Crystal structures, electron spin resonance, and thermogravimetric analysis of three mixed-valence copper cyanide polymers.

The crystal structures of three mixed-valence copper cyanide alkanolamine polymers are presented, together with thermogravimetric analysis (TGA) and electron spin resonance (ESR) data. In all three structures, a CuII moiety on a crystallographic center of symmetry is coordinated by two alkanolamines and links two CuICN chains via cyanide bridging groups to form diperiodic sheets. The sheets are linked together by cuprophilic CuI-CuI interactions to form a three-dimensional network. In poly[bis(µ-3-aminopropanolato)tetra-µ-cyanido-dicopper(I)dicopper(II)], [Cu4(CN)4(C3H8NO)2]n, 1, propanolamine bases have lost their hydroxyl H atoms and coordinate as chelates to two CuII atoms to form a dimeric CuII moiety bridged by the O atoms of the bases with CuII atoms in square-planar coordination. The ESR spectrum is very broad, indicating exchange between the two CuII centers. In poly[bis(2-aminopropanol)tetra-µ-cyanido-dicopper(I)copper(II)], [Cu3(CN)4(C3H9NO)2]n, 2, and poly[bis(2-aminoethanol)tetra-µ-cyanido-dicopper(I)copper(II)], [Cu3(CN)4(CH7NO)2]n, 3, a single CuII atom links the CuICN chains together via CN bridges. The chelating alkanolamines are not ionized, and the OH groups form rather long bonds in the axial positions of the octahedrally coordinated CuII atoms. The coordination geometries of CuII in 2 and 3 are almost identical, except that the Cu-O distances are longer in 2 than in 3, which may explain their somewhat different ESR spectra. Thermal decomposition in 2 and 3, but not in 1, begins with the loss of HCN(g), and this can be correlated with the presence of OH protons on the ligands in 2 and 3, which are not present in 1.

The e-liquid flavoring cinnamaldehyde induces cellular stress responses in human proximal tubule (HK-2) kidney cells.

Flavored e-liquid use has become popular among e-cigarette users recently, but the effects of such products outside the lung are not well characterized. In this work, acute exposure to the popular flavoring cinnamaldehyde (CIN) was performed on human proximal tubule (HK-2) kidney cells. Cells were exposed to 0-100 µM CIN for 24-48 h and cellular stress responses were assessed. Mitochondrial viability via MTT assay was significantly decreased at 20 µM for 24 and 48 h exposure. Seahorse XFp analysis showed significantly decreased mitochondrial energy output at 20 µM by 24 h exposure, in addition to significantly reduced ATP Synthase expression. Seahorse analysis also revealed significantly decreased glycolytic function at 20 µM by 24 h exposure, suggesting inability of glycolytic processes to compensate for reduced mitochondrial energy output. Cleaved caspase-3 expression, a mediator of apoptosis, was significantly increased at the 24 h mark. C/EBP homologous protein (CHOP) expression, a mediator of ER-induced apoptosis, was induced by 48 h and subsequently lost at the highest concentration of 100 µM. This decrease was accompanied by a simultaneous decrease in its downstream target cleaved caspase-3 at the 48 h mark. The autophagy marker microtubule-associated protein 1 A/1B light chain 3 (LC3B-I and LC3B-II) expression was significantly increased at 100 µM by 24 h. Autophagy-related 7 (ATG7) protein and mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1) and PARKIN expression were significantly reduced at 24 and 48 h exposure. These results indicate acute exposure to CIN in the kidney HK-2 model induces mitochondrial dysfunction and cellular stress responses.

Accurate Crystal Structures of C12H9CN, C12H8(CN)2, and C16H11CN Valence Isomers Using Nonspherical Atomic Scattering Factors.

Fourteen crystal structures, mostly from good-quality datasets but including some marginal and twinned exemplars, from a series of novel polycyclic benzo- and naphtho-fused organic nitriles are presented and accurately described, including some related structures of a bromo-substituted and partially hydrogenated analogues. These structures represent a considerable increase in the number of published structures within their archetypes. This work highlights the significant advancement in structural refinement software proffered by NoSpherA2, which enables Hirshfeld Atom Refinement (HAR) of the structures within Olex2 v1.5. This results in the determination of C-H bond lengths with near to neutron diffraction accuracies at far lower experimental cost, and with an average improvement in C-C bond precision of 42% compared to Independent Atom Model refinements. H-atoms (apart from disordered components) refined well with anisotropic displacement parameters. Nonclassical H-bonding (C-H···N≡C) in this series is analyzed, and dipolar nitrile-nitrile interactions (C≡N···C≡N) in three major motifs described by (Wood, P. A. Acta Cryst. B, 2008, 64, 393-396) are found in 9 out of 13 nitrile-containing compounds of this series, a much higher proportion than the global average of 21% of nitrile-containing compounds. The HAR/NoSpherA2 approach shows increasing benefits with better data quality without apparent discontinuities.

A biosynthetically inspired synthesis of (-)-berkelic acid and analogs.

We describe a complete account of our total synthesis and biological evaluation of (-)-berkelic acid and analogs. We delineate a synthetic strategy inspired by a potentially biomimetic union between the natural products spicifernin and pulvilloric acid. After defining optimal parameters, we executed a one-pot silver-mediated in situ dehydration of an isochroman lactol to methyl pulvillorate, the cycloisomerization of a spicifernin-like alkynol to the corresponding exocyclic enol ether, and a subsequent cycloaddition to deliver the tetracyclic core of berkelic acid. Our studies confirm that the original assigned berkelic acid structure is not stable and equilibrates into a mixture of 4 diastereomers, fully characterized by X-ray crystallography. In addition to berkelic acid, C22-epi-berkelic acid, and nor-berkelic acids, we synthesized C26-oxoberkelic acid analogs that were evaluated against human cancer cell lines. In contrast to data reported for natural berkelic acid, our synthetic material and analogs were found to be devoid of activity.

Characterization of novel small-molecule NRF2 activators: Structural and biochemical validation of stereospecific KEAP1 binding.

BACKGROUND: Semi-synthetic oleanane triterpenoid antioxidant inflammation modulators (tpAIMs) are small molecules that interact with KEAP1 cysteine residue 151 (C151) and activate NRF2. Exploration of the structure-activity relationship between the tpAIMs and KEAP1 is limited by the predominantly hydrocarbon nature of the oleanane triterpenoid pentacyclic ring structure. Therefore, we used novel, chemically-tractable, synthetic antioxidant inflammation modulators (sAIMs) to probe the stereoselectivity of the ligand-protein interaction. METHODS: We measured several parameters of NRF2 activation to assess the potency of sAIM enantiomers with natural (tpAIM-like) 4(S),5(S),10(R) or unnatural 4(R),5(R),10(S) configurations. Additionally, we determined the crystal structure of the KEAP1 BTB domain in complex with two different sAIMs. RESULTS: We found that the potencies of sAIM enantiomers in the natural configuration were similar to those of the tpAIM, RTA 405. Strikingly, sAIM enantiomers in the unnatural configuration were 10- to 40-fold less potent than their natural counterparts. Crystallographic studies of sAIMs in complex with the KEAP1 BTB domain demonstrated that these ligands form a covalent bond with C151 and revealed the presence of additional hydrogen bonds, Van der Waals interactions, and pi-stacking interactions. CONCLUSIONS: Although KEAP1 C151 is required for NRF2 activation by tpAIMs and sAIMs, interactions with other KEAP1 residues are critical for the stereospecific recognition and potency of these ligands. GENERAL SIGNIFICANCE: This work demonstrates that reversible cyanoenone Michael acceptors, such as the tpAIMs and sAIMs, can be specifically tuned to regulate redox sensitive cysteine residues on key signaling molecules, an approach with significant promise for innovative drug development.

The effects of environmental variability and spatial sampling on the three-dimensional inversion problem.

The overall goal of this work is to quantify the effects of environmental variability and spatial sampling on the accuracy and uncertainty of estimates of the three-dimensional ocean sound-speed field. In this work, ocean sound speed estimates are obtained with acoustic data measured by a sparse autonomous observing system using a perturbative inversion scheme [Rajan, Lynch, and Frisk, J. Acoust. Soc. Am. 82, 998-1017 (1987)]. The vertical and horizontal resolution of the solution depends on the bandwidth of acoustic data and on the quantity of sources and receivers, respectively. Thus, for a simple, range-independent ocean sound speed profile, a single source-receiver pair is sufficient to estimate the water-column sound-speed field. On the other hand, an environment with significant variability may not be fully characterized by a large number of sources and receivers, resulting in uncertainty in the solution. This work explores the interrelated effects of environmental variability and spatial sampling on the accuracy and uncertainty of the inversion solution though a set of case studies. Synthetic data representative of the ocean variability on the New Jersey shelf are used.

A tetrabromo-1,4-ethanonaphthalene and related dibromo-1,4-ethenonaphthalene.

(1RS,3RS,4RS,10SR)-2,2,3,10-Tetrabromo-1,2,3,4-tetrahydro-1,4-ethanonaphthalene, C12H10Br4, (I), is the first structure to be reported with four Br atoms bound to a 1,4-ethanonaphthalene framework and also the first which possesses three Br atoms in exo positions. Interactions between the Br atoms [three short intramolecular Br...Br distances of 3.1094 (4), 3.2669 (4) and 3.4415 (5) Å] have little effect on the C-C bond lengths but lead to significant twisting of the cage structure compared with the parent hydrocarbon, which is expected to be fully eclipsed at the two saturated C2H4 bridge positions. Chemically related (1SR,4RS)-2,3-dibromo-1,4-ethenonaphthalene, C12H8Br2, (II), obtained by double dehydrobromination of (I), represents the first structure of any halogen-substituted benzobarrelene. This cis-dibromide shows little evidence of steric congestion at the double bond [Br...Br = 3.5276 (8) Å] as a consequence of the large C-C-Br angles [average C=C-Br angle = 126.15 (10)°].

(5Z,7Z,9Z)-5,10-Di-bromo-benzo[8]annulene.

In the structure of the title compound, C12H8Br2, the two bromine substituents are oriented exo to the boat-shaped cyclo-octa-tetra-ene at the two ring sites that are ß to the ring fusion positions. The average Br-C bond distance is 1.919 (2) Å, the average distance for C=C double bonds that are Br substituted is 1.328 (2) Å, while the other two double-bond distances are 1.327 (2) and 1.398 (2) Šfor the non-fused and fused bonds, respectively. Each type of ring inter-atomic distance is within s.u. of the average values for the four known structures, including the title compound, of benzo-fused cyclo-ocata-tetra-enes that are not coordinated to a metal atom. The crystal structure features short Br⋯Br [3.6620 (3) Å] and C⋯H [2.834 (2) and 2.841 (2) Å] contacts.

Dimethyl 7-meth-oxy-tetra-cyclo-[6.4.0.0(2,4).0(3,7)]dodeca-1(12),5,8,10-tetra-ene-3,4-dicarboxyl-ate.

The title compound, C(17)H(16)O(5), is a previously unreported substituted semibulvalene cage compound (that is, a tricyclic hydro-carbon formed from one cyclo-propane and two cyclo-pentene rings which also has one double bond fused to a benzene ring). It has one meth-oxy substituent attached to the bridgehead C atom that links only the two cyclo-pentene rings and two methyl carboxyl-ate groups located on the C atom shared by all three non-benzene rings and that shared only between the cyclo-propane and the cyclo-pentene rings. The stereochemistry of the two enanti-omers (racemate) that assemble in each unit cell is RRRS and SSSR. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds and C-H⋯π inter-actions, forming double-layered sheets lying perpendicular to the a axis.

exo-10,11-Dibromo-tricyclo-[6.3.1.0]dodeca-2,4,6,9-tetra-ene.

The title compound, C(12)H(10)Br(2), is a bridged ring system based on a homobenzonorbornadiene framework. The exo configuration of one of the Br atoms was previously assigned via NMR correlations and has now been confirmed by the geometry of the solid-state structure. The compound features a Br-C-C-Br torsion angle of 66.68 (12)°, whereby the C atoms in the calculation are respectively sp(3)- and sp(2)-hybridized.

A concise synthesis of berkelic acid inspired by combining the natural products spicifernin and pulvilloric acid.

We describe a concise synthesis of the structurally novel fungal extremophile metabolite berkelic acid, an effort leading to an unambiguous assignment of C22 stereochemistry. Our synthetic approach was inspired by the recognition that berkelic acid displays structural characteristics reminiscent of two other fungal metabolites, spicifernin and pulvilloric acid. Based on this notion, we executed a synthesis that features a Ag-catalyzed cascade dearomatization-cycloisomerization-cycloaddition sequence to couple two natural product inspired fragments. Notably, a spicifernin-like synthon was prepared with defined C22 stereochemistry in seven steps and three purifications (24-28% overall yield). A potentially useful anti-selective conjugate propargylation reaction was developed to introduce the vicinal stereodiad. An enantioconvergent synthesis of the other coupling partner, the aromatic precursor to pulvilloric acid methyl ester, was achieved in eight steps and 48% overall yield. The total synthesis of berkelic acid and its C22 epimer was thus completed in a 10 step linear sequence and 11-27% overall yield.

Gold(I)-catalyzed intramolecular hydroamination of unactivated C==C bonds with alkyl ammonium salts.

A mixture of (5)AuCl [ = PCy2[2-(2,6-C6H3(OMe)2)C6H4]] and AgOTf catalyzes the intramolecular hydroamination of unactivated C==C bonds with primary and secondary ammonium salts.

Platinum-catalyzed hydrofunctionalization of unactivated alkenes with carbon, nitrogen and oxygen nucleophiles.

The transition metal-catalyzed addition of the X-H bond of a carbon, nitrogen or oxygen nucleophile across the C[double bond]C bond of an unactivated alkene (hydrofunctionalization) represents an attractive, atom-economical approach to the synthesis of carbocyclic and heterocyclic molecules and for the elaboration of ethylene and 1-alkenes. We have developed a family of Pt(II)-catalyzed protocols for the inter- and intramolecular hydrofunctionalization of unactivated alkenes with a range of H-X nucleophiles including beta-diketones, indoles, amines, carboxamides and alcohols. These transformations display good functional group compatibility, low moisture sensitivity, and often good generality.

Gold(I)-catalyzed enantioselective hydroamination of N-allenyl carbamates.

Treatment of the N-4,5-hexadienyl carbamate 2a with a catalytic 1:2 mixture of [(S)-1]Au2Cl2 [(S)-1 = (S)-3,5-t-Bu-4-MeO-MeOBIPHEP] and AgClO4 in m-xylene at -40 degrees C for 24 h led to isolation of 2-vinylpyrrolidine 3a in 97% yield with 81% ee. Gold(I)-catalyzed enantioselective hydroamination was effective for a number of carbamate groups and tolerated terminal disubstitutution of the allenyl moiety.

Room temperature hydroamination of N-alkenyl ureas catalyzed by a gold(i) N-heterocyclic carbene complex.

[Structure: see text] Treatment of an N-4-pentenyl or N-5-hexenyl urea with a catalytic 1:1 mixture of a gold(I) N,N-diaryl imidazol-2-ylidine complex and AgOTf at or near room temperature leads to intramolecular exo-hydroamination to form the corresponding nitrogen heterocycle in excellent yield.

Gold(I)-catalyzed intramolecular hydroamination of unactivated alkenes with carboxamides.

N-Alkenyl carboxamides undergo gold-catalyzed intramolecular exo-hydroamination to form nitrogen heterocycles in excellent yield.

Platinum-catalyzed intramolecular hydroamination of unactivated olefins with secondary alkylamines.

Reaction of benzyl-2,2-diphenyl-4-pentenylamine with a catalytic 1:2 mixture of [PtCl2(H2C=CH2)]2 (2.5 mol %) and PPh3 in dioxane at 120 degrees C for 16 h led to isolation of 1-benzyl-2-methyl-4,4-diphenylpyrrolidine in 75% yield. A number of gamma- and delta-amino olefins underwent intramolecular hydroamination to form the corresponding pyrrolidine derivatives in moderate to good yield. The reaction displayed excellent functional group compatibility and low moisture sensitivity.

New Type 2 Copper-Cysteinate Proteins. Copper Site Histidine-to-Cysteine Mutants of Yeast Copper-Zinc Superoxide Dismutase.

Preparation and characterization of two new site-directed mutant copper-zinc superoxide dismutase proteins from Saccharomyces cerevisiae, i.e., His46Cys (H46C) and His120Cys (H120C), in which individual histidyl ligands in the copper-binding site were replaced by cysteine, are reported here. These two mutant CuZnSOD proteins may be described as type 2 (or normal) rather than type 1 (or blue) copper-cysteinate proteins and are characterized by their yellow rather than blue color, resulting from intense copper-to-sulfur charge transfer bands around 400 nm, their type 2 EPR spectra, with large rather than small nuclear hyperfine interactions, and their characteristic type 2 d-d electronic absorption spectra. An interesting difference between these two copper site His-to-Cys mutations is that the imidazolate bridge between the two metal sites that is characteristic of the wild-type protein remains intact in the case of the H46C mutant but is not present in the case of the H120C mutant.