 9, Ar = An), which feature two different μ 2 -bridging boryl ligands.

Sensory-directed fractionation of extracts prepared from oat flour (Avena sativa L.) followed by LC-TOF-MS, LC-MS/MS, and 1D/2D-NMR experiments revealed avenanthramides and saponins as the key phytochemicals contributing to the typical astringent and bitter off-taste of oat. Besides avenacosides A and B, two previously unreported bitter-tasting bidesmosidic saponins were identified, namely, 3-(O-α-l-rhamnopyranosyl(1→2)-[β-d-glucopyranosyl(1→3)-β-d-glucopyranosyl(1→4)]-β-d-glucopyranosid)-26-O-β-d-glucopyranosyl-(25R)-furost-5-ene-3β,22,26-triol, and 3-(O-α-l-rhamnopyranosyl(1→2)-[β-d-glucopyranosyl(1→4)]-β-d-glucopyranosid)-26-O-β-d-glucopyranosyl-(25R)-furost-5-ene-3β,22,26-triol. Depending on the chemical structure of the saponins and avenanthramides, sensory studies revealed human orosensory recognition thresholds of these phytochemicals to range between 3 and 170 μmol/L.

Potent, selective, and structurally new inhibitors of the Fe(II) enzyme Escherichia coli peptide deformylase (PDF) were obtained by rational optimization of the weakly binding screening hit (5-chloro-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid hydrazide (1). Three-dimensional structural information, gathered from Ni-PDF complexed with 1, suggested the preparation of two series of related hydroxamic acid analogues, 2-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-N-hydroxy-acetamides (A) and 2-(2,2-dioxo-1,4-dihydro-2H-2lambda(6)-benzo[1,2,6]thiadiazin-3-yl)-N-hydroxy-acetamides (B), among which potent PDF inhibitors (37, 42, and 48) were identified. Moreover, two selected compounds, one from each series, 36 and 41, showed good selectivity for PDF over several endoproteases including matrix metalloproteases. However, these compounds showed only weak antibacterial activity.

Low-molecular-weight beta-sulfonyl- and beta-sulfinylhydroxamic acid derivatives have been synthesized and found to be potent inhibitors of Escherichia coli peptide deformylase (PDF). Most of the compounds synthesized and tested displayed antibacterial activities that cover several pathogens found in respiratory tract infections, including Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The potential of these compounds as antibacterial agents is discussed with respect to selectivity, intracellular concentrations in bacteria, and potential for resistance development.