Total Synthesis of Quebrachamine and Kopsiyunnanine D.

The total syntheses of (±)-quebrachamine and (±)-kopsiyunnanine D are reported. Key transformations include an intermolecular Horner-Wadsworth-Emmons olefination to merge the two fragments convergently and an intramolecular Mitsunobu reaction to introduce the synthetically challenging nine-membered azonane ring efficiently.

Silver/Antimony-Base Multifunctional Double Perovskite with H/F Substitution Enhance Properties.

Two-dimensional double perovskites have experienced rapid development due to their outstanding optoelectronic properties and diverse structural characteristics. However, the synthesis of high-performance multifunctional compounds and the regulation of their properties still lack relevant examples. Herein, we synthesized two multifunctional compounds, (C6H14N)4AgSbBr8 (1) and (F2-C6H12N)4AgSbBr8 (2), which exhibit high solid-state phase transition temperature, bistable dielectric constant switching, second harmonic generation (SHG), and bright emission. Through H/F substitution, the transition temperature increases and achieves a smaller band gap attributed to reduced interlayer spacing. Furthermore, we investigated the broad emission mechanism of the compounds through first-principles calculation and variable-temperature fluorescence, confirming the presence of the STE1 emission. Our work provides insight into the further development of multifunctional compounds and chemical modification that enhances compound properties.

Investigating the Structure-property Relationships of Two Cd-based Hybrid Multifunctional Compounds with High Tc, Bright Fluorescence and Wide Band-gap.

Organic-inorganic hybrid multifunctional materials have shown significant application in lighting and sensor fields, owing to their prominent performance and diversity structures. Herein, we synthesized two multifunctional compounds: (propyl-quinuclidone)2 CdBr4 (1) and (F-butyl-quinuclidone)2 CdBr4 (2). By introducing light-emitting organic cation with flexible long chain, 1 and 2 exhibit excellent transition properties and bright blue-white fluorescence. Then, combine fluorescence lifetime and first-principal calculation, providing evidence for the electron transfer emission. Subsequently, investigated the impact of substituent carbon chain length (methyl to butyl), structural rigidity (C-C to C-F) and halide framework (Cl to I) on the fluorescence properties. Results indicate that Cd⋅⋅⋅Cd distance and structural rigidity play an important role in fluorescence. Overall, our research provides valuable insight and example for chemical modifications enhance compound performance.

2-Chloroethylamine·trifluoromethanesulfonate combined with 18-crown-6: a ferroelectric with excellent dielectric switching properties.

Ferroelectric materials are not only important electronic functional materials, but also considered as the most promising intelligent basic materials, because they show good application prospects. Therefore, it is an urgent task to develop and explore new ferroelectric material systems. In addition, the most important feature of crown ethers is their ability to complex with positive ions, which is extremely useful in synthesis. We report that [NH3C2H4Cl(18-crown-6)](CF3SO3) (1) has a phase transition temperature Tc = 255 K, and there is an obvious SHG switch below Tc. At the same time, the saturation polarization value Ps = 1.25 µC cm-2 is obtained from the hysteresis loop, which directly proves the ferroelectric nature of compound 1. It is noteworthy that the second harmonic response test of compound 1 shows a symmetric transition from a non-centrosymmetric to a centrosymmetric point group, that is a symmetry break from the paraelectric phase to the ferroelectric phase. This work is expected to promote the further exploration of organic crown ether ferroelectrics and provide a way to design and synthesize organic crown ether ferroelectrics.

Zero-Dimensional Sn-Based Enantiomeric Phase-Transition Materials with High-Tc and Dielectric Switching.

The combination of chirality and phase-transition materials has broad application prospects. Therefore, based on the quasi-spherical theory and the thought strategy of introducing chirality, we have successfully synthesized a pair of chiral enantiomeric ligands (R/S)-triethyl-(2-hydroxypropyl)ammonium iodide, which can be combined with a tin hexachloride anion to obtain a pair of new organic-inorganic hybrid enantiomeric high-temperature plastic phase-transition materials: (R/S)-[CH3 CH(OH)CH2 N(CH2 CH3 )3 ]2 SnCl6 (1-R/1-S), which have a high temperature phase transition of Tc =384 K, crystallize in the P21 chiral space group at room temperature, and have obvious CD signals. In addition, compounds 1-R and 1-S have a good low-loss dielectric switch and broadband gap. This work is conducive to the research into chiral high-temperature reversible plastic phase-transition materials, and promotes the development of multi-functional phase-transition materials.

Excellent Switchable Properties, Broad-Band Emission, Ferroelectricity, and High Tc in a Two-Dimensional Hybrid Perovskite: (4,4-DCA)2PbBr4 Exploited by H/F Substitution.

Switchable materials have gained significant attention due to their potential applications in data storage, sensors, and switching devices. Two-dimensional (2D) hybrid perovskites have demonstrated promising prospects for designing switchable materials, where the dynamic motion of the organic components coupled with the distortion of the inorganic framework provides the driving force for triggering multifunctional switchable properties. Herein, through the H/F substitution strategy, we report a polar 2D hybrid lead-based perovskite, (4,4-DCA)2PbBr4 (4,4-DCA = 4,4-difluorocyclohexylammonium) (1), which exhibits dual-stable behavior in a dielectric and second harmonic generation (SHG) response during the reversible phase transition process near the high Curie temperature Tc ∼ 409 K. The phase transition temperature is significantly increased by 41 K compared to the corresponding non-fluorinated (CHA)2PbBr4 (CHA = cyclohexylammonium). Remarkably, the material shows rare broad-band yellow emission under UV excitation, attributed to the induction of self-trapped exciton emission by the distortion of the [PbBr6]4- octahedra, as confirmed by the first-principles analysis. 1 also exhibited ferroelectricity with a saturation polarization value and a small coercive field. This study provides a new insight into the modification of multifunctional switchable materials through the H/F substitution strategy.

High-Temperature Ferroelasticity and Photoluminescence in a 2D Monolayer Perovskite Compound: (C5NH8Br)2PbBr4.

Hybrid organic-inorganic perovskites (HOIPs) have attracted much attention due to their excellent properties and easy synthesis. As far as we know, most documented ferroelastics mainly focus on the 3D (three-dimensional) perovskites, the 2D monolayer perovskite ferroelastics are rarely reported before. In this work, we synthesized a 2D lead-based perovskite (C5NH13Br)2PbBr4 (1) (C5NH13Br = 5-bromoamylamine cation) by introducing flexible chain organic cations. The evolution of ferroelastic domains observed by a polarized light microscope confirms that compound 1 undergoes a ferroelastic phase transition at 392/384 K. In addition, its direct band gap is 2.877 eV. Interestingly, the material emits an attractive blue light (quantum yield 5.06%) under UV light. Three structural descriptors are introduced to quantitatively analyze the relationship between structural distortion and the shape of emission peak. This work provides a way to design multifunctional perovskite-type materials.

Large Spontaneous Polarization Ferroelectric Property, Switchable Second-Harmonic Generation Responses, and Magnetism in an Fe-Based Compound.

Since the switchable spontaneous polarization of ferroelectric materials endows it with many useful properties such as a large pyroelectric coefficient, switchable spontaneous polarization, and semiconductor, it has a wide range of application prospects, and the research of high-performance molecular ferroelectric materials has become a hot spot. We obtained a 0D organic-inorganic hybrid ferroelectric [(CH3)3NCH2CH2CH3]2FeCl4 (1) with well-defined ferroelectric domains and excellent domain inversion and exhibited a relatively large spontaneous polarization (Ps = 9 µC/m-2) and a Curie temperature (Tc) of 394 K. Furthermore, compound 1 belongs to the non-centrosymmetrical space group Cmc21 and has a strong second-harmonic generation signal. Interestingly, we also performed magnetic tests on 1, which confirmed that it is a magnetic material. This work provides clues for exploring the application of high-performance molecular ferroelectric materials in future multifunctional smart devices.

High-Tc 1D Phase-Transition Semiconductor Photoluminescent Material with Broadband Emission.

One dimensional (1D) organic-inorganic halide hybrid perovskites have the advantages of excellent organic cation modifiability and diversity of inorganic framework structures, which cannot be ignored in the development of multi-functional phase-transition materials in photoelectric and photovoltaic devices. Here, we have successfully modified and synthesized an organic-inorganic hybrid perovskite photoelectric multifunctional phase-transition material: [C7 H13 ONCH2 F]⋅PbBr3 (1). The synergistic effect of the order double disorder transition of organic cations and the change of the degree of distortion of the inorganic framework leads to its high temperature reversible phase-transition point of Tc =374 K/346 K and its ultra-low loss high-quality dielectric switch response. Through in-depth research and calculation, compound 1 also has excellent semiconductor characteristics with a band gap of 3.06 eV and the photoluminescence characteristics of self-trapped exciton (STE) broadband emission. Undoubtedly, this modification strategy provides a new choice for the research field of organic-inorganic hybrid perovskite reversible phase-transition photoelectric multifunctional materials with rich coupling properties.

1D Chiral Lead Bromide Perovskite with Superior Second-Order Optical Nonlinearity, Photoluminescence, and High-Temperature Reversible Phase Transition.

Multifunctional materials are an attractive research area. Organic-inorganic hybrid perovskites are widely used in the design of these materials due to their rich properties and flexible composition. It is easy to obtain more photoelectric properties by introducing chiral groups as ligands. In this work, we synthesized chiral one-dimensional organic-inorganic hybrid perovskites, namely (R/S-3-HP)PbBr3 (1R/1S) (3-HP=3-hydroxy-piperidine). The enantiomer compounds undergo reversible phase transition at 349/336 K. Under the excitation light of 339 nm, 1R and 1S have a wide emission peak at 635 nm, showing orange light. In addition, the indirect bandgap is 3.29 eV and the SHG intensity is comparable to that of KDP. This work provides a way to design multifunctional chiral perovskite materials.

Design and Synthesis of Novel Indole Ethylamine Derivatives as a Lipid Metabolism Regulator Targeting PPARα/CPT1 in AML12 Cells.

Peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1 (CPT1) are important targets of lipid metabolism regulation for nonalcoholic fatty liver disease (NAFLD) therapy. In the present study, a set of novel indole ethylamine derivatives (4, 5, 8, 9) were designed and synthesized. The target product (compound 9) can effectively activate PPARα and CPT1a. Consistently, in vitro assays demonstrated its impact on the lipid accumulation of oleic acid (OA)-induced AML12 cells. Compared with AML12 cells treated only with OA, supplementation with 5, 10, and 20 µM of compound 9 reduced the levels of intracellular triglyceride (by 28.07%, 37.55%, and 51.33%) with greater inhibitory activity relative to the commercial PPARα agonist fenofibrate. Moreover, the compound 9 supplementations upregulated the expression of hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) and upregulated the phosphorylation of acetyl-CoA carboxylase (ACC) related to fatty acid oxidation and lipogenesis. This dual-target compound with lipid metabolism regulatory efficacy may represent a promising type of drug lead for NAFLD therapy.

Reactions of cisplatin and oxaliplatin with penicillin G: implications for drug inactivation and biological activity.

Determination of the toxicity of compounds toward cancer cells is a frequent procedure in drug discovery. For metal complexes, which are often reactive prodrugs, care has to be taken to consider reactions with components of the cell culture medium that might change the speciation of the metal complex before it is taken up by the cells. Here, we consider possible reactions between the clinical platinum drugs cisplatin and oxaliplatin with penicillin G, an antibiotic added routinely to cell culture media to prevent bacterial contamination. Platinum has a high affinity for ligands with sulfur donors. Penicillin G is an unstable thioether that degrades in a range of pathways. Nuclear magnetic resonance (NMR) and UV-Vis absorption spectroscopic studies show that reactions with cisplatin can occur within minutes to hours at 310 K, but more slowly with oxaliplatin. The identities of the Pt- adducts were investigated by mass spectrometry. The marked effect on cytotoxicity of co-incubation of cisplatin with penicillin G was demonstrated for the HeLa human cervical cancer cell line. These studies highlight the possibility that reactions with penicillin G might influence the cytotoxic activity of metal complexes determined in culture media.

Two Manganese(II)-Based Hybrid Multifunctional Phase Transition Materials with Strong Photoluminescence, High Quantum Yield, and Switchable Dielectric Properties: (C6NH16)2MnBr4 and (C7NH18)2MnBr4.

Multifunctional materials have always been an attractive research area, but how to combine multiple excellent properties in one compound remains a considerable challenge. Organic-inorganic hybrid compounds are widely used in the design of such materials due to their rich properties and flexible assembly. Herein, two new manganese(II)-based organic-inorganic hybrid compounds, (C6NH16)2MnBr4 (1) and (C7NH18)2MnBr4 (2), are prepared by the solution method. Compounds 1 and 2 both emit extremely strong green light under UV excitation, with high quantum yields of 45.93 and 50.98%, respectively. In addition, reversible solid-state phase transitions and obvious switchable dielectric properties are shown at 378/366 and 361/352 K, respectively. The coexistence of the dual stimulus-response characteristics of temperature and light in compounds 1 and 2 opens a new path for exploring more multifunctional phase transition materials.

Unusual symmetry breaking in high-temperature enantiomeric ferroelectrics with large spontaneous polarization.

Chiral organic-inorganic hybrid perovskites have gained extensive research interest due to their combination of chirality and the excellent optical, electrical and spin properties of perovskite materials, especially in two-dimensional hybrid perovskites. Herein, we report two-dimensional organic-inorganic perovskite enantiomeric ferroelectric [(R)-ß-MPA]2CdCl4 (1) and [(S)-ß-MPA]2CdCl4 (2) (MPA+ =methylphenethylammonium). Their mirror relationships are verified by both circular dichroism (CD) and crystal structures. At the same time, the two exhibit very similar ferroelectricity and related properties, including high Curie temperature (343 K), large spontaneous polarization (4.65 µC cm-2), and low coercive force field (13 kV cm-1). Unusually, at room temperature the crystal phase is monoclinic with the space group C2 and above the phase transition temperature it is triclinic with the space group P1, which means that the symmetry decreases with the increase of temperature. In addition, it exhibits a flexible switchable SHG response, while [(R)-ß-MPA]2CdCl4 and [(S)-ß-MPA]2CdCl4 have wide band gaps of 4.21 and 4.26 eV, respectively, mainly contributed by inorganic CdCl6 octahedra. This discovery opens a new way for the construction of two-dimensional enantiomeric molecular ferroelectrics.

Assembly of multicyclic isoquinoline scaffolds from pyridines: formal total synthesis of fredericamycin A.

The construction of an isoquinoline skeleton typically starts with benzene derivatives as substrates with the assistance of acids or transition metals. Disclosed here is a concise approach to prepare isoquinoline analogues by starting with pyridines to react with ß-ethoxy α,ß-unsaturated carbonyl compounds under basic conditions. Multiple substitution patterns and a relatively large number of functional groups (including those sensitive to acidic conditions) can be tolerated in our method. In particular, our protocol allows for efficient access to tricyclic isoquinolines found in hundreds of natural products with interesting bioactivities. The efficiency and operational simplicity of introducing structural complexity into the isoquinoline frameworks can likely enable the collective synthesis of a large set of natural products. Here we show that fredericamycin A could be obtained via a short route by using our isoquinoline synthesis as a key step.

A Three Protein-Coding Gene Prognostic Model Predicts Overall Survival in Bladder Cancer Patients.

Bladder cancer (BLCA) is the most common urinary tract tumor and is the 11th most malignant cancer worldwide. With the development of in-depth multisystem sequencing, an increasing number of prognostic molecular markers have been identified. In this study, we focused on the role of protein-coding gene methylation in the prognosis of BLCA. We downloaded BLCA clinical and methylation data from The Cancer Genome Atlas (TCGA) database and used this information to identify differentially methylated genes and construct a survival model using lasso regression. We assessed 365 cases, with complete information regarding survival status, survival time longer than 30 days, age, gender, and tumor characteristics (grade, stage, T, M, N), in our study. We identified 353 differentially methylated genes, including 50 hypomethylated genes and 303 hypermethylated genes. After annotation, a total of 227 genes were differentially expressed. Of these, 165 were protein-coding genes. Three genes (zinc finger protein 382 (ZNF382), galanin receptor 1 (GALR1), and structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1)) were selected for the final risk model. Patients with higher-risk scores represent poorer survival than patients with lower-risk scores in the training set (HR = 2.37, 95% CI 1.43-3.94, p = 0.001), in the testing group (HR = 1.85, 95% CI 1.16-2.94, p = 0.01), and in the total cohort (HR = 2.06, 95% CI 1.46-2.90, p < 0.001). Further univariate and multivariate analyses using the Cox regression method were conducted in these three groups, respectively. All the results indicated that risk score was an independent risk factor for BLCA. Our study screened the different methylation protein-coding genes in the BLCA tissues and constructed a robust risk model for predicting the outcome of BLCA patients. Moreover, these three genes may function in the mechanism of development and progression of BLCA, which should be fully clarified in the future.

Multiaction Platinum(IV) Prodrug Containing Thymidylate Synthase Inhibitor and Metabolic Modifier against Triple-Negative Breast Cancer.

Multifunctional platinumIV anticancer prodrugs have the potential to enrich the anticancer properties and overcome the clinical problems of drug resistance and side effects of platinumII anticancer agents. Herein, we develop dual and triple action platinumIV complexes with targeted and biological active functionalities. One complex (PFL) that consists of cisplatin, tegafur, and lonidamine exhibits strong cytotoxicity against triple negative breast cancer (TNBC) cells. Cellular uptake and distribution studies reveal that PFL mainly accumulates in mitochondria. As a result, PFL disrupts the mitochondrial ultrastructure and induces significant alterations in the mitochondrial membrane potential, which further leads to an increase in production of reactive oxygen species (ROS) and a decrease in ATP synthesis in MDA-MB-231 TNBCs. Western blot analysis reveals the formation of ternary complex of thymidylate synthase, which shows the intracellular conversion of tegafur into 5-FU after its release from PFL. Furthermore, treatment with PFL impairs the mitochondrial function, leading to the inhibition of glycolysis and mitochondrial respiration and induction of apoptosis through the mitochondrial pathway. The RNA-sequencing experiment shows that PFL can perturb the pathways involved in DNA synthesis, DNA damage, metabolism, and transcriptional activity. These findings demonstrate that PFL intervenes in several cellular processes including DNA damage, thymidylate synthase inhibition, and perturbation of the mitochondrial bioenergetics to kill the cancer cells. The results highlight the significance of a triple-action prodrug for efficient anticancer therapy for TNBCs.

Metallodrugs are unique: opportunities and challenges of discovery and development.

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

Inhibition of autophagic flux by cyclometalated iridium(iii) complexes through anion transportation.

Synthetic anion transporters that can interfere with the intracellular pH homeostasis are gaining increasing attention for tumor therapy, however, the biological mechanism of anion transporters remains to be explored. In this work, two phosphorescent cyclometalated Ir(iii) complexes containing 2-phenylpyridine (ppy) as the cyclometalated ligand, and 2,2'-biimidazole (H2biim, Ir1) or 2-(1H-imidazol-2-yl)pyridine (Hpyim, Ir2) as the ancillary ligands have been synthesized and characterized. Due to the protonation and deprotonation process of the N-H groups on H2biim and Hpyim, Ir1 and Ir2 display pH-dependent phosphorescence and can specifically image lysosomes. Both Ir1 and Ir2 can act as anion transporters mainly through the anion exchange mechanism with higher potency observed for Ir1. Mechanism investigation shows that Ir1 and Ir2 can induce caspase-independent cell death through reactive oxygen species (ROS) elevation. As Ir1 and Ir2 can alkalinize lysosomes through anion disturbance, they can inhibit autophagic flux. Our work provides a novel anticancer mechanism of metal complexes, which gives insights into the innovative structure-based design of new metallo-anticancer agents.

Mitochondria-Accumulating Rhenium(I) Tricarbonyl Complexes Induce Cell Death via Irreversible Oxidative Stress and Glutathione Metabolism Disturbance.

Mitochondria play a critical role in tumorigenesis. Targeting mitochondria and disturbing related events have been emerging as a promising way for chemotherapy. In this work, two binuclear rhenium(I) tricarbonyl complexes of the general formula [Re2(CO)6(dip)2L](PF6)2 (dip = 4,7-diphenyl-1,10-phenanthroline; L = 4,4'-azopyridine (ReN) or 4,4'-dithiodipyridine (ReS)) were synthesized and characterized. ReN and ReS can react with glutathione (GSH). They exhibit good in vitro anticancer activity against cancer cell lines screened. Besides, they can target mitochondria, cause oxidative stress, and disturb GSH metabolism. Both ReN and ReS can induce necroptosis and caspase-dependent apoptosis simultaneously. We also demonstrate that ReN and ReS can inhibit tumor growth in nude mice bearing carcinoma xenografts. Our study shows the potential of Re(I) complexes as chemotherapeutic agents to kill cancer cells via a mitochondria-to-cellular redox strategy.