Search

Angiogenesis is hijacked by cancer to support tumor growth. RNA modifications such as N6-methyladenosine (m6A) can regulate several aspects of cancer, including angiogenesis. Here, we find that m6A triggers angiogenesis in lung cancer by upregulating vascular endothelial growth factor-A (VEGFA), a central regulator of neovasculature and blood vessel growth. m6A-sequencing and functional studies confirmed that m6A modification of the 5’UTR of VEGFA positively regulates its translation. Specifically, methylation of a 5’UTR internal ribosome entry site (IRES) recruited the YTHDC2/eIF4GI complex to trigger cap-independent translation initiation. Intriguingly, the m6A methylation site A856 of the 5’UTR was located within the conserved upstream open reading frame (uORF) of VEGFA IRES-A, which overcomes uORF-mediated translation suppression while facilitating G-quadruplex-induced translation of VEGFA. Targeted specific demethylation of VEGFA m6A significantly decreased expression of VEGFA and reduced lung cancer cell-driven angiogenesis. In vivo and clinical data confirmed the positive effects of m6A modification of VEGFA on angiogenesis and tumor growth of lung cancer. This study not only reveals that the m6A/VEGFA axis is a potential target for lung cancer therapy but also expands our understanding of the impact of m6A modification of IRES in the 5’UTR of mRNA on translation regulation.

N6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.

Studies on biological functions of RNA modifications such as

To reveal the inner connection between SBS and base asphalt. Firstly, a reasonable asphalt molecular model is established to verify the rationality of the model. Then, MD simulation was carried out with binding energy and diffusion coefficient as evaluation indicators, and the diffusion distribution state of polymer molecules in matrix asphalt was analyzed by FM. By analyzing the above results, the binding energies of SBS and light components (aromatics and saturated) are (170.615 kcal/mol, 156.151 kcal/mol) and the binding energies of heavy components (asphaltene and resin) are (50.262 kcal/mol, 90.085 kcal/mol), indicating that the SBS polymer and the light component are more closely related. The addition of SBS promotes the enhancement of its interaction, and the molecular diffusion rate of the asphalt system generally decreases. It can provide theoretical support for the development of high-performance SBS modified asphalt materials.

N6-Methyladenosine (m6A) modification, which is methylated by methyltransferase-like 3 (METTL3), is critical for the progression of several cancers. However, the roles of m6A in the apoptosis of cancer cells have not been well illustrated. Our present study reveals that deletion of METTL3 promotes the apoptosis and impairs the migration and invasion of colorectal cancer (CRC) cells. Both sequencing analysis and in vitro assays confirm that P53, an important transcription factor of apoptosis, is involved in the m6A-regulated apoptosis of CRC. Mechanically, the occurrence of m6A in P53 coding region (CDS), but not 3’ untranslated region (UTR), inhibited the expression of P53. Loss and gain functional studies confirm that YTHDF2 mediates mRNA degradation of P53 mRNA in an m6A-dependent manner. Moreover, METTL3 up-regulation acts as an adverse prognosis factor for recurrence‐free survival of colorectal cancers. Our study highlights the critical roles of m6A in the regulation of apoptosis, in cancer cells, through modulation of P53 expression.

N

Studies on biological functions of RNA modifications such as N 6 -methyladenosine (m 6 A) in mRNA have sprung up in recent years, while the roles of N 1 -methyladenosine (m 1 A) in cancer progression remain largely unknown. We find m 1 A demethylase ALKBH3 can regulate the glycolysis of cancer cells via a demethylation activity dependent manner. Specifically, sequencing and functional studies confirm that ATP5D, one of the most important subunit of adenosine 5′-triphosphate synthase, is involved in m 1 A demethylase ALKBH3-regulated glycolysis of cancer cells. The m 1 A modified A71 at the exon 1 of ATP5D negatively regulates its translation elongation via increasing the binding with YTHDF1/eRF1 complex, which facilitates the release of message RNA (mRNA) from ribosome complex. m 1 A also regulates mRNA stability of E2F1, which directly binds with ATP5D promoter to initiate its transcription. Targeted specific demethylation of ATP5D m 1 A by dm 1 ACRISPR system can significantly increase the expression of ATP5D and glycolysis of cancer cells. In vivo data confirm the roles of m 1 A/ATP5D in tumor growth and cancer progression. Our study reveals a crosstalk of mRNA m 1 A modification and cell metabolism, which expands the understanding of such interplays that are essential for cancer therapeutic application.

Neuroinflammatory injury, oxidative insults, and neuronal apoptosis are major causes of poor outcomes after subarachnoid hemorrhage (SAH). Pterostilbene (PTE), an analog of resveratrol, has been verified as a potent sirtuin 1 (SIRT1) activator. However, the beneficial actions of PTE on SAH-induced brain injury and whether PTE regulates SIRT1 signaling after SAH remain unknown. We first evaluated the dose-response influence of PTE on early brain impairment after SAH. In addition, EX527 was administered to suppress SIRT1 signaling. The results revealed that PTE significantly attenuated microglia activation, oxidative insults, neuronal damage, and early neurological deterioration. Mechanistically, PTE effectively enhanced SIRT1 expression and promoted nuclear factor-erythroid 2-related factor 2 (Nrf2) accumulation in nuclei. Furthermore, EX527 pretreatment distinctly repressed PTE-induced SIRT1 and Nrf2 activation and deteriorated these beneficial outcomes. In all, our study provides the evidence that PTE protects against SAH insults by activating SIRT1-dependent Nrf2 signaling pathway. PTE might be a therapeutic alternative for SAH.

N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotic mRNAs. Currently available detection methods for locus-specific m6A marks rely on RT-qPCR, radioactive methods, or high-throughput sequencing. Here, we develop a non-qPCR, ultrasensitive, isothermal, and naked-eye visible method for m6A detection based on rolling circle amplification (RCA) and loop-mediated isothermal amplification (LAMP), named m6A-Rol-LAMP, to verify putative m6A sites in transcripts obtained from the high-throughput data. When padlock probes hybridize to the potential m6A sites on targets, they are converted to circular form by DNA ligase in the absence of m6A modification, while m6A modification hinders the sealing of padlock probes. Subsequently, Bst DNA polymerase-mediated RCA and LAMP allow the amplification of the circular padlock probe to achieve the locus-specific detection of m6A. Following optimization and validation, m6A-Rol-LAMP can ultra-sensitively and quantitatively determine the existence of m6A modification on a specific target site as low as 100 amol under isothermal conditions. Detections of m6A can be performed on rRNA, mRNA, lincRNA, lncRNA and pre-miRNA from biological samples with naked-eye observations after dye incubation. Together, we provide a powerful tool for locus-specific detection of m6A, which can simply, quickly, sensitively, specifically, and visually determine putative m6A modification on RNA.

Excited-state symmetry-breaking charge separation (SB-CS) can offer an efficient pathway to solar energy capture and conversion. We synthesized a series of 1,6,7,12-tetrakis(4-t-butylphenoxy)peryle...

Chromophore aggregation strongly impacts the efficiency of organic photovoltaics (OPVs). Perylene-3,4:9,10-bis(dicarboximide) (PDI)-based electron acceptors have been shown to be excellent alternat...

The selective 1,2-aminoacylation of olefins provides opportunities for the rapid construction of nitrogen-containing molecules. However, the lack of CO-free acylation reactions has limited their application. By using photoredox proton-coupled electron transfer (PCET)/Ni dual-catalysis, a highly regio- and diastereoselective amidoacylation of unactivated olefins has been developed. Various acyl electrophiles are compatible, including alkyl- and aryl acyl chlorides and anhydrides, as well as in situ activated carboxylic acids. Hammett studies and other mechanistic experiments to elucidate features of the diastereoselectivity, a transient absorption study of the PCET step, as well as computational evidence, provide an in-depth understanding of the disclosed transformation.

Background: Drug resistance severely reduces treatment efficiency of chemotherapy and leads to poor prognosis. However, regulatory factors of chemoresistant cancer cells are largely unknown. Methods: The expression of estrogen receptor related receptors (ERRs) in chemoresistant cancer cells are checked. The roles of ERRγ in chemoresistance are confirmed by in vitro and in vivo studies. The mechanisms responsible for ERRγ-regulated expression of ABCB1 and CPT1B are investigated. Results: The expression of ERRγ is upregulated in chemoresistant cancer cells. Targeted inhibition of ERRγ restores the chemosensitivity. ERRγ can directly bind to the promoter of ABCB1 to increase its transcription. An elevated interaction between ERRγ and p65 in chemoresistant cells further strengthens transcription of ABCB1. Further, ERRγ can increase the fatty acid oxidation (FAO) in chemoresistant cells via regulation of CPT1B, the rate-limiting enzyme of FAO. The upregulated ERRγ in chemoresistant cancer cells might be due to increased levels of N6-methyladenosine (m6A) can trigger the splicing of precursor ESRRG mRNA. Conclusions: m6A induced ERRγ confers chemoresistance of cancer cells through upregulation of ABCB1 and CPT1B.

Halogenation is an important alkane functionalization strategy, but O2 is widely considered the most desirable terminal oxidant. Here, the aerobic iodination of alkanes, including methane, was performed using catalytic [nBu4N]Cl and light irradiation (390 nm). Up to 10 turnovers of CH3I were obtained from CH4 and air, using a stop-flow microtubing system. Mechanistic studies using cyclohexane as the substrate revealed important details about the iodination reaction. Iodine (I2) serves multiple roles in the catalysis: (1) as the alkyl radical trap, (2) as a precursor for the light absorber, and (3) as a mediator of aerobic oxidation. The alkane activation is attributed to Cl• derived from photofragmentation of the electron donor-acceptor complex of I2 and Cl-. The kinetic profile of cyclohexane iodination showed that aerobic oxidation of I3- to produce I2 in CH3CN is turnover-limiting.

Nanographenes have kindled considerable interest in the fields of materials science and supramolecular chemistry as a result of their unique self-assembling and optoelectronic properties. Encapsulating the contorted nanographenes inside artificial receptors, however, remains challenging. Herein, we report the design and synthesis of a trigonal prismatic hexacationic cage, which has a large cavity and adopts a relatively flexible conformation. It serves as a receptor, not only for planar coronene, but also for contorted nanographene derivatives with diameters of approximately 15 Å and thicknesses of 7 Å. A comprehensive investigation of the host-guest interactions in the solid, solution and gaseous states by experimentation and theoretical calculations reveals collectively an induced-fit binding mechanism with high binding affinities between the cage and the nanographenes. Notably, the photostability of the nanographenes is improved significantly by the ultrafast deactivation of their excited states within the cage. Encapsulating the contorted nanographenes inside the cage provides a noncovalent strategy for regulating their photoreactivity., Encapsulating large and contorted nanographenes inside artificial receptors remain challenging. This work reports the synthesis, characterization and binding properties of a trigonal prismatic cage compound that can serve as a receptor for contorted nanographene derivatives.

Organic radicals are of importance in developing smart materials that have paramagnetic and/or near-infrared optical properties. Their practical applications, however, are limited by the labile nature of the radicals. Here, we demonstrate that by using a tetracationic cyclophane, namely, cyclobis(4,4'-(1,4-phenylene)bispyridine-p-phenylene) (ExBox4+), to encapsulate a naphthalenediimide (NDI) guest, the redox properties of NDI can be modulated. In organic solvents such as MeCN or DMF, ExBox4+ is able to provide the surrounding Coulombic attraction to the NDI•- radical anion and therefore enhance its stability toward oxidation. In water, NDI•- is prone to dimerization, forming its (NDI•-)2 dimer. Under UV-light irradiation, the (NDI•-)2 dimer is observed to disproportionate and yield the dianionic NDI2-. ExBox4+ is able to encapsulate the NDI•- radical anion and prevent its dimerization, and as a consequence, the radical anion is protected from further reduction in a noncovalent manner. We believe that our strategy of modulating the redox properties of NDI by either host-guest recognition or mechanical interlocking can aid and abet the development of radical-based materials, which could be employed in pursuit of applications in many areas, such as transporting spin and charges.

8-Acetonyldihydronitidine (8-AHN) is a potent antitumor compound extracted from Toddalia asiatica. However, the precise molecular antitumor mechanisms of 8-AHN have not been well elucidated. Here, we showed that 8-AHN significantly inhibited the proliferation of human colorectal cell lines via induction of G2/M cell cycle arrest and apoptosis. We found that the p53 played a central role in 8-AHN-induced cell proliferation inhibition. Mechanistically, 8-AHN induced p53 expression and enhanced transcriptional activity, subsequently elevating the expression of p53 target genes, including p21, FAS, and BAX, and then increased the level of activated caspase-3 and decreased the level of cyclin B and cyclin A. Moreover, pifithrin-α, the p53 inhibitor, markedly reversed the above responses induced by 8-AHN, and small interfering RNA-mediated knockdown of TP53 also significantly decreased 8-AHN-induced cell apoptosis. The experiments in vivo showed that 8-AHN significantly suppressed the growth of HCT116 xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. In summary, 8-AHN displays an antitumor effect through cell cycle arrest and apoptosis in colorectal cells via activating p53, which suggests that 8-AHN, exerted a therapeutic potential against colorectal cancer cells, and may be regarded as an effective lead compound.

Bis(bithienyl)-1,2-dicyanoethene (4TCE) is a photoswitch that operates via reversible E/Z photoisomerization following absorption of visible light. cis-to-trans photoisomerization of 4TCE requires excitation below 470 nm, is relatively inefficient (quantum yield 470 nm) are readily attributed to deactivation of two conformers; this assignment is supported by computed thermal populations and absorption strengths of two molecular geometries (PA and PB) characterized by roughly parallel dipoles for the thiophenes on opposite sides of the ethene bond. Only the PB conformer is found to contribute to triplet population and the switching of cis-4TCE: high-energy excitation (

Development of purely organic materials displaying room-temperature phosphorescence (RTP) will expand the toolbox of inorganic phosphors for imaging, sensing or display applications. While molecular solids were found to suppress non-radiative energy dissipation and make the RTP process kinetically favourable, such an effect should be enhanced by the presence of multivalent directional non-covalent interactions. Here we report phosphorescence of a series of fast triplet-forming tetraethyl naphthalene-1,4,5,8-tetracarboxylates. Various numbers of bromo substituents were introduced to modulate intermolecular halogen-bonding interactions. Bright RTP with quantum yields up to 20% was observed when the molecule is surrounded by a Br⋯O halogen-bonded network. Spectroscopic and computational analyses revealed that judicious heavy-atom positioning suppresses non-radiative relaxation and enhances intersystem crossing at the same time. The latter effect was found to be facilitated by the orbital angular momentum change, in addition to the conventional heavy-atom effect. Our results suggest the potential of multivalent non-covalent interactions for excited-state conformation and electronic control., The number and position of halogen substituents in purely organic π–π* chromophores critically affect the efficiency of phosphorescence.

We have studied two regioisomeric terrylenediimide (TDI) dimers in which the 1-positions of two TDIs are linked via 1,3- or 1,4-phenylene spacers, mTDI2 and pTDI, respectively. The nature and the dynamics of the multiexciton state are tuned by altering the through-bond electronic couplings in the ground and excited states and by changing the solvent environment. Our results show that controlling the electronic coupling between the two chromophores by an appropriate choice of linker can result in independent triplet state formation, even though the initial correlated triplet pair state is confined to a dimer. Moreover, even in polar solvents, if the electronic coupling is strong, the correlated triplet pair state is observed prior to symmetry-breaking charge separation. These results point out the close relationship between the singlet, correlated triplet pair, and charge transfer states in molecular dimers.

Photoexcitation of molecular chromophore aggregates can form excimer states that play a significant role in photophysical processes such as charge and energy transfer as well as singlet fission. An excimer state is commonly defined as a superposition of Frenkel exciton and charge transfer states. In this work, we investigate the dynamics of excimer formation and decay in π-stacked 9,10-bis(phenylethynyl)anthracene (BPEA) covalent dimers appended to a xanthene spacer, where the electronic coupling between the two BPEA molecules is adjusted by changing their longitudinal molecular slip distances. Using exciton coupling calculations, we quantify the relative contributions of Frenkel excitons and charge transfer states and find that there is an upper and lower threshold of the charge transfer contribution for efficient excimer formation to occur. Knowing these thresholds can aid the design of molecular aggregates that optimize singlet fission.

Advances in quantum information science (QIS) require the development of new molecular materials to serve as microwave addressable qubits that can be read out optically. Laser photoexcitation of organic π-conjugated molecules often results in spin-polarized phosphorescent triplet states that can be readily observed and manipulated using time-resolved electron paramagnetic resonance (EPR) techniques. Photoexcitation of

Synthetic macrocycles capable of undergoing allosteric regulation by responding to versatile external stimuli are the subject of increasing attention in supramolecular science. Herein, we report a structurally transformative tetracationic cyclophane containing two 3,6-bis(4-pyridyl)-l,2,4,5-tetrazine (4-bptz) units, which are linked together by two p-xylylene bridges. The cyclophane, which possesses modular redox states and structural post-modifications, can undergo two reversibly consecutive two-electron reductions, affording first its bisradical dicationic counterpart, and then subsequently the fully reduced species. Furthermore, one single-parent cyclophane can afford effectively three other new analogs through box-to-box cascade transformations, taking advantage of either reductions or an inverse electron-demand Diels-Alder (IEDDA) reaction. While all four new tetracationic cyclophanes adopt rigid and symmetric box-like conformations, their geometries in relation to size, shape, electronic properties, and binding affinities toward polycyclic aromatic hydrocarbons can be readily regulated. This structurally transformative tetracationic cyclophane performs a variety of new tasks as a result of structural post-modifications, thus serving as a toolbox for probing the radical properties and generating rapidly a range of structurally diverse cyclophanes by efficient divergent syntheses. This research lays a solid foundation for the introduction of the structurally transformative tetracationic cyclophane into the realm of mechanically interlocked molecules and will provide a toolbox to construct and operate intelligent molecular machines.

Protection of enzymes with synthetic materials is a viable strategy to stabilize, and hence to retain, the reactivity of these highly active biomolecules in non-native environments. Active synthetic supports, coupled to encapsulated enzymes, can enable efficient cascade reactions which are necessary for processes like light-driven CO

Implementation of the two-qubit controlled-NOT (CNOT) gate is necessary to develop a complete set of universal gates for quantum computing. Here, we demonstrate that a photogenerated radical (spin qubit) pair within a covalent donor-chromophore-acceptor molecule can be used to successfully execute a CNOT gate with high fidelity. The donor is tetrathiafulvalene (TTF), the chromophore is 8-aminonaphthalene-1,8-dicarboximide (ANI), and the acceptor is pyromellitimide (PI). Selective photoexcitation of ANI with a 416 nm laser pulse results in subnanosecond formation of the TTF•+-ANI-PI•- radical (spin qubit) pair at 85 K having a 1.8 µs phase memory time. This is sufficiently long to execute a CNOT gate using a sequence of five microwave pulses followed by a sequence of two pulses that read out all the elements of the density matrix. Comparing these data to a simulation of the data that assumes ideal conditions results in a fidelity of 0.97 for the execution of the CNOT gate. These results show that photogenerated molecular spin qubit pairs can be used to execute this essential quantum gate at modest temperatures, which affords the possibility that chemical synthesis can be used to develop structures to execute more complex quantum logic operations using electron spins.

Protection of enzymes with synthetic materials is a viable strategy to stabilize, and hence to retain, the reactivity of these highly active biomolecules in non-native environments. Active syntheti...

Along with the advent of supramolecular chemistry, research on fullerene receptors based on noncovalent bonding interactions has attracted a lot of attention. Here, we present the design and synthesis of a cationic molecular cage: a cyclophane composed of two tetraphenylporphyrins, bridged face-to-face by four viologen units in a rhomboid prismatic manner. The large cavity inside the cage, as well as the favorable donor–acceptor interactions between the porphyrin panels and the fullerene guests, enables the cage to be an excellent fullerene receptor. The 1:1 host–guest complexes formed between the cage and both C60 and C70 were characterized in solution by HRMS and NMR, UV–vis and fluorescence spectroscopies, and confirmed in the solid state by single-crystal X-ray diffraction analyses. The results from solution studies reveal that the cage has a much stronger binding for C70 than for C60, resulting in a selective extraction of C70 from a C60-enriched fullerene mixture (C60/C70 = 10/1), demonstrating the ...

Strongly oxidizing photosensitizers (superoxidants) based on organic radical cations are capable of driving energy-demanding reactions using low-energy photons. Here, we show that the peri-xantheno...

An octacationic diazaperopyrenium (DAPP2+)-based homo[2]catenane (DAPPHC8+), wherein no fewer than eight positive charges are associated within a mechanically interlocked molecule, has been produced in 30% yield under ambient conditions as a result of favorable homophilic interactions, reflecting a delicate balance between strong π–π interactions and the destabilizing penalty arising from Coulombic repulsions between DAPP2+ units. This DAPPHC8+ catenane is composed of two identical mechanically interlocked tetracationic cyclophanes, namely DAPPBox4+, each of which contains one DAPP2+ unit and one extended viologen (ExBIPY2+) unit, linked together by two p-xylylene bridges. The solid-state structure of the homo[2]catenane demonstrates how homophilic interactions play an important role in the formation of DAPPHC8+, in which the mean ring planes of the two DAPPBox4+ cyclophanes are oriented at about 60° with respect to each other, with a centroid-to-centroid separation of 3.7 A between the mean planes of the...

Four distinct fluorescent states are achieved in a single Weak-Link Approach (WLA) construct bearing pyrene and tetraphenylethene moieties. The fluorescence of the compound in both the solution and solid phases can be manipulated through reversible coordination chemistry at the PtII center.