Controlling the Triplet Potential Energy Surface of Bimetallic Platinum(II) Complex by Constructing Structure-Property Relationship: A Theoretical Exploration.

For phosphorescent materials, managing the triplet potential energy surface stands for controlling the phosphorescence quantum yield. However, due to the complexity and variability, the triplet potential energy surface can be managed with difficulty. In this work, a series of bimetallic Pt(II) complexes, namely Pt-1, Pt-1-1, Pt-1-2, Pt-2, Pt-3-5, and Pt-6-7, are employed as models to construct a relationship between the structures and triplet potential energy surfaces, aiming to achieve meaningful information to manage the triplet potential energy surface. On the basis of the results, it is observed that the triplet potential energy surface has an intimate connection with the structures of bimetallic Pt(II) complexes. In the case of the primordial Pt(II) complex, the triplet potential energy surface consists of two minimal points, illustrating various properties, which can largely affect the phosphorescence quantum yield. Once the intramolecular steric hindrance, restriction effect, and metallophilic interaction (Pt-Pd/Pd-Pd) are employed by tailoring the structures of primordial Pt(II) complexes, the triplet potential energy surface can be reconstructed via one minimal point-charactered short metal-metal distance, resulting in different photophysical properties. The relationship between the triplet potential energy surface and structure is essentially unveiled from the structural and electronic viewpoints. The conclusions originated from the structural and electronic investigations can be regarded as indicators to accurately and expediently predict the triplet potential energy surfaces of bimetallic Pt(II) complexes. The results presented here are helpful in addressing the designed strategies as they show that the triplet potential energy surfaces of bimetallic Pt(II) complexes can be properly tuned.

Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer.

Compound 6d, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory capability remains unclear. Here, we showed that compound 6d is an inhibitor of Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis of mitochondria. Regarding the underlying mechanism, we identified HDAC6 as a direct substrate for caspase 3, and caspase 3 activation induced by compound 6d directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound 6d promoted autophagy initiation by inhibiting interaction between Bcl-2 and Beclin 1, while it led to the accumulation of ubiquitinated proteins and the reduction of autophagic flux. Collectively, our findings reveal that the Bcl-2-caspase 3-HDAC6 cascade is a crucial regulatory pathway of autophagy and identify compound 6d as a novel lead compound for disrupting the balance between apoptosis and autophagy.

Geometric Signatures as Important Factors to Control the Photo-Stabilities of the Phosphorescent Pd(II)/Pt(II) Complexes: A Case Study.

Operation lifetime, as an important parameter, determines the performance of phosphorescent organic light-emitting diodes (OLEDs). Unveiling the intrinsic degradation mechanism of emission material is crucial for improving the operation's lifetime. In this article, the photo-stabilities of tetradentate transition metal complexes, the popular phosphorescent materials, are explored by means of density functional theory (DFT) and time-dependent (TD)-DFT, aiming to illustrate the geometric signatures as important factors to control the photo-stabilities. Results indicate that for the tetradentate Ni(II), Pd(II), and Pt(II) complexes, the coordinate bonds of the Pt(II) complex exhibit stronger strength. It seems that the strengths of coordinate bonds are closely related to the atomic number of the metal center in the same group, which could be attributed to the various electron configurations. The effect of intramolecular and intermolecular interactions on ligand dissociation is also explored here. The large intramolecular steric hindrance and strong π-π interaction between the Pd(II) complexes caused by aggregation could effectively raise the energy barriers of the dissociation reaction, leading to an unfeasible reaction pathway. Moreover, the aggregation of Pd(II) complex can change the photo-deactivation mechanism as compared to that of monomeric Pd(II) complex, which is favored for avoiding the TTA (triplet-triplet annihilation) process.

An Efficient Synthesis of Naphtho[2,3-b]furan-4,9-diones via Visible-Light-Mediated [3+2] Cycloaddition Reaction.

Naphtho[2,3-b]furan-4,9-dione is an important privileged structural motif which is present in natural products, drugs, and drug candidates. Herein, visible-light-mediated [3+2] cycloaddition reaction for the synthesis of naphtho[2,3-b]furan-4,9-diones and dihydronaphtho[2,3-b]furan-4,9-diones has been developed. Under environmentally friendly conditions, a variety of title compounds were delivered in good yields. This new protocol shows excellent regioselectivity and remarkable functional group tolerance. This approach provides a powerful, green, efficient, and facile means to expand the structural diversity of naphtho[2,3-b]furan-4,9-diones and dihydronaph-tho[2,3-b]furan-4,9-diones as promising scaffolds for novel drug discovery.

Visible-Light-Mediated Catalyst-Free [2+2] Cycloaddition Reaction for Dihydrocyclobuta[b]naphthalene-3,8-diones Synthesis under Mild Conditions.

A facile and efficient visible-light-mediated method for directly converting 1,4-naphthoquinones into dihydrocyclo-buta[b]naphthalene-3,8-diones (DHCBNDOs) under mild and clean conditions without using any photocatalysts is reported. This approach exhibited favorable compatibility with functional groups and afforded a series of DHCBNDOs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically. The readily accessible, low-cost and ecofriendly nature of the developed strategy will endow it with attractive applications in organic and medicinal chemistry.

Zn(OTf)2-Promoted Isocyanide-Based Three-Component Reaction: Direct Access to 2-Oxazolines and ß-Amino Amides.

An efficient one-pot reaction of propargylamides, isocyanides, and water catalyzed by zinc was developed for the rapid construction of 2-oxazolines with a wide functional group tolerance. The methylene-3-oxazoline was proven to play a vitally important role to start the tandem cascade transformation through unfunctionalized alkynes with sequential nucleophilic addition approaches of isocyanide and water. Notably, with a slight alteration of the reaction temperature and the addition of one molecule of water, various ß-amino amide derivatives were synthesized in good to excellent yields.

Dieckmann Condensation of Ugi N-Acylamino Amide Product: Facile Access to Functionalized 2,2-Disubstituted Indolin-3-ones.

Structurally unique 2,2-disubstituted indolin-3-ones with a quaternary carbon center have been constructed through a novel C-C bond formation at the C3 position of Ugi N-acylamino amide adducts employing an organic base-mediated Dieckmann condensation. This facile, flexible protocol can be fine-tuned to construct drug-like pyrazino[1,2-a]indole fragments with the same quaternary carbon center only through the variation of the acid part in Ugi input. This novel and expeditious methodology has a broad scope and can rapidly generate the drug-like indolin-3-one core.

Investigate the Relationship between Structure and Triplet Potential Energy Surface to Control the Phosphorescence Quantum Yield of Platinum(II) Complex: A Theoretical Investigation.

Triplet potential energy surfaces are extremely important for phosphors because they are closely related to radiative and nonradiative decay processes. In this article, the correlations between the strctures and the triplet potential energy surfaces for Pt(II) complexes are investigated in detail with the help of density functional theory (DFT). The calculated results indicate that triplet hypersurface minima with different configurations, i.e., planar and bent, rely on the geometries of the platinum(II) complex. A bent configuration could cause an obvious decrease in the phosphorescence quantum yield, and an unusual low-lying triplet excited-state decay route is proposed. In addition, the extension of π-conjugation and addition of suitable substituents, for example arylboron, are promising strategies for changing the triplet hypersurface to achieve the minimum with a planar configuration, leading to a high phosphorescence quantum yield. Moreover, to predict the triplet hypersurface, a useful and simple strategy has been put forward. In our study, the relationship between the structure and the lowest-lying triplet potential energy surface of a Pt(II) complex is constructed, which is significant and meaningful for controlling the phosphorescence quantum yield to design high-performance phosphorescent materials used in the field of organic light-emitting diodes (OLEDs).

Inhibition of MORC2 Mediates HDAC4 to Promote Cellular Senescence through p53/p21 Signaling Axis.

(1) Background: Colorectal cancer (CRC) is a common gastrointestinal malignancy, accounting for the second largest gastrointestinal tumor. MORC2, a newly discovered chromatin remodeling protein, plays an important role in the biological processes of various cancers. However, the potential mechanistic role of MORC2 in promoting proliferation of CRC carcinoma remains unclear. (2) Methods: The Cancer Genome Atlas database was analyzed using bioinformatics to obtain gene expression and clinical prognosis data. The cell proliferation was assessed by CCK8 and EdU assays, as well as xenograft. SA-beta-gal staining, Western blot, and ELISA assay were using to assess the cell senescence and potential mechanism. (3) Results: Our data showed that MORC2 expression was elevated in CRC patients. Depletion of MORC2 inhibited cellular proliferation both in vivo and in vitro. Further studies showed that the depletion of MORC2 enhanced p21 and p53 expression through decreasing HDAC4 and increasing pro-inflammatory factors IL-6 and IL-8, thus, promoting cellular senescence. (4) Conclusions: We concluded that increased MORC2 expression in CRC might play a critical role in tumorigenesis by regulating the cellular senescence, in addition, MORC2 could be a novel biomarker for clinical outcomes and prognosis and a treatment target for CRC.

Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux.

BACKGROUND: Demethylzeylasteral (T-96) is a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF) that has been reported to exhibit anti-neoplastic effects against several types of cancer cells. However, the potential anti-tumour effects of T-96 against human Prostate cancer (CaP) cells and the possible underlying mechanisms have not been well studied. RESULTS: In the current study, T-96 exerted significant cytotoxicity to CaP cells in vitro and induced cell cycle arrest at S-phase in a dose-dependent manner. Mechanistically, T-96 promoted the initiation of autophagy but inhibited autophagic flux by inducing ROS-mediated endoplasmic reticulum (ER) stress which subsequently activated the extrinsic apoptosis pathway in CaP cells. These findings implied that T-96-induced ER stress activated the caspase-dependent apoptosis pathway to inhibit proliferation of CaP cells. Moreover, we observed that T-96 enhances the sensitivity of CaP cells to the chemotherapeutic drug, cisplatin. CONCLUSIONS: Taken together, our data demonstrated that T-96 is a novel modulator of ER stress and autophagy, and has potential therapeutic applications against CaP in the clinic.

Guanidine-Amide-Catalyzed Aza-Henry Reaction of Isatin-Derived Ketimines: Origin of Selectivity and New Catalyst Design.

Density functional theory (DFT) calculations were performed to investigate the mechanism and the enantioselectivity of the aza-Henry reaction of isatin-derived ketimine catalyzed by chiral guanidine-amide catalysts at the M06-2X-D3/6-311+G(d,p)//M06-2X-D3/6-31G(d,p) (toluene, SMD) theoretical level. The catalytic reaction occurred via a three-step mechanism: (i) the deprotonation of nitromethane by a chiral guanidine-amide catalyst; (ii) formation of C-C bonds; (iii) H-transfer from guanidine to ketimine, accompanied with the regeneration of the catalyst. A dual activation model was proposed, in which the protonated guanidine activated the nitronate, and the amide moiety simultaneously interacted with the ketimine substrate by intermolecular hydrogen bonding. The repulsion of CPh3 group in guanidine as well as N-Boc group in ketimine raised the Pauli repulsion energy (∆EPauli) and the strain energy (∆Estrain) of reacting species in the unfavorable si-face pathway, contributing to a high level of stereoselectivity. A new catalyst with cyclopropenimine and 1,2-diphenylethylcarbamoyl as well as sulfonamide substituent was designed. The strong basicity of cyclopropenimine moiety accelerated the activation of CH3NO2 by decreasing the energy barrier in the deprotonation step. The repulsion between the N-Boc group in ketimine and cyclohexyl group as well as chiral backbone in the new catalyst raised the energy barrier in C-C bond formation along the si-face attack pathway, leading to the formation of R-configuration product. A possible synthetic route for the new catalyst is also suggested.

Microwave-Assisted Copper Catalysis of α-Difluorinated gem-Diol toward Difluoroalkyl Radical for Hydrodifluoroalkylation of para-Quinone Methides.

Reported herein is a unified strategy to generate difluoroalkyl radicals from readily prepared α-difluorinated gem-diols by single electron oxidation. Under microwave irradiation, a catalytic amount of oxidant Cu(OAc)2 succeeds in the formation of transient difluoroalkyl radicals in situ, for the first time. The reaction features a simple protocol, short reaction time, scalability, and high yield. The synthetic utility of this new methodology was also explored for the synthesis of difluoroalkylated spiro-cyclohexadienones, which is an important core structure in natural products and pharmaceuticals.

Strategy Used to Control the Mechanism of Homogeneous Alkyne/Olefin Hydrogenation: AIMD Simulations and DFT Calculations.

Understanding the mechanism of the catalytic reaction is an effective way to design new high-performance catalysts. The mechanisms of alkyne/olefin hydrogenations catalyzed by a nonclassical Co-N2 catalyst are explored by ab initio molecular dynamics simulations and density functional theory calculations. From the calculated results, the hydrogenation mechanisms, i.e., molecular or atomic mechanisms, can be effectively controlled via employing the different interaction between the catalyst and substrates. The origination of excellent selectivity toward E-olefins for the Co-N2 catalyst is also taken into account with the help of investigating the olefin hydrogenation process. The mechanism indicates that the negligible energy barrier of rotation is the main reason for highly selective semihydrogenation of a Co-N2 catalyst, which leads to the trans-olefin formation. These investigations may provide some useful information and guidelines on the current understanding of the hydrogenation reaction and designing the high-performance catalysts.

Future perspective: high-throughput construction of new ultrasensitive cytokine and virion liquid chips for high-throughput screening (HTS) of anti-inflammatory drugs or clinical diagnosis and treatment of inflammatory diseases.

Pathogen-host cell interactions play an important role in many human infectious and inflammatory diseases. Several pathogens, including Escherichia coli (E. coli), Mycobacterium tuberculosis (M. tb), and even the recent 2019 novel coronavirus (2019-nCoV), can cause serious breathing and brain disorders, tissue injury and inflammation, leading to high rates of mortality and resulting in great loss to human physical and mental health as well as the global economy. These infectious diseases exploit the microbial and host factors to induce serious inflammatory and immunological symptoms. Thus the development of anti-inflammatory drugs targeting bacterial/viral infection is an urgent need. In previous studies, YojI-IFNAR2, YojI-IL10RA, YojI-NRP1,YojI-SIGLEC7, and YojI-MC4R membrane-protein interactions were found to mediate E. coli invasion of the blood-brain barrier (BBB), which activated the downstream anti-inflammatory proteins NACHT, LRR and PYD domains-containing protein 2(NLRP2), using a proteomic chip conjugated with cell immunofluorescence labeling. However, the studies of pathogen (bacteria/virus)-host cell interactions mediated by membrane protein interactions did not extend their principles to broad biomedical applications such as 2019-nCoV infectious disease therapy. The first part of this feature article presents in-depth analysis of the cross-talk of cellular anti-inflammatory transduction signaling among interferon membrane protein receptor II (IFNAR2), interleukin-10 receptor subunit alpha (IL-10RA), NLRP2 and [Ca2+]-dependent phospholipase A2 (PLA2G5), based on experimental results and important published studies, which lays a theoretical foundation for the high-throughput construction of the cytokine and virion solution chip. The paper then moves on to the construction of the novel GPCR recombinant herpes virion chip and virion nano-oscillators for profiling membrane protein functions, which drove the idea of constructing the new recombinant virion and cytokine liquid chips for HTS of leading drugs. Due to the different structural properties of GPCR, IFNAR2, ACE2 and Spike of 2019-nCoV, their ligands will either bind the extracellular domain of IFNAR2/ACE2/Spike or the specific loops of the GPCR on the envelope of the recombinant herpes virions to induce dynamic charge distribution changes that lead to the variable electron transition for detection. Taken together, the combined overview of two of the most innovative and exciting developments in the immunoinflammatory field provides new insight into high-throughput construction of ultrasensitive cytokine and virion liquid chips for HTS of anti-inflammatory drugs or clinical diagnosis and treatment of inflammatory diseases including infectious diseases, acute or chronic inflammation (acute gouty arthritis or rheumatoid arthritis), cardiovascular disease, atheromatosis, diabetes, obesity, tissue injury and tumors. It has significant value in the prevention and treatment of these serious and painful diseases. Graphical abstract.

Phosphine ligand-coated Cu nanoparticle-catalyzed selective semihydrogenation of alkynes: electronic or hindrance effects of the ligand?

Understanding the mechanism of a catalytic reaction is of fundamental importance not only scientifically but also technologically to the design of high-performance catalysts. In this work, the mechanisms of 1-phenyl-1-propyne and cis-ß-methylstyrene hydrogenations catalyzed by Cu55 and ligand-coated Cu55 are explored in detail by means of density functional theory (DFT). The calculated results indicate that the semihydrogenation selectivity of the catalyst can be effectively controlled by employing a suitable ligand. That is, the PCy3 and PPh3 ligands used to coat Cu55 can largely raise the energy barrier of the rate-determining step for cis-ß-methylstyrene hydrogenation. By the study of energy decomposition analysis (EDA) and charge density difference, it can be found that the deformation energies of the substrate fragments play a crucial role in the energy barriers of the rate-determining steps. The large hindrance effect of the ligands is beneficial for improving the semihydrogenation selectivity of the catalysts. This study provides significant information for future catalyst design and on the physical origin of the phosphine ligand-coated nanoparticle catalysis for semihydrogenation.

Strategy used to synthesize high activity and low Pd catalyst for Suzuki coupling reaction: an experimental and theoretical investigation.

Unveiling the reaction mechanism is significant for developing high-performance catalysts. In this paper, a series of precisely controlled PdxM147-x (M = Cu, Pt, Au, Rh, Ru) dendrimer encapsulated nanoparticles (DENs) has been successfully synthesized. The mechanisms of PdxM147-x as catalysts for Suzuki cross-coupling reactions were investigated by combining experimental and theoretical methods. The experimental results indicate that Pd74Cu73 DEN shows similar activity to Pd147 DEN and excellent substrate adaptability under mild reaction conditions. Moreover, the Cu component can play an important role in tuning the catalytic activity of PdxCu147-x DEN. Density functional theory (DFT) calculations illustrate that the similar activities of the Pd147 and Pd74Cu73 DENs originate from the comparable energy barriers of the rate-determining steps. The partial density of states (PDOS) and electron density differences demonstrate that Cu decreases the intensities of the valence orbitals of the top and edge Pd atoms and weakens orbital interactions between the intermediates and Pd74Cu73 DEN, leading to low desorption energies of the products. This work can provide a promising strategy to reduce the cost of Pd catalysts in Suzuki cross-coupling reactions.

Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction.

A facile microwave-assisted method for the synthesis of tetramic acid derivatives has been developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods.

Diversity-Oriented Synthesis of Imidazo-Dipyridines with Anticancer Activity via the Groebke-Blackburn-Bienaymé and TBAB-Mediated Cascade Reaction in One Pot.

A facile and metal-free one-pot protocol for the synthesis of fused imidazopyridine scaffolds has been developed. This novel protocol combines the Groebke-Blackburn-Bienaymé reaction (GBBR) with a sequential TBAB-mediated cyclization cascade. Biological evaluation demonstrated that compound 6a inhibits human prostate cancer cell DU-145 proliferation with an IC50 of 1.6 µM. The molecular mechanism study indicates that 6a significantly suppresses the oncogenic Erk kinase phosphorylation at 3 µM.

Small substituent groups as geometric controllers for tridentate platinum(ii) complexes to effectively suppress non-radiative decay processes.

For phosphorescent emitters, the rigidity of the geometry is a crucial indicator, which can directly determine the non-radiative decay rate. In this article, density functional theory (DFT) calculations were performed to investigate the influence of the small substituent groups on the rigidities of tridentate Pt(ii) complexes in detail. The calculated results indicate that the small substituent groups can serve as geometric controllers to suppress the structural distortion on going from the ground state (S0) to the lowest-lying triplet excited state (T1) (Jahn-Teller distortion). For instance, when electron-donating substituent groups, including -NH2, -N(CH3)2 and -OCH3, were employed, the rigidities of the corresponding Pt(ii) complexes can be effectively enhanced because the highest occupied molecular orbital (HOMO)-HOMO-1 energy gaps could be increased. Different from the electron-donating substituent groups, electron-withdrawing substituent groups, i.e., -NO2 and -COCH3, can cause a negligible change in HOMO and HOMO-1 energies during the S0 → T1 transition process, and therefore, for Pt-NO2 and Pt-COCH3, no Jahn-Teller distortion occurs. According to the calculated results, the rigidities of tridentate Pt(ii) complexes could be raised via tuning the energies of the frontier molecular orbital (FMO) with the help of small substituent groups.

The global motion affecting electron transfer in Plasmodium falciparum type II NADH dehydrogenases: a novel non-competitive mechanism for quinoline ketone derivative inhibitors.

With the emergence of drug-resistant Plasmodium falciparum, the treatment of malaria has become a significant challenge; therefore, the development of antimalarial drugs acting on new targets is extremely urgent. In Plasmodium falciparum, type II nicotinamide adenine dinucleotide (NADH) dehydrogenase (NDH-2) is responsible for catalyzing the transfer of two electrons from NADH to flavin adenine dinucleotide (FAD), which in turn transfers the electrons to coenzyme Q (CoQ). As an entry enzyme for oxidative phosphorylation, NDH-2 has become one of the popular targets for the development of new antimalarial drugs. In this study, reliable motion trajectories of the NDH-2 complex with its co-factors (NADH and FAD) and inhibitor, RYL-552, were obtained by comparative molecular dynamics simulations. The influence of cofactor binding on the global motion of NDH-2 was explored through conformational clustering, principal component analysis and free energy landscape. The molecular interactions of NDH-2 before and after its binding with the inhibitor RYL-552 were analyzed, and the key residues and important hydrogen bonds were also determined. The results show that the association of RYL-552 results in the weakening of intramolecular hydrogen bonds and large allosterism of NDH-2. There was a significant positive correlation between the angular change of the key pocket residues in the NADH-FAD-pockets that represents the global functional motion and the change in distance between NADH-C4 and FAD-N5 that represents the electron transfer efficiency. Finally, the possible non-competitive inhibitory mechanism of RYL-552 was proposed. Specifically, the association of inhibitors with NDH-2 significantly affects the global motion mode of NDH-2, leading to widening of the distance between NADH and FAD through cooperative motion induction; this reduces the electron transfer efficiency of the mitochondrial respiratory chain. The simulation results provide useful theoretical guidance for subsequent antimalarial drug design based on the NDH-2 structure and the respiratory chain electron transfer mechanism.