Bei Cao

Cyclometalated Gold(III) Complexes Containing N-Heterocyclic Carbene Ligands Engage Multiple Anti-Cancer Molecular Targets

Metal N-heterocyclic carbene (NHC) complexes are a promising class of anti-cancer agents displaying potent in vitro and in vivo activities. Taking a multi-faceted approach employing two clickable photoaffinity probes, herein we report the identification of multiple molecular targets for anti-cancer active pincer gold(III) NHC complexes. These complexes display potent and selective cytotoxicity against cultured cancer cells and in vivo anti-tumor activities in mice bearing xenografts of human cervical and lung cancers. Our experiments revealed the specific engagement of the gold(III) complexes with multiple cellular targets, including HSP60, vimentin, nucleophosmin, and YB-1, accompanied by expected downstream mechanisms of action. Additionally, PtII and PdII analogues can also bind the cellular proteins targeted by the gold(III) complexes, uncovering a distinct pincer cyclometalated metal-NHC scaffold in the design of anti-cancer metal medicines with multiple molecular targets.

The effects of chelating N4 ligand coordination on Co(II)-catalysed photochemical conversion of CO2 to CO: reaction mechanism and DFT calculations

Here we describe the synthesis and X-ray crystal structures of a panel of cis-[CoII(N4)Cl2] complexes (N4 = tetradentate N atom donor ligand). We also examine the catalytic activities of these complexes in the photochemical and electrochemical reduction of CO2 to CO using [Ir(ppy)3] as the photosensitizer. Among the complexes studied, cis-[CoII(PDP)Cl2] (C1) (PDP = 1,1′-bis(2-pyridinylmethyl)-2,2′-bipyrrolidine) displayed the highest catalytic activity. This Co(II) complex was able to effectively mediate the reduction of CO2 to CO under either electrochemical or visible light photocatalytic conditions. For the electrocatalysis, C1 catalysed CO2 to CO with up to 96% Faraday efficiency at −1.70 V (vs. SCE, SCE = saturated calomel electrode). A selectivity of up to 95% for CO production was achieved in a photocatalytic CO2 reduction system by using C1 as the catalyst, Ir(ppy)3 as the photosensitizer and triethylamine as the electron donor. The Co(I) species in situ generated by the one electron reduction of cis-[CoII(PDP)Cl]+ is suggested to be directly responsible for CO2 activation. Ultrafast time (ns) resolved absorption spectroscopy revealed that the photoinduced electron transfer from the triplet excited state of Ir(ppy)3 to C1 is a key step in the generation of active Co(I) species. The electronic structure and redox properties of the Co(I) species, [CoI(N4)Cl], as well as its role in the catalytic reaction were investigated by DFT calculations. The presence of one chloride ligand cis to the CO2 coordination site neutralizes the positive charge on the Co(I) centre, therefore assisting the bound CO2 molecule in attracting protons. The reaction mechanism for CO2 reduction to CO catalysed by the recently reported [CoII(TPA)Cl]+ (TPA = tris(2-pyridylmethyl)amine) catalyst was also computed. Subtle modifications of the chelating N4 ligand from cis-[CoII(N4)Cl2] were found to have a profound effect on the efficiency of CO2 reduction by DFT calculations.

RhII-Catalyzed Intermolecular C−H Arylation of Aromatics with Diazo Quinones

We developed an efficient synthesis of biaryls by a dirhodium(II)-catalyzed aromatic C-H arylation with diazo quinones. The new biaryl synthesis can be performed under mild and neutral conditions and without directing group chelation assistance. The reaction tolerates various functionalities and is applicable to a broad range of aromatics. The regioselectivity of the C-H arylation was often high and predictable. The synthetic utility of the method was demonstrated by the late-stage modifications of a series of pharmaceuticals and functional materials as well as a short synthesis of a transthyretin amyloid inhibitor.

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal-catalyzed intramolecular C-H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N-heterocyclic carbene ligands which catalyzes the intramolecular C(sp3 )-H amination of a wide variety of alkyl azides under microwave-assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C-H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5-H bond. Mechanistic studies revealed a concerted or a fast re-bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis-octahydroindole, and leelamine derivatives.

Arylruthenium(III) Porphyrin-Catalyzed C–H Oxidation and Epoxidation at Room Temperature and [RuV(Por)(O)(Ph)] Intermediate by Spectroscopic Analysis and Density Functional Theory Calculations

The development of highly active and selective metal catalysts for efficient oxidation of hydrocarbons and identification of the reactive intermediates in the oxidation catalysis are long-standing challenges. In the rapid hydrocarbon oxidation catalyzed by ruthenium(IV) and -(III) porphyrins, the putative Ru(V)-oxo intermediates remain elusive. Herein we report that arylruthenium(III) porphyrins are highly active catalysts for hydrocarbon oxidation. Using catalyst [RuIII(TDCPP)(Ph)(OEt2)] (H2TDCPP = 5,10,15,20-tetrakis(2,6-dichlorophenyl)porphyrin), the oxidation of C-H bonds of various hydrocarbons with oxidant m-CPBA at room temperature gave alcohols/ketones in up to 99% yield within 1 h; use of [ nBu4N]IO4 as a mild alternative oxidant avoided formation of lactone from cyclic ketone in C-H oxidation, and the catalytic epoxidation with up to 99% yield and high selectivity (no aldehydes as side product) was accomplished within 5 min. UV-vis, electrospray ionization-mass spectrometry, resonance Raman, electron paramagnetic resonance, and kinetic measurements and density functional theory calculations lend evidence for the formation of Ru(V)-oxo intermediate [RuV(TDCPP)(O)(Ph)].

Shotgun Proteomics and Quantitative Pathway Analysis of the Mechanisms of Action of Dehydroeffusol, a Bioactive Phytochemical with Anticancer Activity from Juncus effusus

Dehydroeffusol (DHE) is a phenanthrene isolated from the Chinese medicinal plant Juncus effusus. Biological evaluation of DHE reveals in vitro and in vivo anticancer effects. We performed a shotgun proteomic analysis using liquid chromatography-tandem mass spectrometry to investigate the changes in the protein profiles in cancer cells upon DHE treatment. DHE affected cancer-associated signaling pathways, including NF-κB, β-catenin, and endoplasmic reticulum stress. Through quantitative pathway and key node analysis of the proteomics data, activating transcription factor 2 (ATF-2) and c-Jun kinase (JNK) were found to be the key components in DHEs modulated biological pathways. Based on the pathway analysis as well as chemical similarity to estradiol, DHE is proposed to be a phytoestrogen. The proteomic, bioinformatic, and chemoinformatic analyses were further verified with individual cell-based experiments. Our study demonstrates a workflow for identifying the mechanisms of action of DHE through shotgun proteomic analysis.