Profiling withanolide A for therapeutic targets in neurodegenerative diseases.

To identify new potential therapeutic targets for neurodegenerative diseases, we initiated activity-based protein profiling studies with withanolide A (WitA), a known neuritogenic constituent of Withania somnifera root with unknown mechanism of action. Molecular probes were designed and synthesized, and led to the discovery of the glucocorticoid receptor (GR) as potential target. Molecular modeling calculations using the VirtualToxLab predicted a weak binding affinity of WitA for GR. Neurite outgrowth experiments in human neuroblastoma SH-SY5Y cells further supported a glucocorticoid-dependent mechanism, finding that WitA was able to reverse the outgrowth inhibition mediated by dexamethasone (Dex). However, further GR binding and transactivation assays found no direct interference of WitA. Further molecular modeling analysis suggested that WitA, although forming several contacts with residues in the GR binding pocket, is lacking key stabilizing interactions as observed for Dex. Taken together, the data suggest that WitA-dependent induction of neurite outgrowth is not through a direct effect on GR, but might be mediated through a closely related pathway. Further experiments should evaluate a possible role of GR modulators and/or related signaling pathways such as ERK, Akt, NF-κB, TRα, or Hsp90 as potential targets in the WitA-mediated neuromodulatory effects.

Pyrrolizidines for direct air capture and CO2 conversion.

Greenhouse gases such as CO2 strongly contribute to the rising temperatures of our planet, but as long as our society is dependent on fossil fuels, this trend will even increase in the near future. Therefore, CO2 capture and subsequent utilization constitute an approach for decarbonization and CO2 mitigation, and for this purpose, amine scrubbing remains the industrially most established process. In this article, we describe the CO2 capture-ability of pyrrolizidine-based diamines, a scaffold with remarkably good properties to fulfill this challenge. We observed fast equimolar CO2-uptake, as well as high stability of these compounds during multiple capture and release-cycles. In addition, the amines could be utilized for direct air capture. Finally, we demonstrate the utility of the pyrrolizidine absorbents in the reduction of CO2 and for the formation of oxazolidinones.

Antiprotozoal Isoprenoids from Salvia hydrangea.

Fractionation of the n-hexane extract of Salvia hydrangea afforded seven isoprenoids including six new compounds (1-6) and salvadione A (7). Their structures were established by comprehensive spectroscopic and spectrometric data analysis (1D and 2D NMR, HRMS). The absolute configuration of salvadione A (7) was established by single-crystal X-ray diffraction analysis with Cu/Kα radiation. In addition, the absolute configuration of all compounds was determined by electronic circular dichroism spectroscopy. A biosynthetic pathway for the formation of the scaffold of 1 is proposed. The antiprotozoal activity of the compounds against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum was determined, and cytotoxicity was assessed in rat myoblast L6 cells. Perovskone C (2) exhibited good activity against P. falciparum (IC50 0.6 µM) and a selectivity index of 62.2.

Domino Pd0 -Catalyzed C(sp3 )-H Arylation/Electrocyclic Reactions via Benzazetidine Intermediates.

The Pd0 -catalyzed C(sp3 )-H arylation of 2-bromo-N-methylanilides leads to unstable benzazetidine intermediates that rearrange to benzoxazines through 4π electrocyclic ring-opening and 6π electrocyclization. The introduction of a bulky, non-activatable amide group on the nitrogen atom was key to favor the challenging reductive elimination step and disfavor undesired reaction pathways.

Mixed-Valent Molecular Triple Deckers.

Two phenothiazine (PTZ) moieties were connected via naphthalene spacers to a central arene to result in stacked PTZ-arene-PTZ structure elements. Benzene and tetramethoxybenzene units served as central arenes mediating electronic communication between the two PTZ units. Based on cyclic voltammetry, UV/Vis-NIR absorption, EPR spectroscopy, and computational studies, the one-electron oxidized forms of the resulting compounds behave as class II organic mixed-valence species in which the unpaired electron is partially delocalized over both PTZ units. The barrier for intramolecular electron transfer depends on the nature of the central arene sandwiched between the two PTZ moieties. These are the first examples of rigid organic mixed-valent triple-decker compounds with possible electron-transfer pathways directly across a stacked structure, and they illustrate the potential of oligo-naphthalene building blocks for long-range electron transfer and a future molecular electronics technology.

Chiral macrocyclic terpyridine complexes.

The syntheses of novel chiral M(ii) bis(terpyridine) cage complexes Fe(L1)2-c and Ru(L1)2-c are described. The extraordinary design of the precursors Fe(L1)2 and Ru(L1)2 allows perfect preorganization for the final closing step. Due to the rigidity of the spacers between the two terpyridine moieties, the two isolated enantiomers barely racemize at room temperature in solution. The stable and axially chiral bis(terpyridine) Fe(ii) and Ru(ii) complexes were fully characterized by NMR-spectroscopy, UV-Vis spectroscopy, electrochemical measurements, high resolution mass spectrometry, circular dichroism measurements, and X-ray structural analysis.

Catalyst-Controlled Stereodivergent Synthesis of Atropisomeric Multiaxis Systems.

Molecular scaffolds with multiple rotationally restricted bonds allow a precise spatial positioning of functional groups. However, their synthesis requires methods addressing the configuration of each stereogenic axis. We report here a catalyst-stereocontrolled synthesis of atropisomeric multiaxis systems enabling divergence from the prevailing stereochemical reaction path. By using ion-pairing catalysts in arene-forming aldol condensations, a strong substrate-induced stereopreference can be overcome to provide structurally well-defined helical oligo-1,2-naphthylenes. The configuration of up to four stereogenic axes was individually catalyst-controlled, affording quinquenaphthalenes with a unique topology.

Biosynthesis of fragin is controlled by a novel quorum sensing signal.

Members of the diazeniumdiolate class of natural compounds show potential for drug development because of their antifungal, antibacterial, antiviral, and antitumor activities. Yet, their biosynthesis has remained elusive to date. Here, we identify a gene cluster directing the biosynthesis of the diazeniumdiolate compound fragin in Burkholderia cenocepacia H111. We provide evidence that fragin is a metallophore and that metal chelation is the molecular basis of its antifungal activity. A subset of the fragin biosynthetic genes is involved in the synthesis of a previously undescribed cell-to-cell signal molecule, valdiazen. RNA-Seq analyses reveal that valdiazen controls fragin biosynthesis and affects the expression of more than 100 genes. Homologs of the valdiazen biosynthesis genes are found in various bacteria, suggesting that valdiazen-like compounds may constitute a new class of signal molecules. We use structural information, in silico prediction of enzymatic functions and biochemical data to propose a biosynthesis route for fragin and valdiazen.

Chiral Bifunctional Phosphine-Carboxylate Ligands for Palladium(0)-Catalyzed Enantioselective C-H Arylation.

Previous enantioselective Pd0 -catalyzed C-H activation reactions proceeding via the concerted metalation-deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes the development of new chiral bifunctional ligands based on a binaphthyl scaffold which incorporates both a phosphine and a carboxylic acid moiety. The optimal ligand provided high yields and enantioselectivities for a desymmetrizing C(sp2 )-H arylation leading to 5,6-dihydrophenanthridines, whereas the corresponding monofunctional ligands showed low enantioselectivities. The bifunctional system proved applicable to a range of substituted dihydrophenanthridines, and allowed the parallel kinetic resolution of racemic substrates.

Synthesis of trinorbornane.

Herein we report the synthesis and characterisation of the until recently unreported chiral C11 skeleton of tetracyclo[5.2.2.01,6.04,9]undecane ("trinorbornane") which could be obtained in 7% overall yield in 9 steps. This new rigid structural type was found to be present in the computer generated Chemical Universe Data-base (GDB) and has until now no real-world counterpart.

Intramolecular Light-Driven Accumulation of Reduction Equivalents by Proton-Coupled Electron Transfer.

The photochemistry of a molecular pentad composed of a central anthraquinone (AQ) acceptor flanked by two Ru(bpy)32+ photosensitizers and two peripheral triarylamine (TAA) donors was investigated by transient IR and UV-vis spectroscopies in the presence of 0.2 M p-toluenesulfonic acid (TsOH) in deaerated acetonitrile. In ∼15% of all excited pentad molecules, AQ is converted to its hydroquinone form (AQH2) via reversible intramolecular electron transfer from the two TAA units (τ = 65 ps), followed by intermolecular proton transfer from TsOH (τ ≈ 3 ns for the first step). Although the light-driven accumulation of reduction equivalents occurs through a sequence of electron and proton transfer steps, the resulting photoproduct decays via concerted PCET (τ = 4.7 µs) with an H/D kinetic isotope effect of 1.4 ± 0.2. Moreover, the reoxidation of AQH2 seems to take place via a double electron transfer step involving both TAA+ units rather than sequential single electron transfer events. Thus, the overall charge-recombination reaction seems to involve a concerted proton-coupled two-electron oxidation of AQH2. The comparison of experimental data obtained in neat acetonitrile with data from acidic solutions suggests that the inverted driving-force effect can play a crucial role for obtaining long-lived photoproducts resulting from multiphoton, multielectron processes. Our pentad provides the first example of light-driven accumulation of reduction equivalents stabilized by PCET in artificial molecular systems without sacrificial reagents. Our study provides fundamental insight into how light-driven multielectron redox chemistry, for example the reduction of CO2 or the oxidation of H2O, can potentially be performed without sacrificial reagents.

Palladium(0)-catalyzed asymmetric C(sp3)-H arylation using a chiral binol-derived phosphate and an achiral ligand.

The first efficient palladium(0)-catalyzed enantioselective C(sp3)-H activation reaction using a catalytic chiral base and an achiral phosphine ligand is reported. Fine-tuning the binol-derived phosphoric acid pre-catalyst and the reaction conditions was found to be crucial to achieve high levels of enantioselectivity for a variety of indoline products containing both tri- and tetrasubstituted stereocenters.

A nor-diterpene from Salvia sahendica leaves.

Phytochemical investigation of n-hexane extract of Salvia sahendica by normal phase column chromatography resulted in the isolation of six compounds. Structures were established by 1D and 2D NMR spectroscopy, and HRMS, as a new norditerpene 1, and known terpenoids, sclareol (2), oleanolic acid (3), ß-sitosterol (4), salvigenin (5) and 3α-hydroxy-11α,12α-epoxyoleanan-28,13ß-olide (6). The absolute configuration of 1 was confirmed by a combination of X-ray single crystal analysis and electronic circular dichroism spectroscopy. In vitro cytotoxic activity on breast cancer cell line (MDA-MB-231) and also the antimicrobial activity of the pure compounds were tested against Staphylococcus aureus, Bacilus cereus and Escherichia coli.

Intramolecular Inverse Electron-Demand [4 + 2] Cycloadditions of Ynamides with Pyrimidines: Scope and Density Functional Theory Insights.

4-Aminopyridines are valuable scaffolds for the chemical industry in general, from life sciences to catalysis. We report herein a collection of structurally diverse polycyclic fused and spiro-4-aminopyridines that are prepared in only three steps from commercially available pyrimidines. The key step of this short sequence is a [4 + 2]/retro-[4 + 2] cycloaddition between a pyrimidine and an ynamide, which constitutes the first examples of ynamides behaving as electron-rich dienophiles in [4 + 2] cycloaddition reactions. In addition, running the ihDA/rDA reaction in continuous mode in superheated toluene, to overcome the limited scalability of MW reactions, results in a notable production increase compared to batch mode. Finally, density functional theory investigations shed light on the energetic and geometric requirements of the different steps of the ihDA/rDA sequence.

Securigenin glycosides as hypoglycemic principles of Securigera securidaca seeds.

Seeds of Securigera securidaca (Fabaceae) are used in Iranian folk medicine as an antidiabetic treatment. In this study, the antihyperglycemic activity of chloroform and methanol fractions (CF and MF) from S. securidaca seed extract was investigated and their bioactive constituents were identified. The antidiabetic effects of fractions were assessed by streptozocin-induced diabetic Naval Medical Research Institute mice. The hypoglycemic activity of MF at 100 mg/kg and CF at 400 mg/kg was comparable with glibenclamide (3 mg/kg). MF at 400 mg/kg and CF at 600 mg/kg showed equal hypoglycemic responses to 12.5 IU/kg insulin (P > 0.05). Three cardiac glycosides were isolated as active constituents responsible for the hypoglycemic activity. Securigenin-3- O -ß-glucopyranosyl-(1 â†’ 4)-ß-xylopyranoside (1) was a major compound in seeds. Securigenin-3- O -inositol-(1 â†’ 3)-ß-glucopyranosyl-(1 â†’ 4)-ß-xylopyranoside (2) and securigenin-3- O -α-rhamnopyranosyl-(1 â†’ 4)-α-glucopyranoside (3) were found as new natural products. When 1-3 were tested at 10 mg/kg there was a significant reduction of blood glucose levels in diabetic mice, comparable to that of 3 mg/kg glibenclamide (P > 0.05). The hypoglycemic effect was due to an increase in insulin secretion; the insulin levels in the diabetic mice significantly improved and were comparable with those in healthy animals (P > 0.05). Compounds responsible for the hypoglycemic properties of S. securidaca seeds were identified as cardiac glycosides and were found to act via an increase of insulin levels in a diabetic mouse model.

Collective Syntheses of Icetexane Natural Products Based on Biogenetic Hypotheses.

A divergent synthesis of 10 icetexane natural products based on a proposed biogenetic cationic ring expansion of a reduced carnosic acid derivative is described. Of these icetexanes, (+)-salvicanol, (-)-cyclocoulterone, (-)-coulterone, (-)-obtusinone D, and (-)-obtusinone E have been synthesized for the first time. In addition, the hypothesis for the non-enzymatic biogenesis of benzo[1,3]dioxole natural products has been experimentally investigated. Additional experimental evidence for the abiotic formation of the methylenedioxy unit is provided, as photolysis of the quinone (+)-komaroviquinone resulted in the formation of the [1,3]dioxole-containing natural product (-)-cyclocoulterone and (+)-komarovispirone.

Spin-Delocalization in a Helical Open-Shell Hydrocarbon.

Neutral open-shell molecules, in which spin density is delocalized through a helical conjugated backbone, hold promise as models for investigating phenomena arising from the interplay of magnetism and chirality. Apart from a handful of examples, however, the chemistry of these compounds remains largely unexplored. Here, we examine the prospect of extending spin-delocalization over a helical backbone in a model compound naphtho[3,2,1-no]tetraphene, the first helically chiral open-shell hydrocarbon, in which one benzene ring is fused to [5]helicene, forming a phenalenyl subunit. The unpaired electron in this molecule is delocalized over the entire helical core composed of six rings, albeit in a nonuniform fashion, unlike in phenalenyl. In the case of a monosubstituted derivative, the uneven spin-distribution results in a selective σ-dimer formation in solution, as confirmed by 2D NMR spectroscopy. In contrast, the dimerization process is suppressed entirely when four substituents are installed to sterically hinder all reactive positions. The persistent nature of the tetrasubstituted derivative allowed its characterization by EPR, UV-vis, and CD spectroscopies, validating spin-delocalization through a chiral backbone, in accord with DFT calculations. The nonuniform spin-distribution, which dictates the selectivity of the σ-dimer formation, is rationalized by evaluating the aromaticity of the resonance structures that contribute to spin-delocalization.

Formal Total Synthesis of (-)-Jiadifenolide and Synthetic Studies toward seco-Prezizaane-Type Sesquiterpenes.

Synthetic studies toward highly oxygenated seco-prezizaane sesquiterpenes are reported, which culminated in a formal total synthesis of the neurotrophic agent (-)-jiadifenolide. For the construction of the tricyclic core structure, an unusual intramolecular and diastereoselective Nozaki-Hiyama-Kishi reaction involving a ketone as electrophilic coupling partner was developed. In addition, synthetic approaches toward the related natural product (2R)-hydroxy-norneomajucin, featuring a Mn-mediated radical cyclization for the tricycle assembly and a regioselective OH-directed C-H activation are presented.

Inorganic Cyanide as Protecting Group in the Stereospecific Reconstitution of Vitamin B12 from an Artificial Green Secocorrinoid.

The synthesis of vitamin B12 in four steps from an artificial green secocorrinoid is presented. The stereospecific reconstitution of the B-ring of the cobalamin involves a quantitative and rapid ligand-centered radical ring closure reaction leading first to a new B12 derivative with antivitamin activity that is subsequently converted to the natural product. Chemoselectivity in the one-electron reduction of the macrocycle was achieved by introducing inorganic cyanide as an axially coordinating protecting group of the otherwise reduction-sensitive CoIII-ion. The integrity of structure and function of the reconstituted natural product was unequivocally proven by single crystal structural analysis and a microbiological assay using Lactobacillus leichmannii.

Regioisomerism in cationic sulfonyl-substituted [Ir(C

A series of regioisomeric cationic iridium complexes of the type [Ir(C^N)2(bpy)][PF6] (bpy = 2,2'-bipyridine) is reported. The complexes contain 2-phenylpyridine-based cyclometallating ligands with a methylsulfonyl group in either the 3-, 4- or 5-position of the phenyl ring. All the complexes have been fully characterized, including their crystal structures. In acetonitrile solution, all the compounds are green emitters with emission maxima between 493 and 517 nm. Whereas substitution meta to the Ir-C bond leads to vibrationally structured emission profiles and photoluminescence quantum yields of 74 and 77%, placing a sulfone substituent in a para position results in a broad, featureless emission band, an enhanced quantum yield of 92% and a shorter excited-state lifetime. These results suggest a larger ligand-centred ((3)LC) character of the emissive triplet state in the case of meta substitution and a more pronounced charge transfer (CT) character in the case of para substitution. Going from solution to the solid state (powder samples and thin films), the emission maxima are red-shifted for all the complexes, resulting in green-yellow emission. Data obtained from electrochemical measurements and density functional theory calculations parallel the photophysical trends. Light-emitting electrochemical cells (LECs) based on the complexes were fabricated and evaluated. A maximum efficiency of 4.5 lm W(-1) at a maximum luminance of 940 cd m(-2) was observed for the LEC with the complex incorporating the sulfone substituent in the 4-position when operated under pulsed current driving conditions.