HetDDI: a pre-trained heterogeneous graph neural network model for drug-drug interaction prediction.

The simultaneous use of two or more drugs due to multi-disease comorbidity continues to increase, which may cause adverse reactions between drugs that seriously threaten public health. Therefore, the prediction of drug-drug interaction (DDI) has become a hot topic not only in clinics but also in bioinformatics. In this study, we propose a novel pre-trained heterogeneous graph neural network (HGNN) model named HetDDI, which aggregates the structural information in drug molecule graphs and rich semantic information in biomedical knowledge graph to predict DDIs. In HetDDI, we first initialize the parameters of the model with different pre-training methods. Then we apply the pre-trained HGNN to learn the feature representation of drugs from multi-source heterogeneous information, which can more effectively utilize drugs' internal structure and abundant external biomedical knowledge, thus leading to better DDI prediction. We evaluate our model on three DDI prediction tasks (binary-class, multi-class and multi-label) with three datasets and further assess its performance on three scenarios (S1, S2 and S3). The results show that the accuracy of HetDDI can achieve 98.82% in the binary-class task, 98.13% in the multi-class task and 96.66% in the multi-label one on S1, which outperforms the state-of-the-art methods by at least 2%. On S2 and S3, our method also achieves exciting performance. Furthermore, the case studies confirm that our model performs well in predicting unknown DDIs. Source codes are available at https://github.com/LinsLab/HetDDI.

Metal-Organic Layers with Photosensitizer and Pyridine Pairs Activate Alkyl Halides for Photocatalytic Heck-Type Coupling with Olefins.

Photochemical generation of alkyl radicals from haloalkanes often requires strong energy input from ultraviolet light or a strong photoreductant. Haloalkanes can alternatively be activated with nitrogen-based nucleophiles through a sequential SN2 reaction and single-electron reduction to access alkyl radicals, but these two reaction steps have opposite steric requirements on the nucleophiles. Herein, we report the design of Hf12 metal-organic layers (MOLs) with iridium-based photosensitizer bridging ligands and secondary-building-unit-supported pyridines for photocatalytic alkyl radical generation from haloalkanes. By bringing the photosensitizer and pyridine pairs in proximity, the MOL catalysts allowed facile access to the pyridinium salts from SN2 reactions between haloalkanes and pyridines and at the same time enhanced electron transfer from excited photosensitizers to pyridinium salts to facilitate alkyl radical generation. Consequentially, the MOLs efficiently catalyzed Heck-type cross-coupling reactions between haloalkanes and olefinic substrates to generate functionalized alkenes. The MOLs showed 4.6 times higher catalytic efficiency than the homogeneous counterparts and were recycled and reused without a loss of catalytic activity.

Nanoscale Covalent Organic Framework with Staggered Stacking of Phthalocyanines for Mitochondria-Targeted Photodynamic Therapy.

Phthalocyanine photosensitizers (PSs) have shown promise in fluorescence imaging and photodynamic therapy (PDT) of malignant tumors, but their practical application is limited by the aggregation-induced quenching (AIQ) and inherent photobleaching of PSs. Herein, we report the synthesis of a two-dimensional nanoscale covalent organic framework (nCOF) with staggered (AB) stacking of zinc-phthalocyanines (ZnPc), ZnPc-PI, for fluorescence imaging and mitochondria-targeted PDT. ZnPc-PI isolates and confines ZnPc PSs in the rigid nCOF to reduce AIQ, improve photostability, enhance cellular uptake, and increase the level of reactive oxygen species (ROS) generation via mitochondrial targeting. ZnPc-PI shows efficient tumor accumulation, which allowed precise tumor imaging and nanoparticle tracking. With high cellular uptake and tumor accumulation, intrinsic mitochondrial targeting, and enhanced ROS generation, ZnPc-PI exhibits potent PDT efficacy with >95% tumor growth inhibition on two murine colon cancer models without causing side effects.

Simultaneous Protonation and Metalation of a Porphyrin Covalent Organic Framework Enhance Photodynamic Therapy.

Covalent organic frameworks (COFs) have been explored for photodynamic therapy (PDT) of cancer, but their antitumor efficacy is limited by excited state quenching and low reactive oxygen species generation efficiency. Herein, we report a simultaneous protonation and metalation strategy to significantly enhance the PDT efficacy of a nanoscale two-dimensional imine-linked porphyrin-COF. The neutral and unmetalated porphyrin-COF (Ptp) and the protonated and metalated porphyrin-COF (Ptp-Fe) were synthesized via imine condensation between 5,10,15,20-tetrakis(4-aminophenyl)porphyrin and terephthalaldehyde in the absence and presence of ferric chloride, respectively. The presence of ferric chloride generated both doubly protonated and Fe3+-coordinated porphyrin units, which red-shifted and increased the Q-band absorption and disrupted exciton migration to prevent excited state quenching, respectively. Under light irradiation, rapid energy transfer from protonated porphyrins to Fe3+-coordinated porphyrins in Ptp-Fe enabled 1O2 and hydroxyl radical generation via type II and type I PDT processes. Ptp-Fe also catalyzed the conversion of hydrogen peroxide to hydroxy radical through a photoenhanced Fenton-like reaction under slightly acidic conditions and light illumination. As a result, Ptp-Fe-mediated PDT exhibited much higher cytotoxicity than Ptp-mediated PDT on CT26 and 4T1 cancer cells. Ptp-Fe-mediated PDT afforded potent antitumor efficacy in subcutaneous CT26 murine colon cancer and orthotopic 4T1 murine triple-negative breast tumors and prevented metastasis of 4T1 breast cancer to the lungs. This work underscores the role of fine-tuning the molecular structures of COFs in significantly enhancing their PDT efficacy.

Heterogeneous Porous Synergistic Photocatalysts for Organic Transformations.

Recent interest has surged in using heterogeneous carriers to boost synergistic photocatalysis for organic transformations. Heterogeneous catalysts not only facilitate synergistic enhancement of distinct catalytic centers compared to their homogeneous counterparts, but also allow for the easy recovery and reuse of catalysts. This mini-review summarizes recent advancements in developing heterogeneous carriers, including metal-organic frameworks, covalent-organic frameworks, porous organic polymers, and others, for synergistic catalytic reactions. The advantages of porous materials in heterogeneous catalysis originate from their ability to provide a high surface area, facilitate enhanced mass transport, offer a tunable chemical structure, ensure the stability of active species, and enable easy recovery and reuse of catalysts. Both photosensitizers and catalysts can be intricately incorporated into suitable porous carriers to create heterogeneous dual photocatalysts for organic transformations. Notably, experimental evidence from reported cases has shown that the catalytic efficacy of heterogeneous catalysts often surpasses that of their homogeneous analogues. This enhanced performance is attributed to the proximity and confinement effects provided by the porous nature of the carriers. It is expected that porous carriers will provide a versatile platform for integrating diverse catalysts, thus exhibiting superior performance across a range of organic transformations and appealing prospect for industrial applications.

Nanoscale Metal-Organic Layer Reprograms Cellular Metabolism to Enhance Photodynamic Therapy and Antitumor Immunity.

Abnormal cancer metabolism causes hypoxia and immunosuppressive tumor microenvironment (TME), which limits the antitumor efficacy of photodynamic therapy (PDT). Herein, we report a photosensitizing nanoscale metal-organic layer (MOL) with anchored 3­bromopyruvate (BrP), BrP@MOL, as a metabolic reprogramming agent to enhance PDT and antitumor immunity. BrP@MOL inhibited mitochondrial respiration and glycolysis to oxygenate tumors and reduce lactate production. This metabolic reprogramming enhanced reactive oxygen species generation during PDT and reshaped the immunosuppressive TME to enhance antitumor immunity. BrP@MOL-mediated PDT inhibited tumor growth by >90% with a 40% cure rate, rejected tumor re-challenge, and prevented lung metastasis. Further combination with immune checkpoint blockade potently regressed the tumors with >98% tumor inhibition and an 80% cure rate.

A Stable Site-Isolated Mono(phosphine)-Rhodium Catalyst on a Metal-Organic Layer for Highly Efficient Hydrogenation Reactions.

Phosphine-ligated transition metal complexes play a pivotal role in modern catalysis, but our understanding of the impact of ligand counts on the catalysis performance of the metal center is limited. Here we report the synthesis of a low-coordinate mono(phosphine)-Rh catalyst on a metal-organic layer (MOL), P-MOL●Rh, and its applications in the hydrogenation of mono-, di-, and tri-substituted alkenes as well as aryl nitriles with turnover numbers (TONs) of up to 390000. Mechanistic investigations and density functional theory calculations revealed the lowering of reaction energy barriers by the low steric hindrance of site-isolated mono(phosphine)-Rh sites on the MOL to provide superior catalytic activity over homogeneous Rh catalysts. The MOL also prevents catalyst deactivation to enable recycle and reuse of P-MOL●Rh in catalytic hydrogenation reactions.

Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy.

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy. In the meantime, the MOL sensitizes cancer cells to X-ray irradiation and provides potent radiotherapeutic effects. GMP-loaded MOL (GMP/MOL) enhances cytotoxicity by 2-fold and improves radiotherapeutic effects over free GMP in vitro. In a colon cancer model, GMP/MOL retains GMP in tumors for more than four days and, when combined with low-dose radiotherapy, inhibits tumor growth by 98 %. The synergistic chemoradiotherapy enabled by GMP/MOL shows a cure rate of 50 %, improves survival, and ameliorates cancer-proliferation histological biomarkers.

Molecular Engineering of Metal-Organic Layers for Sustainable Tandem and Synergistic Photocatalysis.

Metal-organic layers (MOLs), a monolayered version of metal-organic frameworks (MOFs), have recently emerged as a novel two-dimensional molecular material platform to design multifunctional catalysts. MOLs inherit the intrinsic molecular tunability of MOFs and yet have more accessible and modifiable building blocks. Here we report molecular engineering of six MOLs via modulated solvothermal synthesis between HfCl4 and three photosensitizing ligands followed by postsynthetic modification with two carboxylate-containing cobaloximes for tandem and synergistic photocatalysis. Morphological and structural characterization by transmission electron microscopy and atomic force microscopy and compositional analysis by inductively coupled plasma-mass spectrometry and nuclear magnetic resonance spectroscopy establish the MOLs as flat nanoplates with a periodic lattice structure of hexagonal symmetry. The MOLs efficiently catalyze tandem dehydrogenative coupling reactions and synergistic Heck-type coupling reactions. The most active MOL catalyst was used for the gram-scale synthesis of vesnarinone, a cardiotonic agent, in 80% yield with a turnover number of 400 and in eight consecutive reaction cycles without significant loss of activities.

Self-adaptive Metal-Organic Framework Assembles Di-iron Active Sites to Mimic Monooxygenases.

Despite significant efforts, it remains a challenge to design artificial enzymes that can mimic both structures and functions of natural enzymes. Here, we report the post-synthetic construction of binuclear iron catalysts in MOF-253 to mimic natural di-iron monooxygenases. The adjacent bipyridyl (bpy) linkers in MOF-253 can freely rotate to form the [(bpy)FeIII(µ2-OH)]2 active site in a self-adaptive fashion. The composition and structure of the [(bpy)FeIII(µ2-OH)]2 active sites in MOF-253 were characterized by a combination of inductively coupled plasma-mass spectrometry, thermogravimetric analysis, X-ray absorption spectrometry, and Fourier-transform infrared spectroscopy. The MOF-based artificial monooxygenase effectively catalyzed oxidative transformations of organic compounds, including C-H oxidation and alkene epoxidation reactions, using O2 as the only oxidant, which indicates the successful recapitulation of the structure and functions of natural monooxygenases using readily accessible MOFs. The di-iron system exhibited at least 27 times higher catalytic activity than the corresponding mononuclear control. DFT calculations showed that the binuclear system had a 14.2 kcal/mol lower energy barrier than the mononuclear system in the rate-determining C-H activation process, suggesting the importance of cooperativity of the iron centers in the [(bpy)FeIII(µ2-OH)]2 active site in the rate-determining step. The stability and recyclability of the MOF-based artificial monooxygenase were also demonstrated.

Sequential Modifications of Metal-Organic Layer Nodes for Highly Efficient Photocatalyzed Hydrogen Atom Transfer.

Herein, we report the synthesis of a bifunctional photocatalyst, Zr-OTf-EY, through sequential modifications of metal cluster nodes in a metal-organic layer (MOL). With eosin Y and strong Lewis acids on the nodes, Zr-OTf-EY catalyzes cross-coupling reactions between various C-H compounds and electron-deficient alkenes or azodicarboxylate to afford C-C and C-N coupling products, with turnover numbers of up to 1980. In Zr-OTf-EY-catalyzed reactions, Lewis acid sites bind the alkenes or azodicarboxylate to increase their local concentrations and electron deficiency for enhanced radical additions, while EY is stabilized by site isolation on the MOL to afford a long-lived catalyst for hydrogen atom transfer. The proximity between photostable EY sites and Lewis acids on the nodes of Zr-OTf-EY enhances the catalytic efficiency by approximately 400 times over the homogeneous counterpart in the cross-coupling reactions.

A Spirobifluorene-Based Covalent Organic Framework for Dual Photoredox and Nickel Catalysis.

Covalent organic frameworks (COFs) have emerged as tunable, crystalline, and porous functional organic materials, but their application in photocatalysis has been limited by rapid excited-state quenching. Herein, we report the first example of dual photoredox/nickel catalysis by an sp2 carbon-conjugated spirobifluorene-based COF. Constructed from spirobifluorene and nickel-bipyridine linkers, the NiSCN COF adopted a two-dimensional structure with staggered stacking. Under light irradiation, NiSCN catalyzed amination and etherification/esterification reactions of aryl halides through the photoredox mechanism, with a catalytic efficiency more than 23-fold higher than that of its homogeneous control. NiSCN was used in five consecutive reactions without a significant loss of catalytic activity.

Nanoscale Metal-Organic Framework with an X-ray Triggerable Prodrug for Synergistic Radiotherapy and Chemotherapy.

As heavy-metal-based nanoscale metal-organic frameworks (nMOFs) are excellent radiosensitizers for radiotherapy via enhanced energy deposition and reactive oxygen species (ROS) generation, we hypothesize that nMOFs with covalently conjugated and X-ray triggerable prodrugs can harness the ROS for on-demand release of chemotherapeutics for chemoradiotherapy. Herein, we report the design of a novel nMOF, Hf-TP-SN, with an X-ray-triggerable 7-ethyl-10-hydroxycamptothecin (SN38) prodrug for synergistic radiotherapy and chemotherapy. Upon X-ray irradiation, electron-dense Hf12 secondary building units serve as radiosensitizers to enhance hydroxyl radical generation for the triggered release of SN38 via hydroxylation of the 3,5-dimethoxylbenzyl carbonate followed by 1,4-elimination, leading to 5-fold higher release of SN38 from Hf-TP-SN than its molecular counterpart. As a result, Hf-TP-SN plus radiation induces significant cytotoxicity to cancer cells and efficiently inhibits tumor growth in colon and breast cancer mouse models.

Mechanoregulatory Cholesterol Oxidase-Functionalized Nanoscale Metal-Organic Framework Stimulates Pyroptosis and Reinvigorates T Cells.

Cancer cells alter mechanical tension in their cell membranes. New interventions to regulate cell membrane tension present a potential strategy for cancer therapy. Herein, the increase of cell membrane tension by cholesterol oxidase (COD) via cholesterol depletion in vitro and the design of a COD-functionalized nanoscale metal-organic framework, Hf-TBP/COD, for cholesterol depletion and mechanoregulation of tumors in vivo, are reported. COD is found to deplete cholesterol and disrupt the mechanical properties of lipid bilayers, leading to decreased cell proliferation, migration, and tolerance to oxidative stress. Hf-TBP/COD increases mechanical tension of plasma membranes and osmotic fragility of cancer cells, which induces influx of calcium ions, inhibits cell migration, increases rupturing propensity for effective caspase-1 mediated pyroptosis, and decreases tolerance to oxidative stress. In the tumor microenvironment, Hf-TBP/COD downregulates multiple immunosuppressive checkpoints to reinvigorate T cells and enhance T cell infiltration. Compared to Hf-TBP, Hf-TBP/COD improves anti-tumor immune response and tumor growth inhibition from 54.3% and 79.8% to 91.7% and 95% in a subcutaneous triple-negative breast cancer model and a colon cancer model, respectively.

Direct photo-oxidation of methane to methanol over a mono-iron hydroxyl site.

Natural gas, consisting mainly of methane (CH4), has a relatively low energy density at ambient conditions (~36 kJ l-1). Partial oxidation of CH4 to methanol (CH3OH) lifts the energy density to ~17 MJ l-1 and drives the production of numerous chemicals. In nature, this is achieved by methane monooxygenase with di-iron sites, which is extremely challenging to mimic in artificial systems due to the high dissociation energy of the C-H bond in CH4 (439 kJ mol-1) and facile over-oxidation of CH3OH to CO and CO2. Here we report the direct photo-oxidation of CH4 over mono-iron hydroxyl sites immobilized within a metal-organic framework, PMOF-RuFe(OH). Under ambient and flow conditions in the presence of H2O and O2, CH4 is converted to CH3OH with 100% selectivity and a time yield of 8.81 ± 0.34 mmol gcat-1 h-1 (versus 5.05 mmol gcat-1 h-1 for methane monooxygenase). By using operando spectroscopic and modelling techniques, we find that confined mono-iron hydroxyl sites bind CH4 by forming an [Fe-OH···CH4] intermediate, thus lowering the barrier for C-H bond activation. The confinement of mono-iron hydroxyl sites in a porous matrix demonstrates a strategy for C-H bond activation in CH4 to drive the direct photosynthesis of CH3OH.

Synthesis and Characterization of Ether Adducts of Thorium Tetrahydroborate Th(BH4)4 and Chemical Vapor Deposition of Thorium Boride Thin Films.

Treating ThCl4 with LiBH4 in various ethereal solvents affords the adducts Th(BH4)4(Et2O)2, Th(BH4)4(thf)2, and Th(BH4)4(dme) (thf = tetrahydrofuran and dme = 1,2-dimethoxyethane). The structures of these three compounds have been established by single-crystal X-ray diffraction: if the tetrahydroborate groups are considered as occupying one coordination site, the Et2O and thf complexes adopt trans-octahedral coordination geometries, whereas the dme complex exhibits a cis-octahedral structure. All four BH4- ligands in each compound are tridentate, rendering each thorium center 14-coordinate. The Th···B distances range from 2.64 to 2.67 Å, and the Th-O bond lengths are 2.47-2.52 Å. We propose that crystals of Th(BH4)4(thf)2 are isomorphous with those of U(BH4)4(thf)2, but owing to pseudosymmetry the latter was reported in a unit cell that was too small by a factor of 2. IR spectra and 1H and 11B NMR data are reported as well. All three adducts are volatile, subliming readily at 60 °C and 10-4 Torr, making them potentially useful as precursors for the chemical vapor deposition (CVD) of thin films of thorium boride. Passage of Th(BH4)4(Et2O)2 over glass, Si(100), and aluminum substrates heated to 350 °C yields amorphous films of approximate stoichiometry ThB2; films deposited from Th(BH4)4(thf)2 have stoichiometries closer to ThB2.5 and contain some oxygen. Auger, XPS, XRD, and SEM studies of these films are reported.

Generation and Stabilization of a Dinickel Catalyst in a Metal-Organic Framework for Selective Hydrogenation Reactions.

Although many monometallic active sites have been installed in metal-organic frameworks (MOFs) for catalytic reactions, there are no effective strategies to generate bimetallic catalysts in MOFs. Here we report the synthesis of a robust, efficient, and reusable MOF catalyst, MOF-NiH, by adaptively generating and stabilizing dinickel active sites using the bipyridine groups in MOF-253 with the formula of Al(OH)(2,2'-bipyridine-5,5'-dicarboxylate) for Z-selective semihydrogenation of alkynes and selective hydrogenation of C=C bonds in α,ß-unsaturated aldehydes and ketones. Spectroscopic studies established the dinickel complex (bpy⋅- )NiII (µ2 -H)2 NiII (bpy⋅- ) as the active catalyst. MOF-NiH efficiently catalyzed selective hydrogenation reactions with turnover numbers of up to 192 and could be used in five cycles of hydrogenation reactions without catalyst leaching or significant decrease of catalytic activities. The present work uncovers a synthetic strategy toward solution-inaccessible Earth-abundant bimetallic MOF catalysts for sustainable catalysis.

Enhanced Energy Transfer in A π-Conjugated Covalent Organic Framework Facilitates Excited-State Nickel Catalysis.

Covalent organic frameworks (COFs) have received broad interest owing to their permanent porosity, high stability, and tunable functionalities. COFs with long-range π-conjugation and photosensitizing building blocks have been explored for sustainable photocatalysis. Herein, we report the first example of COF-based energy transfer Ni catalysis. A pyrene-based COF with sp2 carbon-conjugation was synthesized and used to coordinate NiII centers through bipyridine moieties. Under light irradiation, enhanced energy transfer in the COF facilitated the excitation of Ni centers to catalyze borylation and trifluoromethylation reactions of aryl halides. The COF showed two orders of magnitude higher efficiency in these reactions than its homogeneous control and could be recovered and reused without significant loss of catalytic activity.

Diaryl Dihydrophenazine-Based Porous Organic Polymers Enhance Synergistic Catalysis in Visible-Light-Driven Organic Transformations.

Porous organic polymers (POPs) have emerged as a novel class of porous materials that are synthesized by the polymerization of various organic monomers with different geometries and topologies. The molecular tunability of organic building blocks allows the incorporation of functional units for photocatalytic organic transformations. Here, we report the synthesis of two POP-based photocatalysts via homopolymerization of vinyl-functionalized diaryl dihydrophenazine (DADHP) monomer (POP1) and copolymerization of vinyl-functionalized DADHP and 2,2'-bipyridine monomers (POP2). The fluorescence lifetimes of DADHP units in the POPs significantly increased, resulting in enhanced photocatalytic performances over homogeneous controls. POP1 is highly effective in catalysing visible-light-driven C-N bond forming cross-coupling reactions. Upon coordination with Ni2+ ions, POP2-Ni shows strong synergy between photocatalytic and Ni catalytic cycles due to the confinement effect within the POP framework, leading to high efficiency in energy, electron, and organic radical transfer. POP2-Ni displays excellent activity in catalysing C-P bond forming reactions between diarylphosphine oxides and aryl iodides. They increased the photocatalytic activities by more than 30-fold in C-N and C-P cross-coupling reactions. These POP catalysts were readily recovered via centrifugal separation and reused in six catalytic cycles without loss of activities. Thus, photosensitizer-based POPs provide a promising platform for heterogeneous photocatalytic organic transformations.

Metal-Organic Layer Delivers 5-Aminolevulinic Acid and Porphyrin for Dual-Organelle-Targeted Photodynamic Therapy.

The efficacy of photodynamic therapy (PDT) depends on the subcellular localization of photosensitizers. Herein, we report a dual-organelle-targeted nanoparticle platform for enhanced PDT of cancer. By grafting 5-aminolevulinic acid (ALA) to a Hf12 -based nanoscale metal-organic layer (Hf-MOL) via carboxylate coordination, ALA/Hf-MOL enhanced ALA delivery and protoporphyrin IX (PpIX) synthesis in mitochondria, and trapped the Hf-MOL comprising 5,15-di-p-benzoatoporphyrin (DBP) photosensitizers in lysosomes. Light irradiation at 630 nm simultaneously excited PpIX and DBP to generate singlet oxygen and rapidly damage both mitochondria and lysosomes, leading to synergistic enhancement of the PDT efficacy. The dual-organelle-targeted ALA/Hf-MOL outperformed Hf-MOL in preclinical PDT studies, with a 2.7-fold lower half maximal inhibitory concentration in cytotoxicity assays in vitro and a 3-fold higher cure rate in a colon cancer model in vivo.