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Tumor cells may aberrantly express metabolic enzymes to adapt to their environment for survival and growth. Targeting cancer-specific metabolic enzymes is a potential therapeutic strategy. Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and links the tricarboxylic acid cycle and glycolysis/gluconeogenesis. Mitochondrial PEPCK (PEPCK-M), encoded by PCK2, is an isozyme of PEPCK and is distributed in mitochondria. Overexpression of PCK2 has been identified in many human cancers and demonstrated to be important for the survival program initiated upon metabolic stress in cancer cells. We evaluated the expression status of PEPCK-M and investigated the function of PEPCK-M in breast cancer.We checked the expression status of PEPCK-M in breast cancer samples by immunohistochemical staining. We knocked down or overexpressed PCK2 in breast cancer cell lines to investigate the function of PEPCK-M in breast cancer.PEPCK-M was highly expressed in estrogen receptor-positive (ERPEPCK-M promotes proliferation and cell cycle progression in ER

Non-alternant non-benzenoid π-conjugated polycyclic hydrocarbons (PHs) are expected to exhibit very different electronic properties from the all-benzenoid PHs. Herein, we report the synthesis and physical properties of three azulene-fused acene molecules (1, 2 and 3), which are isoelectronic to the pentacene, hexacene and heptacene, respectively. X-ray crystallographic analysis, NMR spectra, and theoretical calculations reveal a localised aromatic backbone comprising all the six- and five-membered rings while the seven-membered ring remains non-aromatic. They display properties of both azulene and acenes and are much more stable than the respective acenes. The dications of 1, 2 and 3 were formed by chemical oxidation. Notably, 3

We acknowledge the financial support from King AbdullahUniversity of Science and Technology (KAUST).

Pancreatic neuroendocrine tumor (pNET) is a pancreatic neoplasm with neuroendocrine differentiation. pNET in early stage can be treated with surgical resection with long‐term survival, whereas the prognosis of pNET with locoregional or distant metastasis is relatively poor. Lymphangiogenesis is essential for tumor metastasis via the lymphatic system and may overhead distant metastasis. c‐Myc overexpression is involved in tumorigenesis. The role of c‐Myc in lymphangiogenesis is unclear. In this study, we evaluated the mechanism and effect of c‐Myc on lymphangiogenesis of pNET via interaction of lymphatic endothelial cells (LECs) and pNET cells. Lymph node metastasis was evaluated in pNET xenograft mice. Potential target agents to inhibit lymph node metastasis were evaluated in an animal model. We found that vascular endothelial growth factor C (VEGFC) expression and secretion was increased in pNET cell lines with c‐Myc overexpression. c‐Myc transcriptionally upregulates VEGFC expression and the secretion of pNET cells by directly binding to the E‐box of the VEGFC promoter and enhances VEGF receptor 3 phosphorylation and the tube formation of LECs. c‐Myc overexpression is associated with lymph node metastasis in pNET xenograft mice. Combinational treatment with an mTOR inhibitor and c‐Myc inhibitor or VEGFC‐neutralizing chimera protein reduced lymph node metastasis in the mice with c‐Myc overexpression. The mTOR inhibitor acts on lymphangiogenesis by reducing VEGFC expression in pNET cells and inhibiting the tube formation of LECs. In conclusion, mTOR and c‐Myc are important for lymphangiogenesis of pNET and are potential therapeutic targets for prevention and treatment of lymph node metastasis in pNET., c‐Myc promotes lymph node metastases of pancreatic neuroendocrine tumors via upregulation of vascular endothelial growth factor C (VEGFC). Combined targeting of mTOR with c‐Myc or VEGFC is a potential therapy for the treatment of pNET.

Substituted cyclohexylamines are becoming increasingly important in drug discovery. Asymmetric Heck insertion/amination of nonconjugated cyclodienes proceeds to give 5-aryl cyclohexenylamines with good enantioselectivity and exclusive trans configurations. Primary and secondary anilines, indoline, and benzylamines are suitable amines. The weakly donating diphosphite Kelliphite forms a deep unsymmetrical pocket, which is essential for stereoselective anti attack of amines. Agency for Science, Technology and Research (A*STAR) Economic Development Board (EDB) Accepted version We acknowledge financial support from Peking UniversityShenzhen Graduate School, Shenzhen Bay Laboratory(21230011-Scripps), Nanyang Technological University,GSK-EDB Trust Fund (2017 GSK-EDB Green and Sustain-able Manufacturing Award) and A*STAR Science andEngineering Research Council (AME IRG A1783c0010).

The dearomatization of 3-nitroindoles through a chiral-phosphine-mediated [3+2] annulation reaction is described. This method makes use of readily available 3-nitroindoles as an aromatic feedstock and rapidly delivers a wide range of cyclopentaindoline alkaloid scaffolds in a highly enantioselective manner. Notably, phosphine-triggered cyclization has not been utilized previously in a dearomatization process.

We gratefully acknowledge the financial support from King Abdullah University of Science and Technology; Competitive Research Grant (URF/1/1378) and Baseline Funding, and from Chinese NSFC (51672309) and the Fundamental Research Funds for the Central Universities (18CX07009A).

We are grateful for the financial support from King Abdullah University of Science and Technology and a SABIC Chair Professorship to K.-W.H.

Financial support for this work was provided by the King Abdullah University of Science and Technology (URF/1/3018–01-01).

The photoelectrochemical (PEC) approach is attractive as a promising route for the nitrogen reduction reaction (NRR) toward ammonia (NH3 ) synthesis. However, the challenges in synergistic management of optical, electrical, and catalytic properties have limited the efficiency of PEC NRR devices. Herein, to enhance light-harvesting, carrier separation/transport, and the catalytic reactions, a concept of decoupling light-harvesting and electrocatalysis by employing a cascade n+ np+ -Si photocathode is implemented. Such a decoupling design not only abolishes the parasitic light blocking but also concurrently improves the optical and electrical properties of the n+ np+ -Si photocathode without compromising the efficiency. Experimental and density functional theory studies reveal that the porous architecture and N-vacancies promote N2 adsorption of the Au/porous carbon nitride (PCN) catalyst. Impressively, an n+ np+ -Si photocathode integrating the Au/PCN catalyst exhibits an outstanding PEC NRR performance with maximum Faradaic efficiency (FE) of 61.8% and NH3 production yield of 13.8 µg h-1 cm-2 at -0.10 V versus reversible hydrogen electrode (RHE), which is the highest FE at low applied potential ever reported for the PEC NRR.

The remote hydrogen plasma is able to create abundant S-vacancies on amorphous molybdenum sulfide (a-MoSx ) as active sites for hydrogen evolution. The results demonstrate that the plasma-treated a-MoSx exhibits superior performance and higher stability than Pt in a proton exchange membrane based electrolyzers measurement as a proof-of-concept of industrial application.

Designing supported well-defined bis(carbene) complexes remains a key challenge in heterogeneous catalysis. The reaction of W(≡CtBu)(CH2 tBu)3 with amine-modified mesoporous SBA15 silica, which has vicinal silanol/silylamine pairs [(≡SiOH)(≡SiNH2 )], leads to [(≡SiNH2 -)(≡SiO-)W(≡CHtBu)(CH2 tBu)2 ] and [(≡SiNH2 -)(≡SiO-)W(=CHtBu)2 (CH2 tBu). Variable temperature, (1) H-(1) H 2D double-quantum, (1) H-(13) C HETCOR, and HETCOR with spin diffusion solid-state NMR spectroscopy demonstrate tautomerization between the alkyl alkylidyne and the bis(alkylidene) on the SBA15 surface. Such equilibrium is possible through the coordination of W to the surface [(≡Si-OH)(≡Si-NH2 )] groups, which act as a [N,O] pincer ligand. DFT calculations provide a rationalization for the surface-complex tautomerization and support the experimental results. This direct observation of such a process shows the strong similarity between molecular mechanisms in homogeneous and heterogeneous catalysis. In propane metathesis (at 150 °C), the tungsten bis(carbene) tautomer is favorable, with a turnover number (TON) of 262. It is the highest TON among all the tungsten alkyl-supported catalysts.

An unsymmetrically protonated PN(3) -pincer complex in which ruthenium is coordinated by one nitrogen and two phosphorus atoms was employed for the selective generation of hydrogen from formic acid. Mechanistic studies suggest that the imine arm participates in the formic acid activation/deprotonation step. A long life time of 150 h with a turnover number over 1 million was achieved.

Acene-based materials have promising applications for organic electronics but the major constrain comes from their poor stability. Herein a new strategy to stabilize reactive acenes, by fusion of an anti-aromatic pentalene unit onto the zigzag edges of two acene units to form a Z-shaped acene dimer, is introduced. The Z-shaped acene dimers are extremely stable and show a small energy gap resulting from intramolecular donor-acceptor interactions. X-ray crystallographic analysis revealed their unique geometry and one-dimensional slip-stack columnar structure. Besides optical and electrochemical characterizations, solution-processed field-effect transistors were also fabricated.

A well-defined PN3-Ru pincer complex (5) bearing a redox-active bipyridine ligand with an aminophosphine arm has been established as an effective and stable molecular electrocatalyst for CO2 reduction to CO and HCOOH with negligible formation of H2 in a H2O/MeCN mixture. Done in a pince: A PN3-Ru pincer complex (see figure) has been found to show high activity and stability as a molecular electrocatalyst for CO2 reduction to CO and HCOOH in MeCN/H2O.

N-heterocyclic carbenes have been utilised as highly efficient nucleophilic organocatalysts to mediate vinylogous Mukaiyama/Michael reactions of 2-(trimethylsilyloxy)furan with enones to afford γ-substituted butenolides in 44–99 % yield with 3:1–32:1 diastereoselectivity.

Three meso-ester boron dipyrromethene (BODIPY) dyes have been synthesized and functionalized with aggregation-induced emission (AIE)-active tetraphenylethene or triphenylethene moieties. It was found that functionalizing at the different positions of the BODIPY core resulted in the final dye having different emission properties in response to aggregation: from aggregation-induced quenching (ACQ) to being AIE active. X-ray crystallographic analysis was thus performed to provide an explanation for these differences.

This work was supported by the National Natural Science Foundation of China (Nos. 21162022, 21428302) and Shihezi University (Nos. 2011ZRKXTD04, 2012ZRKXJQ06).

Three soluble and stable thienoacene-fused pentalene derivatives (1-3) with different π-conjugation lengths were synthesized. X-ray crystallographic analysis and density functional theory (DFT) calculations revealed their unique geometric and electronic structures due to the interaction between the aromatic thienoacene units and antiaromatic pentalene moiety. As a result, they all possess a small energy gap and show amphoteric redox behaviour. Time dependent (TD) DFT calculations were used to explain their unique electronic absorption spectra. These new compounds exhibited good thermal stability and ordered packing in solid state and thus their applications in organic field-effect transistors (OFETs) were also investigated. The highest field-effect hole mobility of 0.016, 0.036 and 0.001 cm(2) V(-1) s(-1) was achieved for solution-processed thin films of 1-3, respectively.

Two soluble and stable 1,2:8,9-dibenzozethrene derivatives (3 a,b) are synthesized through a palladium-catalyzed cyclodimerization reaction. X-ray crystallographic analysis shows that these molecules are highly twisted owing to congestion at the cove region. Broken-symmetry DFT calculations predict that they have a singlet biradical ground state with a smaller biradical character and a large singlet–triplet energy gap; these predictions are supported by NMR and electronic absorption measurements. They have small energy gaps and exhibit far-red/near-infrared absorption/emission and amphoteric redox behaviors.

Polycyclic hydrocarbon compounds with a singlet biradical ground state show unique physical properties and promising material applications; therefore, it is important to understand the fundamental structure/biradical character/physical properties relationships. In this study, para-quinodimethane (p-QDM)-bridged quinoidal perylene dimers 4 and 5 with different fusion modes and their corresponding aromatic counterparts, the pericondensed quaterrylenes 6 and 7, were synthesized. Their ground-state electronic structures and physical properties were studied by using various experiments assisted with DFT calculations. The proaromatic p-QDM-bridged perylene monoimide dimer 4 has a singlet biradical ground state with a small singlet/triplet energy gap (-2.97 kcal mol(-1)), whereas the antiaromatic s-indacene-bridged N-annulated perylene dimer 5 exists as a closed-shell quinoid with an obvious intramolecular charge-transfer character. Both of these dimers showed shorter singlet excited-state lifetimes, larger two-photon-absorption cross sections, and smaller energy gaps than the corresponding aromatic quaterrylene derivatives 6 and 7, respectively. Our studies revealed how the fusion mode and aromaticity affect the ground state and, consequently, the photophysical properties and electronic properties of a series of extended polycyclic hydrocarbon compounds.

Organic semiconductors demonstrate several advantages over conventional inorganic materials for novel electronic and optoelectronic applications, including molecularly tunable properties, flexibility, low-cost, and facile device integration. However, before organic semiconductors can be used for the next-generation devices, such as ultrafast photodetectors (PDs), it is necessary to develop new materials that feature both high mobility and ambient stability. Toward this goal, a highly stable PD based on the organic single crystal [PtBr2 (5,5'-bis(CF3 CH2 OCH2 )-2,2'-bpy)] (or "Pt complex (1o)") is demonstrated as the active semiconductor channel-a material that features a lamellar molecular structure and high-quality, intraligand charge transfer. Benefitting from its unique crystal structure, the Pt-complex (1o) device exhibits a field-effect mobility of ≈0.45 cm2 V-1 s-1 without loss of significant performance under ambient conditions even after 40 days without encapsulation, as well as immersion in distilled water for a period of 24 h. Furthermore, the device features a maximum photoresponsivity of 1 × 103 A W-1 , a detectivity of 1.1 × 1012 cm Hz1/2 W-1 , and a record fast response/recovery time of 80/90 µs, which has never been previously achieved in other organic PDs. These findings strongly support and promote the use of the single-crystal Pt complex (1o) in next-generation organic optoelectronic devices.

A series of meso-ester-substituted BODIPY deriva- tives 1-6 are synthesized and characterized. In particular, dyes functionalized with oligo(ethylene glycol) ether styryl or naphthalene vinylene groups at the a positions of the BODIPY core (3-6) become partially soluble in water, and their absorptions and emissions are located in the far-red or near-infrared region. Three synthetic approaches are at- tempted to access the meso-carboxylic acid (COOH)-substi- tuted BODIPYs 7 and 8 from the meso-ester-substituted BODIPYs. Two feasible synthetic routes are developed suc- cessfully, including one short route with only three steps. The meso-COOH-substituted BODIPY 7 is completely soluble in pure water, and its fluorescence maximum reaches around 650 nm with a fluorescence quantum yield of up to 15 %. Time-dependent density functional theory calculations are conducted to understand the structure-optical proper- ties relationship, and it is revealed that the Stokes shift is de- pendent mainly on the geometric change from the ground state to the first excited singlet state. Furthermore, cell stain- ing tests demonstrate that the meso-ester-substituted BODIPYs (1 and 3-6) and one of the meso-COOH-substituted BODIPYs (8) are very membrane-permeable. These features make these meso-ester- and meso-COOH-substituted BODIPY dyes attractive for bioimaging and biolabeling applications in living cells.

The first highly enantioselective direct vinylogous aldol reaction between allyl aryl ketones and isatins is developed using a L-valine derived bifunctional amino-thiourea catalyst.

Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a formidable challenge in organic chemistry. Herein, we report a novel approach to activating remote C-H bonds at the C5 position of 8-aminoquinoline through copper-catalyzed sulfonylation under mild conditions. Our strategy shows high conversion efficiency, a broad substrate scope, and good toleration with different functional groups. Furthermore, our mechanistic investigations suggest that a single-electron-transfer process plays a vital role in generating sulfonyl radicals and subsequently initiating C-S cross-coupling. Importantly, our copper-catalyzed remote functionalization protocol can be expanded for the construction of a variety of chemical bonds, including C-O, C-Br, C-N, C-C, and C-I. These findings provide a fundamental insight into the activation of remote C-H bonds, while offering new possibilities for rational design of drug molecules and optoelectronic materials requiring specific modification of functional groups.

N-Heterocyclic carbene (NHC)-catalyzed vinylogous Mukaiyama aldol reaction of ketones was developed. Under the catalysis of 5 mol% NHC, α-keto esters and α-trifluoromethyl ketones reacted with 2-(trimethysilyloxy)furan efficiently to produce γ-substituted butenolides containing adjacent quaternary and tertiary carbon centers in high yields with good diastereoselectivities.

An efficient N-heterocyclic carbene (NHC)-catalyzed vinylogous Michael addition of deconjugated butenolides was developed. In the presence of 5 mol % of the NHC catalyst, both γ-alkyl- and aryl-substituted deconjugated butenolides undergo vinylogous Michael addition with various α, β-unsaturated ketones, esters, or nitriles to afford γ,γ-disubstituted butenolides containing adjacent quaternary and tertiary carbon centers in good to excellent yields with excellent diastereoselectivities. In this process, the free carbene is assumed to act as a strong Bronsted base to promote the conjugate addition.

The title compounds are prepared as potential building blocks for the synthesis of mycotoxins Fumitremorgin A and Verruculogen or their derivatives.

We thank Prof. John Hartwig for useful discussions. The financial support from National Natural Science Foundation of China (21072030) and Fuzhou University (022318) to Z.W. and KAUST to K.-W.H. are acknowledged.

Pincers do the trick: The conversion of ethanol to ethyl acetate and hydrogen was achieved using a pincer-Ru catalyst in a Pd-Ag membrane reactor. Near quantitative conversions and yields could be achieved without the need for acid or base promoters or hydrogen acceptors (see scheme).

Enanatiopure β-methyl-γ-monofluoromethyl alcohols were prepared from the allylic alkylation between fluorobis(phenylsulfonyl)methane with Morita-Baylis-Hillman carbonates. The reaction was catalyzed by using the Cinchona alkaloid derivative, (DHQD)(2)AQN. The origin of the stereoselectivity was verified by DFT methods. Calculated geometries and relative energies of various transition states strongly support the observed stereoselectivity.

We thank the National University of Singapore and the Ministry of Education (MOE) of Singapore (R-143-000-362-112) for generous financial support.

Bicyclic guanidines are able to catalyze the protonation reactions of 2-phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The protonation reaction of itaconimides with secondary phosphine oxides is also known. Herein, the tandem conjugate addition-enantioselective protonation of N-substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is investigated. The rotational barrier of the C-N axis of N-2-tert-butyl phenylitaconimide is also studied, both experimentally and computationally.

Small organic molecules capable of hydrogen-bonding interactions with substrates have found widespread application in asymmetric catalysis. In particular, thiourea-based organic molecules have become the most prominent hydrogen-bonddonor catalysts in a wide variety of organic reactions. In this context, bifunctional organic molecules containing a tertiary amino functionality and a thiourea moiety are remarkably useful organic catalysts. Despite their tremendous utility, these bifunctional catalysts are derived from a very limited range of chiral structural scaffolds, including cyclohexane-1,2diamine, 1,1’-binaphthyl-2,2’-diamine, and cinchona alkaloids. The development of readily accessible novel bifunctional catalysts of this nature would be highly desirable. As part of our research program towards the development of practical organocatalysts based on primary amino acids, we were intrigued by the possibility of designing novel tertiary amine– thiourea catalysts on the basis of simple amino acids. The facile conversion of natural amino acids into 1,2-diamines and the availability of structurally diverse side chains make this method very attractive. To investigate the validity of this approach, we selected l-tryptophan as the chiral precursor. We reasoned that the indole moiety would be capable of engaging in aromatic and hydrogen-bonding interactions with substrates, and these effects may result in efficient chiral induction (Scheme 1). Fluorinated molecules are of high importance in the pharmaceutical industry, and their asymmetric preparation has drawn great attention. The catalytic construction of fluorinated quaternary carbon stereocenters is a formidable synthetic challenge. A number of excellent methods based on metal catalysis have been reported; however, organocatalytic approaches for the creation of fluorinated quaternary centers are rather limited. Recently, organocatalytic synthetic methods with fluorinated substrates have become an alternative and viable option for accessing chiral fluorinated molecules. In such approaches, racemic fluorinated nucleophiles are used as substrates. A C C bond is formed rather than a C F bond, and full advantage is taken of the high electronegativity and small molecular radius of the fluorine atom. We and others have used fluorinated substrates in this way in organocatalytic Michael and alkylation reactions for the construction of fluorinated chiral molecules. To assess the utility of tryptophan-based bifunctional catalysts, we chose to focus on the direct asymmetric Mannich reaction of a-fluorinated b-ketoesters, as such reactions yield structurally demanding and biologically important a-fluorob-amino acids. Organocatalytic asymmetric Mannich reactions of b-ketoesters and malonates were reported recently by the research groups of Schaus, Deng, and Dixon, all of whom employed organic catalysts derived from cinchona alkaloids. Herein, we report that tryptophan-based bifunctional thiourea derivatives promote the asymmetric Mannich reaction of fluorinated substrates to afford highly optically enriched fluorine-containing molecules containing adjacent quaternary and tertiary stereocenters. We selected the Mannich reaction of a-fluoro-b-ketoester 1a with N-Boc imine 2a as a model reaction and examined the catalytic effects of various bifunctional catalysts (Table 1). Quinidine-derived thioureas and a quinidine-derived sulfonamide gave disappointing results (Table 1, entries 1–3). On the other hand, the tryptophan-based thiourea derivatives Trp-1–Trp-3 were found to be good catalysts. They afforded the Mannich product 3a in quantitative yield and with good diastereoselectivity and enantioselectivity (Table 1, entries 4– 6). Under optimized reaction conditions, the fluorinated product containing adjacent quaternary and tertiary stereoScheme 1. Thiourea catalyst based on a primary amino acid (tryptophan).

The perfect combination: The title reaction provides adducts having quaternary carbon centers bearing a fluorine atom with high ee and d.r. values (see scheme). The mechanism and origin of stereoselectivity were elucidated by DFT calculations. The bifunctional mode of the guanidine catalysis was demonstrated in the transition states resulting from the DFT results.

For the first time, amino-acid derived bifunctional phosphines are used as catalysts to synthesize a wide range of substituted thiazolone and oxazolone derivatives.

Work on a new class of PN 3 -pincer ligands for metal–ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN 3 -transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN 3 -pincer complexes for metal–ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN 3 -pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN 3 -pincer ligands’ dearomatization–rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.