A Novel, Simple and Efficient Synthesis of Ferrocenyl Enones and Alkynols

Propargylic alcohols are versatile precursors to many organic molecules including natural products and pharmaceutical compounds.[1] In our continuing interest in the development of practical methods for synthesis of ferrocene derivatives, we decided to investigate the efficiencies of ferrocenylacetylene addition to aromatic aldehydes under t-BuOKcatalyzed condition.[2] Interestingly, we found that the usually reliable coupling reaction between terminal alkyne of type 1 and aromatic aldehydes of type 2 does not furnish the expected propargylic alcohols, but that the isomeric aryl enones 3are found in high yield and very short reaction time (10～20 min). This provided a promising protocol for preparation of ferrocenyl chalcones in a practical, economical and mild sense compared with the traditional method. To the best of our knowledge, this unusual reaction was first observed for the addition of ferrocenylacetylene to aldehyde in a base-catalyzed manner (Eq. 1).     

High-throughput cytochrome p450 inhibition assays by ultrafast gradient liquid chromatography with tandem mass spectrometry using monolithic columns

A generic method employing ultrafast liquid chromatography with tandem mass spectrometry (LC/MS/MS) was developed and employed for routine screening of drug candidates for inhibition of five major human cytochrome p450 (CYP) isozymes, CYP3A4, CYP2D6, CYP2C9, CYP2C19, and CYP1A2. The method utilized a monolithic silica rod column to allow fast flow rates to significantly reduce chromatographic run time. The major metabolites of six CYP-specific probe substrates for the five p450 isoforms were monitored and quantified to determine IC(50) values of five drug compounds against each p450 isozyme. Human liver microsomal incubation samples at each test compound concentration were combined and analyzed simultaneously by the LC/MS/MS method. Each pooled sample containing six substrates and an internal standard was separated and detected in only 24 seconds. The combination of ultrafast chromatography and sample pooling techniques has significantly increased sample throughput and shortened assay turnaround time, allowing a large number of compounds to be screened rapidly for potential p450 inhibitory activity, to aid in compound selection and optimization in drug discovery.     

Sc(OTf)3-catalyzed efficient synthesis of beta,beta-bis(indolyl) ketones by the double indolylation of acetic acid 2-methylene-3-oxobutyl ester

In the presence of 5 mol% Sc(OTf)3, double indolylation of acetic acid 2-methylene-3-oxo-butyl ester with differently substituted indoles readily afforded beta,beta-bis(indolyl) ketones. The reaction may proceed via a Sc(OTf)3-catalyzed SN2'-type substitution and subsequent conjugate addition.     

Structural Relationships between the Hemiporphyrazine Macrocyclic Ligand and its Metal Complexes. II.: Planar Neutral Ligand,C26H16N8, and Four Isomorphous Metal Complexes, [M(C26H16N8)(H2O)], M=Mn(II), Co(II), Cu(II), Zn(II)

Crystal and molecular structures of the planar neutral ligand, C₂₆H₁₆N₈, and the four isomorphous five-coordinated metal complexes, [M(C₂₆H₁₆N₈)(H₂O)], M = Mn(II), Co(II), Cu(II), Zn(II), have been determined from three-dimensional X-ray diffraction data. The free ligand hpH₂, C₂₆H₁₆N₈, belongs to the P 2₁/c space group with Z=2, a=4.142(3), b=23.736(6), c=10.338(3) Ä, β=94.66(6)°. The metal complexes monohydrate Mhp-H₂O all belong to the orthorhombic Pcab space group with Z=8. The dimensions are roughly 8.8×19.3×23.7 ų. In each structure, the macrocyclic ligand has an almost planar conformation which differs from the saddle shaped ligand hydrate (hpH₂·H₂O) and the nickel complex [Nihp]⁵. The distances from the center of the macrocyclic ring to the nitrogen atom of the free ligand are 1.907(6) and 2.245(6)Å. The coordination geometry in these four complexes is square pyramidal with a water molecule as an axial ligand. The bond distances of M(II)-O(H₂O), M(II)-N1 (imine), M(II)-N3 (pyridine) are: 2.19(1), 2.00(2), 2.27(2)Å respectively for the manganese complex; 2.08(1), 1.97(1), 2.23(1)Å for the cobalt complex; 2.33(1), 1.92(3), 2.18(1)Å for the copper complex; 2.110(5), 1.964(6), 2.252(6)Å for the zinc complex. The variation of metal-ligand distances can be correlated to the metal d orbital occupancy. A comparison with similar ligands will be presented.     

Amphotericin B and Curcumin Co-Loaded Porous Microparticles as a Sustained Release System against Candida albicans

Amphotericin B (AMB) is an antifungal drug used for serious fungal infections. However, AMB has adverse reactions such as nephrotoxicity, which limit the clinical application of AMB alone or in combination with other antifungal drugs. Nano or micro drug delivery systems (DDS) have been proven to be effective in reducing the toxic and side effects of drugs. Further, the combination of AMB with other compounds with antifungal activity, such as curcumin (CM), may enhance the synergistic effects. Herein, AMB and CM were co-loaded into porous poly (lactic-co-glycolic acid) (PLGA) microparticles (MPs) to prepare AMB/CM-PLGA MPs. The AMB/CM-PLGA MPs showed a remarkably reduced hemolysis (62.2 ± 0.6%) compared to AMB (80.9 ± 1.1%). The nephrotoxicity of AMB/CM-PLGA MPs is significantly lower than that of AMB. In vitro, AMB/CM-PLGA MPs had better inhibitory effects on the adhesion and biofilm formation of Candida albicans compared with AMB. Experiments on mice infected with C. albicans showed that AMB/CM-PLGA MPs have a better therapeutic effect than AMB in vivo. In summary, AMB/CM-PLGA MPs may be a novel and promising therapeutic candidate for fungal infection.     

Investigation on the Peroxidase-like Activity of Vitamin B6 and Its Applications in Colorimetric Detection of Hydrogen Peroxide and Total Antioxidant Capacity Evaluation

The peroxidase-like activity of vitamin B6 (VB6) was firstly demonstrated by catalyzing the peroxidase chromogenic substrate 3,3′,5,5′-tetramethylbenzidine (TMB) at the existence of H₂O₂. The influence of different factors on the catalytic property of VB6, including pH, temperature, VB6 concentration, and incubation time, were investigated. The steady-state kinetic study results indicate that VB6 possesses higher affinity to H₂O₂ than natural horseradish peroxidase and some other peroxidase mimics. Besides, the radical quenching experiment results confirm that hydroxyl radical (•OH) accounts for the catalytic process. Based on the excellent peroxidase-like catalytic activity of VB6, the colorimetric methods for H₂O₂ and gallic acid (GA) detection were developed by measuring the absorbance variance of the catalytic system. Under the optimal conditions, the linear ranges of the methods for H₂O₂ and GA determination with good selectivity are 50.0–600.0 μM and 10.0–50.0 μM, respectively. In addition, the developed method was applied in the detection of H₂O₂ in milk samples and evaluation of total antioxidant capacity of different tea infusions. This study may broaden the application prospect of VB6 in environmental and biomedical analysis fields, contribute to profound insight of the physiological functions of VB6, as well as lay foundation for further excavation of small-molecule peroxidase mimics.     

Cardiac-specific overexpression of Ndufs1 ameliorates cardiac dysfunction after myocardial infarction by alleviating mitochondrial dysfunction and apoptosis

Myocardial infarction (MI) is the leading cause of premature death among adults. Cardiomyocyte death and dysfunction of the remaining viable cardiomyocytes are the main pathological factors of heart failure after MI. Mitochondrial complexes are emerging as critical mediators for the regulation of cardiomyocyte function. However, the precise roles of mitochondrial complex subunits in heart failure after MI remain unclear. Here, we show that NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) expression is decreased in the hearts of heart failure patients and mice with myocardial infarction. Furthermore, we found that cardiac-specific Ndufs1 overexpression alleviates cardiac dysfunction and myocardial fibrosis in the healing phase of MI. Our results demonstrated that Ndufs1 overexpression alleviates MI/hypoxia-induced ROS production and ROS-related apoptosis. Moreover, upregulation of Ndufs1 expression improved the reduced activity of complex I and impaired mitochondrial respiratory function caused by MI/hypoxia. Given that mitochondrial function and cardiomyocyte apoptosis are closely related to heart failure after MI, the results of this study suggest that targeting Ndufs1 may be a potential therapeutic strategy to improve cardiac function in patients with heart failure.Subject terms: Heart failure, Myocardial infarction, Myocardial infarction     

Promote the conductivity of solid polymer electrolyte at room temperature by constructing a dual range ionic conduction path

Poly(ethylene oxide)(PEO) is a classic matrix model for solid polymer electrolyte which can not only dissociate lithium-ions(Li+),but also can conduct Li+through segmental motion in long-range.However,the crystal aggregation state of PEO restricts the conduction of Li⁺ especially at room temperature.In this work,an amorphous polymer electrolyte with ethylene oxide(EO) and propylene oxide(PO) block structure(B-PEG@DMC) synthesized by the transesterification is firstly obtained,showing ...