Recent advances in organic molecule reactions on metal surfaces.

Chemical reactions of organic molecules on metal surfaces have been intensively investigated in the past decades, where metals play the role of catalysts in many cases. In this review, first, we summarize recent works on spatial molecules, small H2O, O2, CO, CO2 molecules, and the molecules carrying silicon groups as the new trends of molecular candidates for on-surface chemistry applications. Then, we introduce spectroscopy and DFT study advances in on-surface reactions. Especially, in situ spectroscopy technologies, such as electron spectroscopy, force spectroscopy, X-ray photoemission spectroscopy, STM-induced luminescence, tip-enhanced Raman spectroscopy, temperature-programmed desorption spectroscopy, and infrared reflection adsorption spectroscopy, are important to confirm the occurrence of organic reactions and analyze the products. To understand the underlying mechanism, the DFT study provides detailed information about reaction pathways, conformational evolution, and organometallic intermediates. Usually, STM/nc-AFM topological images, in situ spectroscopy data, and DFT studies are combined to describe the mechanism behind on-surface organic reactions.

Arsenic exposure induced renal fibrosis via regulation of mitochondrial dynamics and the NLRP3-TGF-ß1/SMAD signaling pathway.

Environmental arsenic exposure is one of the major global public health problems. Studies have shown that arsenic exposure can cause renal fibrosis, but the underlying mechanism is still unclear. Integrating the in vivo and in vitro models, this study investigated the potential molecular pathways for arsenic-induced renal fibrosis. In this study, SD rats were treated with 0, 5, 25, 50, and 100 mg/L NaAsO2 for 8 weeks via drinking water, and HK2 cells were treated with different doses of NaAsO2 for 48 h. The in vivo results showed that arsenic content in the rats' kidneys increased as the dose increased. Body weight decreased and kidney coefficient increased at 100 mg/L. As a response to the elevated NaAsO2 dose, inflammatory cell infiltration, renal tubular injury, glomerular atrophy, tubulointerstitial hemorrhage, and fibrosis became more obvious indicated by HE and Masson staining. The kidney transcriptome profiles further supported the protein-protein interactions involved in NaAsO2-induced renal fibrosis. The in vivo results, in together with the in vitro experiments, have revealed that exposure to NaAsO2 disturbed mitochondrial dynamics, promoted mitophagy, activated inflammation and the TGF-ß1/SMAD signaling pathway, and finally resulted in fibrosis. In summary, arsenic exposure contributed to renal fibrosis via regulating the mitochondrial dynamics and the NLRP3-TGF-ß1/SMAD signaling axis. This study presented an adverse outcome pathway for the development of renal fibrosis due to arsenic exposure through drinking water.

Activation of prefrontal cortex and striatal regions in rats after shifting between rules in a T-maze.

Prefrontal cortical and striatal areas have been identified by inactivation or lesion studies to be required for behavioral flexibility, including selecting and processing of different types of information. In order to identify these networks activated selectively during the acquisition of new reward contingency rules, rats were trained to discriminate orientations of bars presented in pseudorandom sequence on two video monitors positioned behind the goal sites on a T-maze with return arms. A second group already trained in the visual discrimination task learned to alternate left and right goal arm visits in the same maze while ignoring the visual cues still being presented. In each experimental group, once the rats reached criterion performance, the brains were prepared after a 90-min delay for later processing for c-fos immunohistochemistry. While both groups extinguished a prior strategy and acquired a new rule, they differed by the identity of the strategies and previous learning experience. Among the 28 forebrain areas examined, there were significant increases in the relative density of c-fos immunoreactive cell bodies after learning the second rule in the prefrontal cortex cingulate, the prelimbic and infralimbic areas, the dorsomedial striatum and the core of the nucleus accumbens, the ventral subiculum, and the central nucleus of the amygdala. These largely correspond to structures previously identified in inactivation studies, and their neurons fire synchronously during learning and strategy shifts. The data suggest that this dynamic network may underlie reward-based selection for action-a type of cognitive flexibility.

Discovery of a first-in-class CDK2 selective degrader for AML differentiation therapy.

The discovery of effective therapeutic treatments for cancer via cell differentiation instead of antiproliferation remains a great challenge. Cyclin-dependent kinase 2 (CDK2) inactivation, which overcomes the differentiation arrest of acute myeloid leukemia (AML) cells, may be a promising method for AML treatment. However, there is no available selective CDK2 inhibitor. More importantly, the inhibition of only the enzymatic function of CDK2 would be insufficient to promote notable AML differentiation. To further validate the role and druggability of CDK2 involved in AML differentiation, a suitable chemical tool is needed. Therefore, we developed first-in-class CDK2-targeted proteolysis-targeting chimeras (PROTACs), which promoted rapid and potent CDK2 degradation in different cell lines without comparable degradation of other targets, and induced remarkable differentiation of AML cell lines and primary patient cells. These data clearly demonstrated the practicality and importance of PROTACs as alternative tools for verifying CDK2 protein functions.

Desilylative Coupling Involving C(sp2)-Si Bond Cleavage on Metal Surfaces.

Desilylative coupling involving C-Si bond cleavage has emerged as one of the most important synthetic strategies for carbon-carbon/heteroatom bond formation in solution chemistry. However, in on-surface chemistry, C-Si bond cleavage remains a synthetic challenge. Here, we report the implementation of C(sp2)-Si bond cleavage and subsequent C-C bond formation on metal surfaces. The combination of scanning tunneling microscopy and density functional theory calculation successfully reveals that the incorporation of the C-Br group on the arylsilanes is critical to the success of this desilylative coupling reaction on metal surfaces. Our study represents a promising approach for the removal of protecting silyl groups in on-surface chemistry.

Surface Characterization of the Solution-Processed Organic-Inorganic Hybrid Perovskite Thin Films.

The surface properties of organic-inorganic hybrid perovskites can strongly affect the efficiency and stability of corresponding devices. Even though different surface passivation methods are developed, the microscopic structures of solution-processed perovskite film surfaces are not systematically studied. This study uses low-temperature scanning tunneling microscopy to study the organic-inorganic hybrid perovskite thin films, MA0.4 FA0.6 PbI3 and MAPbI3 , synthesized by the spin-coating method. Flat surface structures, atomic steps, and crystal grain boundaries are resolved at an atomic resolution. The surface imperfections are also characterized, as well as the dominant defects. Simulations on different types of iodine vacancy configurations are performed by density functional theory calculations. In addition, it is observed that the surface iodine lattice structure is unstable during scanning. Tip scanning can also cause the vertical migration of surface iodine ions. The measurements provide the direct visualizations of the surface imperfections of the solution-processed perovskite films. They are essential for understanding the surface-related optoelectronic effects and rationally designing more efficient surface passivation methods.

Retinitis pigmentosa 2 pathogenic mutants degrade through BAG6/HUWE1 complex.

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease which is the major cause of vision loss. X-linked RP patients account for 5%-15% of all inherited RP cases and mutations in RP2 (Retinitis pigmentosa 2) were responsible for about 20% X-linked RP families. A majority of RP2 pathogenic mutations displayed a vulnerable protein stability and degraded rapidly through ubiquitin-proteasome system (UPS). Though the RP2 protein could be readily recovered by proteasome inhibitors, e.g., MG132, their applications for RP2-related RP therapy were limited by their nonspecific characterization. In the present study, we aimed to identify UPS-related factors, such as E3 ligases, which are specifically involved in degradation of RP2 pathogenic mutants. We identified several E3 ligases, such as HUWE1, and the co-chaperon BAG6 specifically interacting with RP2 pathogenic mutants. Knockdown of HUWE1 and BAG6 could partially rescue the reduced protein levels of RP2 mutants. BAG6 is required for recruitment of HUWE1 to ubiquitinate RP2 mutants at the K268 site. The HUWE1 inhibitor BI8622 could restore the levels of RP2 mutant and then the binding to its partner ARL3 in retina cell lines. This study revealed the details of UPS-related degradation of RP2 mutants and possibly provided a potential treatment for RP2-related RP.

Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells.

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.

Effect of nighttime sleep duration and midday napping in early pregnancy on gestational diabetes mellitus.

PURPOSE: To explore the effect of nighttime sleep duration and midday napping in early pregnancy on gestational diabetes mellitus (GDM) among Chinese women. METHODS: Information on midday napping and nighttime sleep duration was assessed by a questionnaire. Diagnostic information of GDM was derived from the routine oral glucose tolerance test (OGTT) during the second trimester of pregnancy. RESULTS: A total of 500 pregnant women, including 196 patients with GDM and 304 controls, were included in the present study. In the case group, 47% of women took a midday nap > 1 h/day, and the proportion was 22% in the control group. Compared with women who had a midday nap ≤ 1 h/day, women who had a nap > 1 h/day had a significantly increased risk of GDM (OR 3.00, 95% CI 1.87, 4.82, p < 0.001). Compared with women who had a nighttime sleep of 7 to 8.9 h/night, women who slept < 7 or ≥ 9 h/night all had a significantly increased risk of GDM. Stratified analyses showed that compared with the nighttime sleep duration of 7 to 8.9 h/day, the GDM risk of the < 7 h/night group increased among mothers who had a midday nap ≤ 1 h/day. The impact was stronger than among women who had a nap > 1 h/day (p = 0.006). CONCLUSIONS: Shorter or longer nighttime sleep duration and longer midday napping duration in early pregnancy were all related to GDM. Midday napping would reduce the risk of GDM among mothers with shorter nighttime sleep duration.

A Unidirectional Surface-Anchored N-Heterocyclic Carbene Rotor.

A molecular rotor based on N-heterocyclic carbenes (NHCs) has been rationally designed following theoretical predictions, experimentally realized, and characterized. Utilizing the structural tunability of NHCs, a computational screening protocol was first applied to identify NHCs with asymmetric rotational potentials on a surface as a prerequisite for unidirectional molecular rotors. Suitable candidates were then synthesized and studied using scanning tunneling microscopy/spectroscopy (STM/STS), analytical theoretical models, and molecular dynamics simulations. For our best NHC rotor featuring a mesityl N substituent on one side and a chiral naphthylethyl substituent on the other, unidirectional rotation is driven by inelastic tunneling of electrons from the NHC to the STM tip. While electrons preferentially tunnel through the mesityl N substituent, the chiral naphthylethyl substituent controls the directionality. Such NHC-based surface rotors open up new possibilities for the design and construction of functionalized molecular systems with high catalytic applicability and superior stability compared with other classes of molecular rotors.

Azo bond formation on metal surfaces.

The formation of azo compounds via redox cross-coupling of nitroarenes and arylamines, challenging in solution phase chemistry, is achieved by on-surface chemistry. Reaction products are analyzed with a cryogenic scanning tunneling microscope (STM) and X-ray photoelectron spectroscopy (XPS). By using well-designed precursors containing both an amino and a nitro functionality, azo polymers are prepared on surface via highly efficient nitro-amino cross-coupling. Experiments conducted on other substrates and surface orientations reveal that the metal surface has a significant effect on the reaction efficiency. The reaction was further found to proceed from partially oxidized/reduced precursors in dimerization reactions, shedding light on the mechanism that was studied by DFT calculations.

Aryl Triflates in On-Surface Chemistry.

The reactivity of aryl triflates in on-surface C-C coupling is reported. It is shown that the triflate group in aryl triflates enables regioselective homo coupling with preceding or concomitant hydrodetriflation on Cu(111). Three different symmetrical π-systems with two and three triflate functionalities were used as monomers leading to oligomeric conjugated π-systems. The cascade, comprising different intermediates at different reaction temperatures as observed for one of the molecules, proceeds via initial removal of the trifluoromethyl sulfonyl group to give an aryloxy radical which in turn is deoxygenated to the corresponding aryl radical. Thermodynamically driven regioselective 1,2-hydrogen atom transfer leads to a translocated aryl radical which in turn undergoes coupling. For a sterically more hindered bistriflate, where one ortho position was blocked, dehydrogenative coupling occurred at remote position with good regioselectivity. Starting materials, intermediates as well as products were analyzed by scanning tunneling microscopy. Structures and suggested mechanism were further supported by DFT calculations.

Diamantane Suspended Single Copper Atoms.

Single chains of metal atoms are expected to be perfect one-dimensional nanowires in nanotechnology, due to their quantum nature including tunable electronic or spin coupling strengths. However, it is still rather difficult to fabricate such nanowires with metallic atoms under directional and separation control. Here, we succeeded in building higher-order single diamondoid-chains from the lower-order chains using a chemically well-controlled approach that employs diamondoids on metal surfaces. This approach results in higher-order diamondoid double chains by linking two neighboring single chains, and ultimately forms a central chain consisting of single Cu atoms suspended by the diamantane framework. The suspended Cu atoms are placed above the metal surface with a periodic distance of 0.67 ± 0.01 nm. Our bottom-up approach will allow detailed experimental investigations of the properties of these exciting suspended metal atoms (for example, quantized conductance, spin coupling, as well as transfer, etc.). Furthermore, we also identified different spatial configurations on the metal surfaces in on-surface reaction processes using high-resolution AFM imaging and density functional theory computations. Our findings broaden the on-surface synthesis concept from 2D planar aromatic molecules to 3D bulky aliphatic molecules.

Spin-Triplet-Mediated Up-Conversion and Crossover Behavior in Single-Molecule Electroluminescence.

Scanning-tunneling-microscope-induced light emission serves as a powerful approach in revealing and manipulating the optical properties of molecular species, intermolecular energy transfer, and plasmon-molecule coupling. Earlier studies have established the existence of molecular up-conversion electroluminescence in diverse situations, but the underlying microscopic mechanisms are still under active debate, dominated by intermolecular triplet-triplet annihilation and plasmonic pumping. Here we report on the experimental realization of up-conversion electroluminescence from a prototypical single phthalocyanine molecule, allowing us to unambiguously rule out mechanisms based on intermolecular coupling and also offering unprecedented opportunities to elucidate much richer characteristics unforeseen in previous studies. In particular, the bias-dependent emission intensity displays three distinct regions with different nonlinear current dependences, which can be attributed to crossover behavior caused by the interplay between inelastic electron scattering and carrier-injection processes. We also develop a microscopic description to capture the essential physics involved in up-conversion electroluminescence mediated by a proper intermediate spin-triplet state.

On-Surface Reactive Planarization of Pt(II) Complexes.

A series of Pt(II) complexes with tetradentate luminophores has been designed, synthesized, and deposited on coinage metal surfaces with the aim to produce highly planar self-assembled monolayers. Low-temperature scanning tunneling microscopy (STM) and density functional theory (DFT) calculations reveal a significant initial nonplanarity for all complexes. A subsequent metal-catalyzed separation of the nonplanar moiety at the bridging unit via the scission of a C-N bond is observed, leaving behind a largely planar core complex. The activation barrier of this bond scission process is found to depend strongly on the chemical nature of both bridging group and coordination plane, and to increase from Cu(111) through Ag(111) to Au(111).

α-Diazo Ketones in On-Surface Chemistry.

Polymerization of a biphenyl bis α-diazo ketone on Cu(111) and Au(111) surfaces to provide furandiyl bridged poly-para-phenylenes is reported. Polymerization on Cu(111) occurs via initial N2 fragmentation leading to Cu-biscarbene complexes at room temperature as polymeric organometallic structure. At 135 °C, carbene coupling affords polymeric α,ß-unsaturated 1,4-diketones, while analogous alkene formation on the Au(111) surface occurs at room temperature. Further temperature increase leads to deoxygenative cyclization of the 1,4-diketone moieties to provide alternating furandiyl biphenyl copolymers on Cu(111) (165 °C) and Au(111) (240 °C) surfaces. This work shows a new approach to generate Cu-biscarbene intermediates on surfaces, opening the pathway for the controlled generation of biphenyl copolymers.

In Vitro-In Vivo Extrapolation of OATP1B-Mediated Drug-Drug Interactions in Cynomolgus Monkey.

Hepatic organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share >90% degree of gene and amino acid sequence homology with human orthologs, we evaluated the in vitro-in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using plated cynomolgus monkey hepatocytes showed active uptake Km values of 2.0 and 3.9 µM for OATP1B probe substrates, pitavastatin and rosuvastatin, respectively. Rifampicin inhibited pitavastatin and rosuvastatin active uptake in monkey hepatocytes with IC50 values of 3.0 and 0.54 µM, respectively, following preincubation with the inhibitor. Intravenous pharmacokinetics of 2H4-pitavastatin and 2H6-rosuvastatin (0.2 mg/kg) and the oral pharmacokinetics of cold probes (2 mg/kg) were studied in cynomolgus monkeys (n = 4) without or with coadministration of single oral ascending doses of rifampicin (1, 3, 10, and 30 mg/kg). A rifampicin dose-dependent reduction in i.v. clearance of statins was observed. Additionally, oral pitavastatin and rosuvastatin plasma exposure increased up to 19- and 15-fold at the highest dose of rifampicin, respectively. Use of in vitro IC50 obtained following 1 hour preincubation with rifampicin (0.54 µM) predicted correctly the change in mean i.v. clearance and oral exposure of statins as a function of mean unbound maximum plasma concentration of rifampicin. This study demonstrates quantitative translation of in vitro OATP1B IC50 to predict DDIs using cynomolgus monkey as a preclinical model and provides further confidence in application of in vitro hepatocyte data for the prediction of clinical OATP1B-mediated DDIs.

Metabolism of a 5HT6 Antagonist, 2-Methyl-1-(Phenylsulfonyl)-4-(Piperazin-1-yl)-1H-Benzo[d]imidazole (SAM-760): Impact of Sulfonamide Metabolism on Diminution of a Ketoconazole-Mediated Clinical Drug-Drug Interaction.

SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.

Reaction Selectivity in On-Surface Chemistry by Surface Coverage Control-Alkyne Dimerization versus Alkyne Trimerization.

This work reports the influence of molecular coverage in on-surface C-C-bond formation on reaction outcome. 6-Ethynyl-2-naphthoic acid (ENA) was chosen as organic component and Ag(111) as substrate. The alkyne moiety in ENA can either react by dimerization to ENA dimers (Glaser coupling or hydroalkynylation) or cyclotrimerization to generate a benzene core as connecting moiety. Dimer formation is preferred at high surface coverage whereas trimerization is the major reaction pathway at low coverage. Mechanistic studies are provided.

Substrate-Mediated C-C and C-H Coupling after Dehalogenation.

Intermolecular C-C coupling after cleavage of C-X (mostly, X = Br or I) bonds has been extensively studied for facilitating the synthesis of polymeric nanostructures. However, the accidental appearance of C-H coupling at the terminal carbon atoms would limit the successive extension of covalent polymers. To our knowledge, the selective C-H coupling after dehalogenation has not so far been reported, which may illuminate another interesting field of chemical synthesis on surfaces besides in situ fabrication of polymers, i.e., synthesis of novel organic molecules. By combining STM imaging, XPS analysis, and DFT calculations, we have achieved predominant C-C coupling on Au(111) and more interestingly selective C-H coupling on Ag(111), which in turn leads to selective synthesis of polymeric chains or new organic molecules.