Construction of Polycarbonates with Pendant Multifunctional Groups via a One-Step CO2/ Diepoxide Copolymerization Approach.

A "one-step" strategy has been demonstrated for the tunable synthesis of multifunctional aliphatic polycarbonates (APCs) with ethylene oxide (EO), ethylene carbonate (EC), and cyclohexene oxide (CHO) side groups by the copolymerization of 4-vinyl-1-cyclohexene diepoxide with carbon dioxide under an aminotriphenolate iron/PPNBz (PPN = bis(triphenylphosphine)-iminium, Bz = benzoate) binary catalyst. By adjusting the PPNBz-to-iron complex ratio and incorporating auxiliary solvents, the content of functional side groups can be tuned within the ranges of 53-75% for EO, 18-47% for EC, and <1-7% for CHO. The yield and molecular weight distribution of the resulting multifunctional APCs are affected by the viscosity of the polymerization system. The use of tetrahydrofuran as an auxiliary solvent enables the preparation of narrow-distribution polycarbonates at high conversion. This work presents a novel perspective for the preparation of tailorable multifunctional APCs.

In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization.

Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK]2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.

Design and synthesis of potent PAR-1 antagonists based on vorapaxar.

A series of novel vorapaxar analogues with different amino substitutes at the C-7, C-9a and aromatic substitutes at the C-4 position were designed, synthesized, and evaluated for their inhibitory activity to PAR-1. Several compounds showed good potency in antagonist activity based on the intracellular calcium mobilization assay and excellent pharmacokinetics profile in rats. Among these analogues, 3d exhibited excellent PAR-1 inhibitory activity (IC50 = 0.18 µM) and the lower ability to cross the blood-brain barrier compared with vorapaxar (IC50 = 0.25 µM). Compound 3d has the potential to be developed as a new generation of PAR-1 antagonists with a better therapeutic window.

Self-Assembled ROS-Sensitive Polymer-Peptide Therapeutics Incorporating Built-in Reporters for Evaluation of Treatment Efficacy.

One of the major challenges in current cancer therapy is to maximize therapeutic effect and evaluate tumor progression under the scheduled treatment protocol. To address these challenges, we synthesized the cytotoxic peptide (KLAKLAK)2 (named KLAK) conjugated amphiphilic poly(ß-thioester)s copolymers (H-P-K) composed of reactive oxygen species (ROS) sensitive backbones and hydrophilic polyethylene glycol (PEG) side chains. H-P-K could self-assemble into micelle-like nanoparticles by hydrophobic interaction with copolymer backbones as cores and PEG and KLAK as shells. The assembled polymer-peptide nanoparticles remarkably improved cellular internalization and accumulation of therapeutic KLAK in cells. Compared to free KLAK peptide, the antitumor activity of H-P-K was significantly enhanced up to ∼400 times, suggesting the effectiveness of the nanoscaled polymer-peptide conjugation as biopharmaceuticals. The higher antitumor activity of nanoparticles was attributed to the efficient disruption of mitochondrial membranes and subsequent excessive ROS production in cells. To realize the ROS monitoring and treatment evaluation, we encapsulated squaraine (SQ) dyes as built-in reporters in ROS-sensitive H-P-K micelles. The overgenerated ROS around mitochondria stimulated the swelling of nanoparticles and subsequent release of SQ, which formed H-aggregates and significantly increased the photoacoustic (PA) signal. We believed that this self-assembled polymer-peptide nanotherapeutics incorporating built-in reporters has great potential for high antitumor performance and in situ treatment evaluation.

pH-Sensitive polymer assisted self-aggregation of bis(pyrene) in living cells in situ with turn-on fluorescence.

Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self-aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future.

Synthesis of High Molecular Weight Cyclic Poly(ε-caprolactone)s of Variable Ring Size Based on a Light-Induced Ring-Closure Approach.

High molecular weight cyclic poly(ε-caprolactone)s (cPCLs) with variable ring size are synthesized via light-induced ring closure of α,ω-anthracene-terminated PCL (An-PCL-An). The ring size of cPCL is tunable simply by adjusting the polymer concentration from 10 to 100 mg mL(-1) in THF. The cyclo-addition via the bimolecular cyclization of An-PC-An is well characterized by a variety of analyses such as (1) H NMR and UV-vis spectroscopies, gel-permeation chromatography, and differential scanning calorimetry. The reversible dimerization of An induced by heating enables the cyclic PCL to have a switchable "on-off" capability. This novel light-induced ring-closure technique can be one of the most powerful candidates for producing various well-defined cyclic polymers in highly concentrated polymer solution.

Temperature-controlled tunable emission of Bi3+-doped Rb2SnCl6 all-inorganic vacancy ordered lead-free perovskite for advanced anticounterfeiting.

At present, tuning the luminescence characteristics of phosphors by external physical stimuli such as temperature and pressure has attracted the interest of researchers. However, the emission-tunable luminescence processes by temperature or pressure in lead-free perovskite with ordered vacancy materials have not been systematically studied. In this study, Bi3+-doped Rb2SnCl6 crystals were successfully synthesized using a simple precipitation method, and these crystals demonstrated a remarkable enhancement of luminescence intensity compared with the unannealed ones at 140-200 °C, and with a red-shift in the emission peak from 450 to 500 nm. It was found that the annealing treatment increased the Bi-Cl bond length leading to emission red-shift and achieved the change in the emission intensity due to the band gap modulation of the material. Furthermore, a candidate material for the color-changing optical security strategies was obtained by combining the Bi3+-doped Rb2SnCl6 phosphor and printing ink. This work is a valuable reference for the rational design of luminescent perovskites with promising new functionalities and stimulates the great potential of luminescent perovskites in developing promising phosphors for advanced anticounterfeiting.

(E)-4-[(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino-meth-yl]-2-meth-oxy-phenyl 4-bromo-benzene-sulfonate.

In the title compound, C(25)H(22)BrN(3)O(5)S, the central benzene ring makes dihedral angles of 4.41 (10), 67.09 (9) and 62.05 (10)°, respectively, with the pyrazolone, bromo-benzene and terminal phenyl rings. The dihedral angle between the pyrazolone and phenyl rings is 57.75 (11)°. In the crystal, two pairs of C-H⋯O hydrogen bonds link the mol-ecules into inversion dimers. A weak intra-molecular C-H⋯O hydrogen bonds is also observed.

(E)-2-Bromo-4-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)imino-meth-yl]-6-meth-oxy-phenyl 4-methyl-benzene-sulfonate.

In the title compound, C(26)H(24)BrN(3)O(5)S, the central benzene ring makes dihedral angles of 6.27 (6), 33.63 (6) and 69.31 (5)°, respectively, with the pyrazolone ring, the bromo-benzene ring and the terminal phenyl ring. An intra-molecular C-H⋯O hydrogen bond occurs. The crystal packing features weak non-classical C-Br⋯O inter-actions [Br⋯O = 3.222 (2) Å] that form inversion-related dimers.

Construction of Bio-Based Polyurethanes via Olefin Metathesis and Their Thermal Reversible Behavior.

With the increase in awareness of environmental protection and the shortage of oil resources, bio-based polyurethane has attracted increasing attention due to its ecological friendliness, low cost and easy degradation. In this paper, using Eugenol (Eug) derived from plant essential oils as the raw resource, syringyl ethanol (Syol) was prepared, and three monomers were obtained by the reaction of the Eug or Syol with Hexamethylene diisocyanate (HDI)or 4,4'-methylene di (phenyl isocyanate) (MDI), respectively. Then, three novel bio-based polyurethanes, P(Eug-HDI), P(Syol-HDI) and P(Syol-MDI), were synthesized by olefin metathesis polymerization. The effects of the catalyst type, reaction solvent, reaction temperature, reaction time, molar ratio of catalyst dosage and metal salts on the Eug-HDI olefin metathesis polymerization were investigated in detail. Under the optimal conditions, the yield reached 64.7%. It is worth noting that the addition of metal Ni salts could significantly promote the polymerization, in which NiI2 could increase the yield to 86.6%. Furthermore, the thermal decomposition behaviors of these bio-based polyurethanes were explored by DSC and variable temperature infrared spectroscopy. The test results showed that P(Eug-HDI) had a reversible thermal decomposition and a certain self-healing performance. This paper provided a new method for the preparation of bio-based polyurethane.

Progress in research on gut microbiota in ethnic minorities in China and consideration of intervention strategies based on ethnic medicine: A review.

One of the variables affecting gut microbiota is ethnicity. There are 56 ethnic subgroups in China, and their intestinal flora differs. A wealth of medical resources has also been produced by the presence of numerous ethnic minorities. In this study, we reviewed the pertinent literature on the intestinal flora of ethnic minorities in China and abroad using the CiteSpace visualization software, and we used bibliometric techniques to find the most widely prescribed medications for preventing and treating endemic diseases in ethnic minorities. Based on the gut microbiology of minority populations, we suggest that by comprehensive development involving literature, experimental, and clinical research, the pharmacological action mechanisms for interventions in endemic diseases can be drawn from ethnic medicine. This point of view has not been discussed before and will offer a fresh perspective on the creation and application of ethnic medications as well as a fresh method for the management of prevalent diseases in ethnic communities.

4-Meth-oxy-3-(4-nitro-benz-yloxy)benzaldehyde.

In the title compound, C(15)H(13)NO(5), the two benzene rings make a dihedral angle of 3.98 (7)°. The crystal packing is stabilized by weak non-classical inter-molecular C-H⋯O inter-actions that link mol-ecules into centrosymmetric tetra-mers.

Construction of Mechanically Reinforced Thermoplastic Polyurethane from Carbon Dioxide-Based Poly(ether carbonate) Polyols via Coordination Cross-Linking.

Using carbon dioxide-based poly(propylene ether carbonate) diol (PPCD), isophorone diisocyanate (IPDI), dimethylolbutyric acid (DMBA), ferric chloride (FeCl3), and ethylene glycol (EG) as the main raw materials, a novel thermoplastic polyurethane (TPU) is prepared through coordination of FeCl3 and DMBA to obtain TPU containing coordination enhancement directly. The Fourier transform infrared spectroscopy, 1H NMR, gel permeation chromatography, UV-Vis spectroscopy, tensile testing, dynamic mechanical analysis, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis were explored to characterize chemical structures and mechanical properties of as-prepared TPU. With the increasing addition of FeCl3, the tensile strength and modulus of TPU increase. Although the elongation at break decreases, it still maintains a high level. Dynamic mechanical analysis shows that the glass-transition temperature moves to a high temperature gradually along with the increasing addition of FeCl3. X-ray diffraction results indicate that TPUs reinforced with FeCl3 or not are amorphous polymers. That FeCl3 coordinates with DMBA first is an effective strategy of getting TPU, which is effective and convenient in the industry without the separation of intermediate products. This work confirms that such Lewis acids as FeCl3 can improve and adjust the properties of TPU contenting coordination structures with an in-situ reaction in a low addition amount, which expands their applications in industry and engineering areas.

Mitochondria-Targeted Self-Assembly of Peptide-Based Nanomaterials.

Mitochondria are well known to serve as the powerhouse for cells and also the initiator for some vital signaling pathways. A variety of diseases are discovered to be associated with the abnormalities of mitochondria, including cancers. Thus, targeting mitochondria and their metabolisms are recognized to be promising for cancer therapy. In recent years, great efforts have been devoted to developing mitochondria-targeted pharmaceuticals, including small molecular drugs, peptides, proteins, and genes, with several molecular drugs and peptides enrolled in clinical trials. Along with the advances of nanotechnology, self-assembled peptide-nanomaterials that integrate the biomarker-targeting, stimuli-response, self-assembly, and therapeutic effect, have been attracted increasing interest in the fields of biotechnology and nanomedicine. Particularly, in situ mitochondria-targeted self-assembling peptides that can assemble on the surface or inside mitochondria have opened another dimension for the mitochondria-targeted cancer therapy. Here, we highlight the recent progress of mitochondria-targeted peptide-nanomaterials, especially those in situ self-assembly systems in mitochondria, and their applications in cancer treatments.

Structural Simplification of Marine Natural Products: Discovery of Hamacanthin Derivatives Containing Indole and Piperazinone as Novel Antiviral and Anti-phytopathogenic-fungus Agents.

With the increasing severity of plant diseases and the emergence of pathogen resistance, there is an urgent need for the development of new efficient and environment-friendly pesticides. Marine natural product (MNP) resources are rich and diverse. Structural simplification based on MNPs is an important strategy to find novel pesticide candidates. In this work, the marine natural product 6″-debromohamacanthin A (1a) was efficiently prepared and selected as the parent structure. A series of hamacanthin derivatives were designed, synthesized, and studied on the antiviral and antifungal activities. Most of these compounds displayed higher antiviral activities than ribavirin. The antiviral activities of compounds 1a and 13e-13h are similar to or higher than that of ningnanmycin (perhaps the most efficient anti-plant-virus agent). Compound 13h was selected for further antiviral mechanism research via transmission electron microscopy, molecular docking, and fluorescence titration. The results showed that compound 13h could bind to TMV CP and interfere with the assembly process of TMV CP and RNA. In addition, these hamacanthin derivatives also exhibited broad-spectrum inhibitory effects against eight common agricultural pathogens. Compounds 1a, 12b, and 12f with excellent fungicidal activities can be considered as new fungicidal candidates for further research. These results provide a basis for the application of hamacanthin alkaloids in crop protection.

Pityriacitrin marine alkaloids as novel antiviral and anti-phytopathogenic-fungus agents.

BACKGROUND: Plant diseases have been gripping agricultural production, seriously affecting the growth and yields of crops. Marine natural products are an important source for novel drugs discovery. In this work, pityriacitrin marine alkaloids were selected as the parent structures. A series of pityriacitrin alkaloid analogues were rationally designed, synthesized and evaluated for their antiviral activities and fungicidal activities. RESULT: Most of these compounds were demonstrated to have higher antiviral activities than ribavirin. Particularly, compounds 3a, 3e, 8f, 8g, and 9g displayed higher anti-TMV activities than ningnanmycin at 500 µg·mL-1 . Mechanism research revealed that 3a could bind to TMV CP with an excellent affinity (Ka  = 8.67 × 106 L·mol-1 ), thus interfere with the assembly of virus particles. These alkaloids also showed broad-spectrum fungicidal activities against eight kinds of phytopathogenic fungi. Compound 5f with 1.43-3.84 µg·mL-1 EC50 value against three fungi emerged as a new fungicidal candidate. CONCLUSION: Pityriacitrin alkaloids and their derivatives were synthesized and evaluated for anti-TMV and fungicidal activities for the first time. Compounds 3a and 5f with excellent activities emerged as new candidates for antiviral research and fungicidal research, respectively. Current work provided a new idea for the molecular design and development of novel plant virus and fungi inhibitors in the future. © 2021 Society of Chemical Industry.

2,5,11,14-Tetra-oxa-8-aza-dispiro-[13.4.0]nona-deca-15,17,19-triene.

The title compound, C(14)H(21)NO(4), has been synthesized from o-dihydroxy-benzene by a three-step reaction. There are two chemically equal but crystallographically independent mol-ecules in the asymmetric unit. The crystal packing is governed by C-H⋯O hydrogen bonds and C-H⋯π inter-actions, forming an infinite network.

Recent progress of therapeutic peptide based nanomaterials: from synthesis and self-assembly to cancer treatment.

Peptides have shown great potential in cancer treatment due to their good biocompatibility and low toxicity. However, the bioavailability and adverse immune response of peptides limit their further translation from bench to bedside. Over the past few decades, various peptide-based nanomaterials have been developed for drug delivery and cancer treatment. Compared with therapeutic peptides alone, self-assembled peptide nanomaterials have obvious advantages, such as improved stability and biodistribution for high-performance cancer therapy. In this review, we have described the synthesis, self-assembly and the anti-cancer application of therapeutic peptides and their conjugates, particularly polymer-peptide conjugates (PPCs).

Synthesis of aryl sulfides by decarboxylative C-S cross-couplings.

Without the need for organohalide precursors, the convenient and general synthesis of aryl (or diaryl) sulfides can be achieved by using aryl carboxylic acids and thiols or disulfides for decarboxylative C-S cross-coupling catalyzed by a bimetallic system (see scheme).

Enzyme-sensitive cytotoxic peptide-dendrimer conjugates enhance cell apoptosis and deep tumor penetration.

Peptide nanodrugs have been developed as promising antitumor chemotherapeutics because they partially overcome the drawbacks of free peptide drugs, but insufficient tumor penetration and interference of peptide function limit their further application. In this work, we have developed multifunctional peptide conjugated dendrimers for improving tumor penetration, cancer cell-specific peptide delivery and anticancer ability. The cytotoxic peptide KLAK, cell-penetrating peptide TAT and matrix metalloproteinase 2 (MMP2)-sensitive peptide-poly(ethylene glycol) (PEG) were conjugated onto dendrimers by one-pot synthesis to gain PKT-S-PEG. The enzyme-sensitive properties and incubation stability of the dendrimers were investigated by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Moreover, the cell viability, internalization pathway, mitochondria-regulated apoptosis and tumor penetration ability were measured by CCK-8 assay, lysosome colocalization, JC-1 assay and multicellular spheroid (MCS) experiments, respectively, in human primary glioblastoma (U87) cells. PKT-S-PEG showed significantly enhanced intracellular delivery performance, antitumor efficacy and deep tumor penetration capacity compared to a control non-MMP2 sensitive dendrimer PKT-C-PEG. The MMP2-overexpressing tumor microenvironment caused deprotection by removal of PEG, resulting in the decrease of particle size and exposure of KLAK and TAT, which enhanced tumor penetration, the entry of bioactive peptides into cells and subsequently the effective disruption of mitochondria. We believe that the peptide-dendrimer conjugate has potential for specific and effective delivery of peptide-based therapeutics into tumors.