Enhanced Stability and Solidification of Volatile Eugenol by Cyclodextrin-Metal Organic Framework for Nasal Powder Delivery.

Eugenol (Eug) holds potential as a treatment for bacterial rhinosinusitis by nasal powder drug delivery. To stabilization and solidification of volatile Eug, herein, nasal inhalable γ-cyclodextrin metal-organic framework (γ-CD-MOF) was investigated as a carrier by gas-solid adsorption method. The results showed that the particle size of Eug loaded by γ-CD-MOF (Eug@γ-CD-MOF) distributed in the range of 10-150 µm well. In comparison to γ-CD and ß-CD-MOF, γ-CD-MOF has higher thermal stability to Eug. And the intermolecular interactions between Eug and the carriers were verified by characterizations and molecular docking. Based on the bionic human nasal cavity model, Eug@γ-CD-MOF had a high deposition distribution (90.07 ± 1.58%). Compared with free Eug, the retention time Eug@γ-CD-MOF in the nasal cavity was prolonged from 5 min to 60 min. In addition, the cell viability showed that Eug@γ-CD-MOF (Eug content range 3.125-200 µg/mL) was non-cytotoxic. And the encapsulation of γ-CD-MOF could not reduce the bacteriostatic effect of Eug. Therefore, the biocompatible γ-CD-MOF could be a potential and valuable carrier for nasal drug delivery to realize solidification and nasal therapeutic effects of volatile oils.

Unveiling Pre-Transmetalation Intermediates in Base-Free Suzuki-Miyaura Cross-Couplings: A Computational Study.

The pre-transmetalation intermediates are critically important in Suzuki-Miyaura cross-coupling (SMC) reactions and have become a hot spot of the current research. However, the pre-transmetalation intermediates under base-free conditions have not been clear. Herein, a comprehensive theoretical study is performed on the base-free Pd-catalyzed desulfonative SMC reaction. The fragile coordination feature and the acceleration role of the RuPhos chelate ligand are revealed. The hydrogen-bond complex between the Pd-F complex and aryl boronic acid is identified as an important pre-transmetalation intermediate, which increases the energy span to 32.5 kcal/mol. The controlling factor for the formation of the hydrogen-bond complexes is attributed to the electronegativities of halogen atoms in the metal halide complexes. What is more, other reported SMC reaction systems involving metal halide complexes and aryl boronic acids are reconsidered and suggest that the hydrogen-bond complexes widely exist as stable pre-transmetalation intermediates with influencing the catalytic activities. The earth-abundant Ni-catalyzed desulfonative SMC reaction is further designed and predicted to have a higher activity than the original Pd-catalyzed SMC reaction.

Rhodium-Catalyzed Hydrolytic Cleavage of the Silicon-Carbon Bond of Silacyclobutanes to Access Silanols.

Herein, we report the first rhodium-catalyzed hydrolytic cleavage of the silicon-carbon bond in silacyclobutanes using water as the reactant. A series of silacyclobutanes could be employed in this reaction in the presence of the Rh/BINAP complex, resulting in the corresponding silanols in good yields. Additionally, a chiral 1,1,4,4-tetraaryl-2,3-O-isopropylidene-l-threitol-derived phosphoramidite ligand could be used in this reaction to yield Si-stereogenic silanol with promising enantioselectivity.

Solvent-Free Loading of Vitamin A Palmitate into ß-Cyclodextrin Metal-Organic Frameworks for Stability Enhancement.

Cyclodextrin metal-organic frameworks (CD-MOFs) exhibit a high structural diversity, which contributes to their functional properties. In this study, we have successfully synthesized a novel type of ß-cyclodextrin metal-organic framework (ß-CD-POF(I)) that exhibits excellent drug adsorption capacity and enhances stability. Single-crystal X-ray diffraction analysis revealed that ß-CD-POF(I) possessed the dicyclodextrin channel moieties and long-parallel tubular cavities. Compared with the reported ß-CD-MOFs, the ß-CD-POF(I) has a more promising drug encapsulation capability. Here, the stability of vitamin A palmitate (VAP) was effectively improved by the solvent-free method. Molecular modeling and other characterization techniques like synchrotron radiation Fourier transform infrared spectroscopy (SR-FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), and nitrogen adsorption isotherm were applied to confirm that the VAP was successfully encapsulated into the channel formed by the dicyclodextrin pairs. Furthermore, the mechanism of stability enhancement for VAP was determined to be due to the constraint and separation effects of ß-CD pairs on VAP. Therefore, ß-CD-POF(I) is capable of trapping and stabilizing certain unstable drug molecules, offering benefits and application possibilities. One kind of cyclodextrin particle with characteristic shapes of dicyclodextrin channel moieties and parallel tubular cavities, which was synthesized by a facile process. Subsequently, the spatial structure and characteristics of the ß-CD-POF(I) were primarily confirmed. The structure of ß-CD-POF(I) was then compared to that of KOH-ß-CD-MOF, and a better material for vitamin A palmitate (VAP) encapsulation was determined. VAP was successfully loaded into the particles by solvent-free method. The arrangement of spatial structure made cyclodextrin molecular cavity encapsulation in ß-CD-POF(I) more stable for VAP capture than that of KOH-ß-CD-MOF.

His-Ala-Phe-Lys peptide from Burkholderia arboris possesses antifungal activity.

Burkholderia arboris, which belongs to the Burkholderia cepacia complex, has been shown to possess antifungal activity against several plant fungal pathogens; however, the antifungal compounds are yet to be identified. Here, we identified the antifungal compounds produced by B. arboris using genetic and metabolomic approaches. We generated a Tn5 transposon mutation library of 3,000 B. arboris mutants and isolated three mutants with reduced antifungal activity against the plant fungal pathogen Fusarium oxysporum. Among the mutants, the M464 mutant exhibited the weakest antifungal activity. In the M464 genome, the transposon was inserted into the cobA gene, encoding uroporphyrin-III methyltransferase. Deletion of the cobA gene also resulted in reduced antifungal activity, indicating that the cobA gene contributed to the antifungal activity of B. arboris. Furthermore, a comparison of the differential metabolites between wild type B. arboris and the ∆cobA mutant showed a significantly decreased level of tetrapeptide His-Ala-Phe-Lys (Hafk) in the ∆cobA mutant. Therefore, a Hafk peptide with D-amino acid residues was synthesized and its antifungal activity was evaluated. Notably, the Hafk peptide displayed significant antifungal activity against F. oxysporum and Botrytis cinerea, two plant pathogens that cause destructive fungal diseases. Overall, a novel antifungal compound (Hafk) that can be used for the biocontrol of fungal diseases in plants was identified in B. arboris.

Pseudo-resonance structures in chiral alcohols and amines and their possible aggregation states.

We now report that some chiral compounds, like alcohols, which are not sterically hindered atropisomers nor epimer mixtures, exhibit two sets of simultaneous NMR spectra in CDCl3. Some other chiral alcohols also simultaneously exhibit two different NMR spectra in the solid state because two different conformers, A and B had different sizes because their corresponding bond lengths and angles are different. These structures were confirmed in the same solid state by X-ray. We designate these as pseudo-resonance for a compound exhibiting several different corresponding lengths that simultaneously coexist in the solid state or liquid state. Variable-temperature NMR, 2D NMR methods, X-ray, neutron diffraction, IR, photo-luminesce (PL) and other methods were explored to study whether new aggregation states caused these heretofore unknown pseudo-resonance structures. Finally, eleven chiral alcohols or diols were found to co-exist in pseudo-resonance structures by X-ray crystallography in a search of the CDS database.

Marine fungal metabolites as a source of drug leads against aquatic pathogens.

Aquatic pathogens, including Vibrio, Edwardsiella, Pseudomonas, and Aeromonas, which could result in bacterial diseases to aquaculture, have seriously threatened the world aquaculture production. Marine-derived fungi, which could produce novel secondary metabolites with significant antibacterial activity, may be an important source for finding effective agents against aquatic pathogens. In this review, a systematically overview of the harm of several aquatic pathogens, and 134 antibacterial secondary metabolites against aquatic pathogens from 13 genera of marine-derived fungi, were summarized and concluded. The aim of this review is to find out the relationships between activity and structural type, between bioactive compounds and their hosts, and so on. Altogether, 95 references published during 1997-2021 were cited. KEY POINTS: •Aquatic pathogens, which could result in bacterial diseases to aquaculture, were described. •Marine fungal metabolites with activities against aquatic pathogens were summarized. •The distributions of these bioactive marine fungal metabolites were analyzed.

A Novel Azaphilone Muyophilone A From the Endophytic Fungus Muyocopron laterale 0307-2.

Two known azaphilone derivatives, 4,6-dimethylcurvulinic acid (1) and austdiol (2), and their novel heterotrimer, muyophilone A (3), were isolated and identified from an endophytic fungus, Muyocopron laterale 0307-2. Their structures and stereochemistry were established by extensive spectroscopic analyses including HRMS, NMR spectroscopy, electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopic methods, as well as single crystal X-ray diffraction. In the structure of 3, two compound 2-derived azaphilone units were connected through an unprecedented five-membered carbon bridge which was proposed to be originated from compound 1. Compound 3 represents the first example of azaphilone heterotrimers.

Modulation of miR-382-5p reduces apoptosis of myocardial cells after acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is a severe cardiovascular condition. Blocking the apoptosis of myocardial cells may mitigate AMI. Excessive expression of Stanniocalcin-1 (STC1) plays a protective role in the heart by inhibiting myocardial cell apoptosis. Here, we looked at the mechanism by which miR-382-5p regulates STC1 and affects myocardial cell apoptosis after AMI. METHODS: An AMI mouse model with a descending anterior ligament coronary artery and an HL-1 cell model with reproducible hypoxia/reoxygenation (H/R) were established. For pathological changes in myocardial tissues, terminal deoxynucleotidyl transferase dUTP nick end labelling staining and haematoxylin and eosin staining were performed. STC1 mRNA and miR-382-5p levels were measured using quantitative real-time PCR. Protein levels of STC1 and apoptosis-related proteins were measured by western blotting. The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide assay was used to detect cell viability, and a dual-luciferase reporter assay was carried out to verify potential targets of miR-382-5p. RESULTS: The level of miR-382-5p was raised in myocardial tissues of AMI mice and H/R-induced HL-1 cells. Compared with the control group, the myocardial tissue cells in the AMI group were disordered, with evident necrosis of myocardial cells, apoptosis and inflammatory infiltration. Interference with miR-382-5p inhibited myocardial cell apoptosis after H/R, as well as inferior lactate dehydrogenase. Also, miR-382-5p adversely regulated STC1 and the expression of STC1 was increased after transfection with miR-382-5p antagomir. Furthermore, interference with miR-382-5p reduced myocardial cell apoptosis after H/R by increasing the expression level of STC1. CONCLUSION: To summarise, our study showed an increase in miR-382-5p in myocardial tissues in the AMI mouse model. Interference with miR-382-5p reduced apoptosis of myocardial cells after AMI and the effect was achieved by increasing STC1 expression.

Heteroatom (N, P, As, Sb, Bi) Effects on the Resonance-Stabilized 2-, 3-, and 4-Picolyl Radicals.

Important recent experimental studies have allowed the isomer-selective identification of the 2-, 3-, and 4-picolyl radicals. The picolyl radicals and their valence isoelectronic P, As, Sb, and Bi congeners are investigated here. For the three observed parent radicals, the theoretical ionization potentials agree with experiment to within 0.02 eV. Two rules are proposed for predicting vertical ionization potentials (EVIE) and relative energies. The EVIE values for these radicals will be higher when large percentages of the SOMO orbitals are distributed on the atoms with greater electronegativities. The cations of these systems were also studied along with the closed-shell methylpyridines and their P, As, Sb, and Bi analogs. The energies for the cationic species will lie lower when high percentages of π natural localized molecular orbitals occur on the more electronegative atoms. The structures of the 2- and 4-isomers strongly depend upon the heteroatoms, with the C-C linkages adopting a single-double alternating bond manner when the heteroatoms become heavier. The 3-isomers adopt roughly equal C-C bond distances with small changes from N to Bi.

A new epimer of azaphilone derivative pinophilin B from the gorgonian-derived fungus Aspergillus fumigatus 14-27.

A new epimer of azaphilone derivative pinophilin B, epi-pinophilin B (1), and three known analogues (2-4) were obtained from the culture of the gorgonian-derived fungus Aspergillus fumigatus 14-27. The structures of 1-4, including their relative configurations were determined by extensive spectroscopic analysis and comparing with literature data. The absolute configuration of 1 was determined by electronic circular dichroism (ECD) and optical rotatory (OR) calculations methods. Compounds 1-4 were isolated from A. fumigatus for the first time. Their antibacterial and cytotoxic activities were also evaluated.

Marine-derived fungi as a source of bioactive indole alkaloids with diversified structures.

Marine-derived fungi are well known as rich sources of bioactive natural products. Growing evidences indicated that indole alkaloids, isolated from a variety of marine-derived fungi, have attracted considerable attention for their diverse, challenging structural complexity and promising bioactivities, and therefore, indole alkaloids have potential to be pharmaceutical lead compounds. Systemic compilation of the relevant literature. In this review, we demonstrated a comprehensive overview of 431 new indole alkaloids from 21 genera of marine-derived fungi with an emphasis on their structures and bioactivities, covering literatures published during 1982-2019.

Marine Natural Products as a Source of Drug Leads against Respiratory Viruses: Structural and Bioactive Diversity.

Respiratory viruses, including influenza virus, respiratory syncytial virus, coronavirus, etc., have seriously threatened the human health. For example, the outbreak of severe acute respiratory syndrome coronavirus, SARS, affected a large number of countries around the world. Marine organisms, which could produce secondary metabolites with novel structures and abundant biological activities, are an important source for seeking effective drugs against respiratory viruses. This report reviews marine natural products with activities against respiratory viruses, the emphasis of which was put on structures and antiviral activities of these natural products. This review has described 167 marinederived secondary metabolites with activities against respiratory viruses published from 1981 to 2019. Altogether 102 references are cited in this review article.

Absolute Configurations and Chitinase Inhibitions of Quinazoline-Containing Diketopiperazines from the Marine-Derived Fungus Penicillium polonicum.

Three new quinazoline-containing diketopiperazines, polonimides A-C (1-3), along with four analogues (4-7), were obtained from the marine-derived fungus Penicillium polonicum. Among them, 2 and 4, 3 and 5 were epimers, respectively, resulting the difficulty in the determination of their configurations. The configurations of 1-3 were determined by 1D nuclear overhauser effect (NOE), Marfey and electron circular dichroism (ECD) methods. Nuclear magnetic resonance (NMR) calculation with the combination of DP4plus probability method was used to distinguish the absolute configurations of C-3 in 3 and 5. All of 1-7 were tested for their chitinase inhibitory activity against OfHex1 and OfChi-h and cytotoxicity against A549, HGC-27 and UMUC-3 cell lines. Compounds 1-7 exhibited weak activity towards OfHex1 and strong activity towards OfChi-h at a concentration of 10.0 µM, with the inhibition rates of 0.7%-10.3% and 79.1%-95.4%, respectively. Interestingly, 1-7 showed low cytotoxicity against A549, HGC-27 and UMUC-3 cell lines, suggesting that good prospect of this cluster of metabolites for drug discovery.

Dipleosporalones A and B, Dimeric Azaphilones from a Marine-Derived Pleosporales sp. Fungus.

Dipleosporalones A and B (1 and 2), two new [2 + 2] azaphilone dimers, were obtained from a marine-derived Pleosporales sp. fungus. The absolute configurations of 1 and 2 were elucidated by calculations of their ECD spectra. Dipleosporalone A (1) possessed an unprecedented skeleton with an uncommon 6/4/6 ring system. Compounds 1 and 2 showed cytotoxicity about 30-90-fold more potent than that of their monomer pinophilin B.

Reduction of Dinitrogen via 2,3'-Bipyridine-Mediated Tetraboration.

A new molecular system for nitrogen reduction, involving a 2,3'-bipyridine-anchored, end-on-bridging dinitrogen complex of the Me2B-BMe2 intermediate (4), has been explored by theoretical methods. The 2,3'-bipyridine-mediated cleavage of the Bsp3-Bsp3 bond in 4 may lead to transient electron-rich sp3-hybridized boron species and subsequent activation of the strong N≡N triple bond of the complexed N2. Through a boryl transfer sequence, a catalytic cycle may be achieved for the reductive addition of diboranes to a dinitrogen molecule with an energy span of 23 kcal/mol. In addition, the reaction is exothermic by 80.5 kcal/mol, providing a substantive chemical driving force.

Unusual η1 -Coordinated Alkyne and Alkene Complexes.

This mechanistic study demonstrates that an unusual η1 -coordinated alkyne complex is critical for the 1-pentyne 1,1-diboration reaction. The comparative studies suggest the "pull-push" antagonistic effect arising from Lewis acidity and steric congestion as the reason for the existence of η1 -coordinated alkyne complexes. Analogous η1 -coordinated alkene complexes are also predicted and seem to be promising for their application to the important olefin polymerization reaction.

Asperienes A-D, Bioactive Sesquiterpenes from the Marine-Derived Fungus Aspergillus flavus.

Marine-derived fungi of the genera Aspergillus could produce novel compounds with significant bioactivities. Among these fungi, the strain Aspergillus flavus is notorious for its mutagenic mycotoxins production. However, some minor components with certain toxicities from A. flavus have not been specifically surveyed and might have potent biological activities. Our investigation of the marine-derived fungus Aspergillus flavus CF13-11 cultured in solid medium led to the isolation of four C-6'/C-7' epimeric drimane sesquiterpene esters, asperienes A-D (1-4). Their absolute configurations were assigned by electronic circular dichroism (ECD) and Snatzke's methods. This is the first time that two pairs of C-6'/C-7' epimeric drimane sesquiterpene esters have successfully been separated. Aperienes A-D (1-4) displayed potent bioactivities towards four cell lines with the IC50 values ranging from 1.4 to 8.3 µM. Interestingly, compounds 1 and 4 exhibited lower toxicities than 2 and 3 toward normal GES-1 cells, indicating more potential for development as an antitumor agent in the future.

Discovery of Bioactive Indole-Diketopiperazines from the Marine-Derived Fungus Penicillium brasilianum Aided by Genomic Information.

Identification and analysis of the whole genome of the marine-derived fungus Penicillium brasilianum HBU-136 revealed the presence of an interesting biosynthetic gene cluster (BGC) for non-ribosomal peptide synthetases (NRPS), highly homologous to the BGCs of indole-diketopiperazine derivatives. With the aid of genomic analysis, eight indole-diketopiperazines (1-8), including three new compounds, spirotryprostatin G (1), and cyclotryprostatins F and G (2 and 3), were obtained by large-scale cultivation of the fungal strain HBU-136 using rice medium with 1.0% MgCl2. The absolute configurations of 1-3 were determined by comparison of their experimental electronic circular dichroism (ECD) with calculated ECD spectra. Selective cytotoxicities were observed for compounds 1 and 4 against HL-60 cell line with the IC50 values of 6.0 and 7.9 µM, respectively, whereas 2, 3, and 5 against MCF-7 cell line with the IC50 values of 7.6, 10.8, and 5.1 µM, respectively.