肝脏体外实验模型在毒理学中的应用

简要介绍了肝脏体外实验模型,并简述了其在外源性化合物毒性、药物代谢和新药研发中的应用.     

Quantitative Structure–Activity Relationships (QSARs) of Pyrimidine Nucleosides as HIV-1 Antiviral Agents

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.     

新型噁唑烷酮类抗菌药物的研究进展

目的阐述唑烷酮类抗菌药物的最新研究进展。方法根据近期关于新的唑烷酮类抗菌药物研究开发现状的29篇相关文献,对唑烷酮的3位芳基和5位侧链的结构改造特点进行整理和归纳。结果与结论大多数化合物具有提高的抗G+菌活性,部分化合物显示出抗G-菌的活性。另外,还介绍了一类具有扩大的抗菌谱的唑烷酮与其他类型抗菌药物形成的拼合化合物。     

Intestinal Absorption Screening of Mixtures from Combinatorial Libraries in the Caco-2 Model

Purpose. Understanding how chemical structures influence transport across the intestinal mucosa will greatly enhance the discovery of orally available drugs. In an attempt to accelerate defining such relationships between structure and transport, six arbitrary mixtures of N-substituted glycine (NSG) peptoids containing 24 physicochemically diverse compounds were evaluated in the Caco-2 model of intestinal absorption. Methods. Samples were analyzed by HPLC and the areas of the peaks representing the components of each mixture were summed to measure 'aggregate' apparent permeability coefficients (P _app) a score of the influence of the common structural element within each mixture towards absorption. Mass spectrometry was used to identify the chemical structure of Caco-2 permeable compounds. Results. Three linear trimeric mixtures were examined and, for each mixture, none of the components was detected in receiver chambers. It was concluded that the components of these mixtures each had a P _app value less than 0.8 × 10^–6 cm/sec, a permeability less than mannitol. Three dimeric mixtures were examined and they exhibited aggregate P _app values of 9.2 × 10^–6 , 14 × 10^–6 and 6.9 × 10^–6 cm/sec. These transport rates reflected the transport of most of the components of each mixture. Furthermore, the components of the dimeric mixtures which were transported at a rate greater than mannitol were apparently transported by passive mechanisms. Conclusions. This study demonstrated that mixtures can be used to study structure-transport relationships in the Caco-2 model. The information obtained from this type of study will be integrated into the design of future chemical libraries. Other potential uses of chemical mixtures with the Caco-2 model are also discussed.     

苹果酸舒尼替尼杂质的遗传毒性（Q）SAR评价及Ames试验评估

目的 对苹果酸舒尼替尼的3个已知杂质进行（定量）构效关系计算机模型［（Q）SAR］评价,并对杂质E进行细菌回复突变（Ames）试验研究。方法 根据国际人用药品注册技术协调会（ICH）M7指导原则的要求,采用基于专家知识规则的Derek和基于统计学的Sarah两类（Q）SAR评价系统,对苹果酸舒尼替尼的3个杂质——杂质v-7、杂质v-1及杂质E进行评价和分类。对于确定为遗传毒性阳性的杂质E,采用Ames试验进行验证。结果 苹果酸舒尼替尼的杂质v-7、杂质v-1预测结果为阴性,杂质E预测结果为阳性,且分类为3类。在加与不加S9的条件下,Ames试验中杂质E8～5000μg·皿^-1质量浓度回复突变菌落数均未超过溶剂对照组的2倍,试验结果为阴性。结论 苹果酸舒尼替尼的3个杂质——杂质v-7、杂质v-1及杂质E均可以按照非遗传毒性杂质进行控制。     

异苯并呋喃酮-3-乙酰胺类化合物的合成及其抗惊活性构效关系的初步探讨

设计合成了１１个新的异苯并呋喃酮３乙酰胺类化合物，它们均未见文献报道，产物经核磁共振氢谱和元素分析确证．抗惊实验表明：当酰胺氮原子上的取代基为脂肪取代基且碳原子总数在６～１０个之间时，该类化合物才有较好的抗惊活性．并对其构效关系进行了初步讨论     

Selective COX-2 inhibitors as anticancer agents: a patent review (2014-2018)

Introduction: COX-2 is a key enzyme in the process of prostaglandins (PGs) synthesis. The products of this enzyme could play a major role as the mediators of the inflammatory response and some other medical states such as cancer. The design and synthesis of novel selective COX-2 inhibitors have always been attractive to researchers. This review discusses the structures of novel COX-2 inhibitors synthesized during the last five years and describes their efficacy as anticancer agents.

Areas covered: It is well established that COX-2 is overexpressed in many different cancers and treatment with selective COX-2 inhibitors could relieve their symptoms and limit their adverse sequences.

Expert opinion: The diversity of selective COX-2 inhibitors is mainly related to the types of scaffolds. Monocyclic, bicyclic, tricyclic, and acyclic scaffolds with different pharmacological effects and toxicological profiles could be found in the family of selective COX-2 inhibitors. The great interest of the researchers in this field is due to the importance of selective COX-2 inhibitors as a relatively safe and effective set of compounds which could present different properties such as antirheumatic, anti-inflammatory, antiplatelet, anti-Alzheimer’s disease, anti-Parkinson’s disease, and anticancer.     

Identification of structure-activity relationships for adverse effects of pharmaceuticals in humans: Part B. Use of (Q)SAR systems for early detection of drug-induced hepatobiliary and urinary tract toxicities

This report describes the development of quantitative structure-activity relationship (QSAR) models for predicting rare drug-induced liver and urinary tract injury in humans based upon a database of post-marketing adverse effects (AEs) linked to ∼1600 chemical structures. The models are based upon estimated population exposure using AE proportional reporting ratios. Models were constructed for 5 types of liver injury (liver enzyme disorders, cytotoxic injury, cholestasis and jaundice, bile duct disorders, gall bladder disorders) and 6 types of urinary tract injury (acute renal disorders, nephropathies, bladder disorders, kidney function tests, blood in urine, urolithiases). Identical training data sets were configured for 4 QSAR programs (MC4PC, MDL-QSAR, BioEpisteme, and Predictive Data Miner). Model performance was optimized and was shown to be affected by the AE scoring method and the ratio of the number of active to inactive drugs. The best QSAR models exhibited an overall average 92.4% coverage, 86.5% specificity and 39.3% sensitivity. The 4 QSAR programs were demonstrated to be complementary and enhanced performance was obtained by combining predictions from 2 programs (average 78.4% specificity, 56.2% sensitivity). Consensus predictions resulted in better performance as judged by both internal and external validation experiments.     

2，4－二氨基－5－甲基－6－（取代苯胺基）甲基－吡啶〔2，3－4〕并嘧啶类化合物的合成及其定量构效关系

参照ＪＲＰｉｐｅｒ的方法合成了１６个２，４－二氨基－５－甲基－６－（取代苯胺基）甲基－吡啶（２，３－ｄ）并嘧啶类化合物（Ⅲ），用Ｈａｎｓｃｈ方法研究了它们对Ｌ１２１０细胞株抑制作用的定量构效关系，初步结果为：ｌｏｇ１／Ｃ＝－１．７５（±０．６２）π２＋２．４４（±０．６１）π５，６－１．５７（±０．５０）Σσ＋６．９４（±０．２２）ｎ＝１５，ｒ＝０．９５２，ｓ＝０．２５６还需扩大（Ⅲ）的取代基疏水性参数的变化幅度以进一步研究其构效关系。     

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 31): 2-Heteroaryl Derivatives

A range of 14 derivatives of flavone-8-acetic acid (FAA) with a heterocyclic substituent in place of the 2-phenyl group have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. Some of the compounds, notably 2c, d and s , showed significant in vivo activity and these require further studies in order to evaluate their potential for development.     

安梦(褪黑素)胶囊的研制和初步性能评价

报道了安梦（褪黑素）胶囊的研制,考察了其助眠功能,并进行了部分安全毒理学评价。安梦（褪黑素）胶囊主要功效成分为褪黑素,并以超细珍珠粉和活性钙为辅助成分。助眠功能性检测表明该产品可以改善睡眠,延长睡眠时间。已检安全性毒理学项目未显示毒副作用。     

Correlation of Partitioning of Nitroimidazoles in the n-Octanol/Saline and Liposome Systems with Pharmacokinetic Parameters and Quantitative Structure–Activity Relationships (QSAR)

The partitioning of a series of nine nitroimidazole drugs in liposomes (log K _m) of various compositions has been determined and compared to their partitioning in the n-octanol/saline system (log K) at 30°C. The log K _m ranged from 1.5 to 0.5 and was three- to fourfold greater than the log K; further, the linear correlation coefficient was greatest when cholesterol (CHOL)-free liposomes were used. Functional-group contributions were compared from their hydrophobic substituent constants and, except in the case of RO-07-2044 and iodoazomycin riboside, yielded negative values in all systems. Literature values of four pharmacokinetic parameters obtained in dogs and acute LD₅₀ values of the nitroimidazoles in BALB/c mice were highly correlated with log K or log K _m only in CHOL-free liposomes. Comparing the relative sensitizing effect of the nitroimidazoles in murine EMT-6 or Chinese hamster V79 tumor cell cultures and their partition coefficients, the correlation in EMT-6 cells was poor, whereas the correlation in V79 cells was >0.9 when log K _m was used but <0.6 when log K was used. Thus, the liposome model is a better predictor of nitroimidazole activity than the n-octanol/saline system and, also, it is a more flexible model for selecting the optimum conditions for QSAR studies.     

Toxicology mechanism of the persistent organic pollutants (POPs) in fish through AhR pathway

With the development of industry and agriculture, the cases of cancer and tumor have been increasing gradually in the last 30 years, and quite a few cases are caused by persistent organic pollutants (POPs), some of them belonging to environmental endocrine disruptors, and they have become ubiquitous in the environment, especially in the aquatic ecosystem; so this issue has aroused the extensive attention of the world. The mechanism of POPs toxicology is very complicated, but it is mainly mediated by the aryl hydrocarbon receptor (AhR) pathway in fish. In order to gain a comprehensive understanding of the AhR pathway, the present paper focuses on reviewing it from four major steps, including formation of cytosolic complex, translocation of AhR, heterodimerization of AhR, and induction of CYP1A. This study summarized the isoform numbers of AhR pathway genes and the expression patterns in the regulation process of POPs toxicology in zebrafish.     

A robust structure-activity relationship (SAR) model for esters that cause skin irritation in humans.

A structure-activity relationship (SAR) model has been developed to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochemical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regression analysis indicated candidate models for further analysis. Regression analyses identified significant models (p < 0.05) that had variables that were also significant (p < 0.05). These candidate models were evaluated using linear discriminant analysis to determine if the irritant esters could be discriminated from nonirritant esters. The stability of the model was evident from the consistency of parameters among ten submodels generated using multiple random sampling of the database. The sensitivity of the ten models, evaluated by "leave-one-out" cross-validation, ranged from 0. 846 to 0.923, with a mean of 0.885 +/- 0.025 (95% CI). The specificity ranged from 0.615 to 0.923, with a mean of 0.738 +/- 0.06 (CI). Compared with nonirritant esters, irritant esters had lower density, lower water solubility, lower sum of partial positive charges, higher Hansen hydrogen bonding parameter, and higher Hansen dispersion parameter. The results indicate that physicochemical features of esters contribute to their ability to cause skin irritation in humans, and that chemical partitioning into the epidermis and intermolecular reactions are likely important components of the response. This model is applicable for prediction of human irritation of esters yet untested.     

Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

This article provides an overview of approximately 300 secondary metabolites with inhibitory activity against protein tyrosine phosphatase 1B (PTP1B), which were isolated from various natural sources or derived from synthetic process in the last decades. The structure-activity relationship and the selectivity of some compounds against other protein phosphatases were also discussed. Potential pharmaceutical applications of several PTP1B inhibitors were presented.     

Implementation of Good Laboratory Practices (GLP) in basic scientific research: Translating the concept beyond regulatory compliance

The principles of Good Laboratory Practices (GLPs) are mainly intended for the laboratories performing studies for regulatory compliances. However, today GLP can be applied to broad disciplines of science to cater to the needs of the experimental objectives, generation of quality data and assay reproducibility. Considering its significance, it can now be applied in academics; industries as well as government set ups throughout the world. GLP is the best way to promote the reliability, reproducibility of the test data and hence facilitates the international acceptability. Now it is high time to translate and implement the concept of GLP beyond regulatory studies. Thus, it can pave the way for better understanding of scientific problems and help to maintain a good human and environmental health. Through this review, we have made an attempt to explore the uses of GLP principles in different fields of science and its acceptability as well as looking for its future perspectives.     

Use of category approaches,read-across and (Q)SAR: General considerations

Read-across has generated much attention since it may be used as an alternative approach for addressing the information requirements under regulatory programmes, notably the EU’s REACH regulation. Read-across approaches are conceptually accepted by ECHA and Member State Authorities (MS) but difficulties remain in applying them consistently in practice. Technical guidance is available and there are a plethora of models and tools that can assist in the development of categories and read-across, but guidance on how to practically apply categorisation approaches is still missing. This paper was prepared following an ECETOC (European Centre for Ecotoxicology and Toxicology) Task Force that had the objective of summarising guidance and tools available, reviewing their practical utility and considering what technical recommendations and learnings could be shared more widely to refine and inform on the current use of read-across. The full insights are recorded in ECETOC Technical Report TR No. 116. The focus of this present paper is to describe some of the technical and practical considerations when applying read-across under REACH. Since many of the deliberations helped identify the issues for discussion at a recent ECHA/Cefic LRI workshop on “read-across”, summary outcomes from this workshop are captured where appropriate for completeness.     

Development of quantitative structure-activity relationship (QSAR) models to predict the carcinogenic potency of chemicals. II. Using oral slope factor as a measure of carcinogenic potency

The overall risk associated with exposure to a chemical is determined by combining quantitative estimates of exposure to the chemical with their known health effects. For chemicals that cause carcinogenicity, oral slope factors (OSFs) and inhalation unit risks are used to quantitatively estimate the carcinogenic potency or the risk associated with exposure to the chemical by oral or inhalation route, respectively. Frequently, there is a lack of animal or human studies in the literature to determine OSFs. This study aims to circumvent this problem by developing quantitative structure-activity relationship (QSAR) models to predict the OSFs of chemicals. The OSFs of 70 chemicals based on male/female human, rat, and mouse bioassay data were obtained from the United States Environmental Protection Agency's Integrated Risk Information System (IRIS) database. A global QSAR model that considered all 70 chemicals as well as species and/or sex-specific QSARs were developed in this study. Study results indicate that the species and sex-specific QSARs (r(2)>0.8, q(2)>0.7) had a better predictive abilities than the global QSAR developed using data from all species and sexes (r(2)=0.77, q(2)=0.73). The QSARs developed in this study were externally validated, and demonstrated reasonable predictive abilities.     

Structure-activity relationships and in silico models of P-glycoprotein (ABCB1) inhibitors

Abstract

1. The efflux pump p-glycoprotein (P-gp/ABCB1) has received enormous attention in drug (xenobiotic) disposition due to its role in modulation of the drug availability and in protection of sensitive organs.

2. P-gp mediated efflux is one of main mechanisms for multidrug resistance in cancer cells. A main approach to reverse the resistance and restore the drug efficacy is to use specific inhibitors of P-gp that suppress the efflux activity.

3. This review summarizes the binding capabilities of known chemical inhibitors based on the analyses of structure–activity relationships, and computational modeling of the inhibitors as well as the binding site of P-gp protein.

4. The molecular models will facilitate the design of lead inhibitors as drug candidates. Also, it helps scientists in early drug discovery phase to synthesize chemical series with better understanding of their P-gp binding liabilities.