Global Structure-Acute Toxicity Relationships for Mice Using Structural Parameter Ratios: New Approach to Molecular Design and Screening

Abstract

A method for a preliminary survey of the relationship between molecular structure and performance was described using 1506 random data of structure-acute toxicity for mice (intravenously dosed). The structural patterns of the weakest toxic structures (111) were extracted from the data and the patterns discriminated for 64.2% of the other structures (1395). As for the 826 structures of strongest toxicity, 78.3% were discriminated by these structural patterns. These results were obtained by using structural parameter ratios to describe the structural patterns and the exhaustive elimination process to select the best parameter ratio from many candidates. The results were summarized in the form of a chart which can be used for practical screening for the weakest toxic structures.     

联保贷款中的策略性违约规避机制设计

针对联保贷款的策略性违约问题,通过对其产生原因的分析以及对现有文献中解决措施的探讨,设计了一个弹性联保贷款合约。该合约的特点在于,随着企业愿意承担的连带责任的增加,企业可获得的期望收益也随之增加,旨在从正面激励企业主动为同伴承担还款责任,达到规避策略性违约的目的。通过数值分析验证了该弹性合约的特性以及适用范围。并进一步在两企业模式基础上进行拓展,讨论了多于两企业的情况下该弹性合约的适用条件。     

Study of degradation behavior of besifloxacin,characterization of its degradation products by LC–ESI–QTOF–MS and their in silico toxicity prediction

Knowledge and understanding of the stability profile of a drug is important as it affects its safety and efficacy. In the present work, besifloxacin, a new, fourth‐generation fluoroquinolone antibiotic, was subjected to different forced‐degradation conditions as per International Conference on Harmonization (ICH) guidelines such as hydrolysis (acid, base and neutral), oxidation, thermal and photolysis. The drug degraded under acidic, basic, oxidative and photolytic conditions while it was found to be stable under dry heat and neutral hydrolytic conditions. In total, five degradation products (DPs) were formed under different conditions—DP1 and DP2 (photolysis), DP3 (oxidation), DP4 (acidic), DP3 and DP5 (basic). The chromatographic separation of besifloxacin and its degradation products was achieved on a Sunfire C₁₈ (250 mm × 4.6 mm, 5 μm) column with 0.1% aqueous formic acid–acetonitrile as a mobile phase. The gradient RP‐HPLC method was developed and validated as per ICH guidelines. The degradation products were characterized with the help of LC–ESI–QTOF mass spectrometric studies and the most likely degradation pathway of the drug was proposed. In silico toxicity assessment of the drug and its degradation products was carried out, which indicated that DP3 and DP4 carry a mutagenicity alert.     

Differential Response of Pentanal and Hexanal Exhalation to Supplemental Oxygen and Mechanical Ventilation in Rats

High inspired oxygen during mechanical ventilation may influence the exhalation of the previously proposed breath biomarkers pentanal and hexanal, and additionally induce systemic inflammation. We therefore investigated the effect of various concentrations of inspired oxygen on pentanal and hexanal exhalation and serum interleukin concentrations in 30 Sprague Dawley rats mechanically ventilated with 30, 60, or 93% inspired oxygen for 12 h. Pentanal exhalation did not differ as a function of inspired oxygen but increased by an average of 0.4 (95%CI: 0.3; 0.5) ppb per hour, with concentrations doubling from 3.8 (IQR: 2.8; 5.1) ppb at baseline to 7.3 (IQR: 5.0; 10.8) ppb after 12 h. Hexanal exhalation was slightly higher at 93% of inspired oxygen with an average difference of 0.09 (95%CI: 0.002; 0.172) ppb compared to 30%. Serum IL-6 did not differ by inspired oxygen, whereas IL-10 at 60% and 93% of inspired oxygen was greater than with 30%. Both interleukins increased over 12 h of mechanical ventilation at all oxygen concentrations. Mechanical ventilation at high inspired oxygen promotes pulmonary lipid peroxidation and systemic inflammation. However, the response of pentanal and hexanal exhalation varies, with pentanal increasing by mechanical ventilation, whereas hexanal increases by high inspired oxygen concentrations.     

Low‐Fouling Electrosprayed Hemoglobin Nanoparticles with Antioxidant Protection as Promising Oxygen Carriers

Despite all the attempts to create advanced hemoglobin (Hb)‐based oxygen carriers (HBOCs) employing an encapsulation platform, major challenges including attaining a high Hb loading and long circulation times still need to be overcome. Herein, the fabrication, for the first time, of nanoparticles fully made of Hb (Hb‐NPs) employing the electrospray technique is reported. The Hb‐NPs are then coated by antioxidant and self‐polymerized poly(dopamine) (PDA) to minimize the conversion of Hb into nonfunctional methemoglobin (metHb). The PDA shell is further functionalized with poly(ethylene glycol) (PEG) to achieve stealth properties. The results demonstrate that the as‐prepared Hb‐NPs are hemo‐ and biocompatible while offering antioxidant protection and decreasing the formation of metHb. Additionally, decoration with PEG results in decreased protein adsorption onto the Hb‐NPs surface, suggesting a prolonged retention time within the body. Finally, the Hb‐NPs also preserve the reversible oxygen‐binding and releasing properties of Hb. All in all, within this study, a novel HBOCs with high Hb content is fabricated and its potential as an artificial blood substitute is evaluated.     

Tin(IV) Schiff base complexes derived from pyridoxal: Synthesis,spectroscopic properties and cytotoxicity

The synthesis of monomeric pentacoordinated diorganotin(IV) complexes derived from pyridoxal hydrochloride and 4‐ or 5‐R ‐substituted ortho ‐aminophenols is described. The complexes were characterized using UV–visible, infrared, mass, ¹H NMR, ¹³C NMR and ¹¹⁹Sn NMR spectral techniques. The molecular structure of three complexes was established using X‐ray diffraction: 3b and 3d show a distorted trigonal bipyramidal geometry, in which the basal plane is defined by the butyl groups and the iminic nitrogen atom, whereas the oxygen atoms from the aromatic ring occupy axial positions; in contrast, complex 3e exhibits a square pyramidal geometry. The cytotoxic activity of all complexes against human cell lines U‐251 (glioblastoma), K‐562 (chronic myelogenous leukemia), HCT‐15 (human colorectal cancer), MCF‐7 (human breast cancer) and SKLU‐1 (non‐small‐cell lung cancer) was evaluated, and the inhibitory percentage values indicated higher activity than the reference standard, cisplatin. Acute toxicity studies were performed in vivo for the prepared complexes to determine the lethal medium dose (LD₅₀) after intraperitoneal administration to mice.     

Cytotoxic Activity of Ammonium Tellurates

The cytotoxic activity of a series of methylammonium tellurates on human fibrosarcoma HT-1080, mouse hepatoma MG-22A, and mouse fibroblasts 3T3 cell lines is described. The role of tellurates as free radical regulators is discussed.     

Synthesis and Comparison of Extraction Properties of p‐tert‐Butylcalix[n]arene Nitrile Derivatives for Selected Metals and Dichromate Anions

The article describes the syntheses and extraction properties of two p‐tert‐butylcalix[6]arene nitrile derivatives (3 and 4). The trinitrile derivative 3 has been synthesized from 5,11,17,23,29,35‐hexa‐tert‐butyl‐37,38,39,40,41,42‐hexahydroxycalix[6]arene 1. The compound 1 was directly converted to its hexanitrile derivative 4. In these syntheses, it was thought to explore the role of nitrile sites in the extraction of various metal cations and HCr₂O₇ ^?/Cr₂O₇ ^2? anions. The liquid‐liquid extraction properties of 3 and 4 towards selected alkali/transition metal cations and HCr₂O₇ ^?/Cr₂O₇ ^2? anions are reported. It has been observed that receptor 3 does not extract alkali/transition metal cations effectively, but shows affinity towards HCr₂O₇ ^?/Cr₂O₇ ^2? anions at low pH. The compound 4 is an effective form for transferring Ni²⁺ selectively, while it shows poor transferring ability for HCr₂O₇ ^?/Cr₂O₇ ^2? anions from an aqueous into a dichloromethane layer. It was observed that the cavity size of the calix[n]arenes and the cooperativity of the functionalities play important roles in two phase extraction systems.     

ToxML,a data exchange standard with content controlled vocabulary used to build better (Q)SAR models

Development of accurate quantitative structure–activity relationship (QSAR) models requires the availability of high quality validated data. International regulations such as REACH in Europe will now accept (Q)SAR-based evaluations for risk assessment. The number of toxicity datasets available for those wishing to share knowledge, or to use for data mining and modelling, is continually expanding. The challenge is the current use of a multitude of different data formats. The issues of comparing or combining disparate data apply both to public and proprietary sources. The ToxML project addresses the need for a common data exchange standard that allows the representation and communication of these data in a well-structured electronic format. It is an open standard based on Extensible Markup Language (XML). Supporting information for overall toxicity endpoint data can be included within ToxML files. This makes it possible to assess the quality and detail of the data used in a model. The data file model allows the aggregation of experimental data to the compound level in the detail needed to support (Q)SAR work. The standard is published on a website together with tools to view, edit and download it.