Study on the quantitative structure–toxicity relationships of benzoic acid derivatives in rats via oral LD50

Quantitative structure–toxicity relationship (QSTR) studies play an important role in toxicity forecasting, which is widely used in the study of modern compounds. Benzoic acid derivatives are an important type of organic chemicals. Most of them may cause serious public health and environmental problems. The effect of quantum-chemistry parameters on the toxicity of benzoic acid derivatives in rats via oral 50% lethal dose (LD₅₀) was studied by QSTR, and a model to predict the toxicity of benzoic acid derivatives was constructed. In order to obtain an accurate model, cross factors were considered and a model for predicting the toxicity of benzoic acid derivatives in rats via oral LD₅₀ was built using a linear regression method (correlation 0.990). The novel model is - log^toxi = 0.144\textLogP - 0.0269SAG + 0.0000127HoF - 0.000377PE - \log^{toxi} = 0.144{\text{Log}}P - 0.0269SAG + 0.0000127HoF - 0.000377PE , R ² = 0.990, C(p) = 4.000, mean square error (MSE) = 0.785. The model demonstrated good forecasting ability.     

Investigation on the substitution effects of the flavonoids as potent anticancer agents: a structure–activity relationships study

Three series of flavonoid analogues substituted with different aminomethyl substitutions at C-6, C-7, and C-8 were designed and synthesized for the structure–activity relationship studies as potent anticancer agents. The prepared analogues were evaluated for their in vitro inhibitory activity against the growth of the hepatic cancer cell lines HepG2 and SMMC-7721. Structure–activity relationships indicated that not only the compounds with amino methyl groups were more active than those without the groups in the same series but also the compounds substituted by aminomethyl groups at position C-8 were more active than those at positions C-6 and C-7.     

Synthesis and structure–activity relationships of serotonin derivatives effect on α-glucosidase inhibition

The α-glucosidase inhibitory activities of serotonin derivatives were evaluated. Two serotonin derivatives, N-p-coumaroyl serotonin (2) and N-caffeoyl serotonin (4) exhibited most potent inhibition on α-glucosidase, whereas, cinnamic acid derivatives were less efficient. Furthermore, we analyzed their structural importance for α-glucosidase inhibition. The linkage of cinnamic acid moiety and serotonin moiety and the olefin in cinnamic acid moiety of serotonin derivatives were crucial for α-glucosidase inhibition. This is the first report on structure–activity relationships (SAR) for the α-glucosidase inhibitory activity of serotonin derivatives.     

Structure–effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination

OBJECTIVES: Amiodarone (AMI) has proven to be a potent anti-arrhythmic compound. Due to the structural similarity between AMI and thyroid hormone, it is possible that the drug could inhibit the activity of the 5'-thyroxine-deiodinase. METHODS: AMI analogues resulting from (1) dealkylation, (2) deiodination and (3) deamination were synthesised and used as inhibitors in an in vitro biotransformation reaction of thyroxine (T4) to 3,3',5'-triiodothyronine (T3). Using high-performance liquid chromatography and ultraviolet detection for quantifying T3, it was found that the 5'-T4 deiodinase type I was involved in the reaction. On separate occasions, AMI or an AMI analogue was added to the reaction as an inhibitor. RESULTS: All studied AMI analogues inhibited 5'-T4 deiodination competitively (Ki value range 25-360 microM). In the concentration range of 1-1000 microM, AMI and its N-desethylated, deiodinated analogues inhibited 5'-T4 deiodination very weakly. AMI analogues with a hydroxyl group at the 4-position were strong inhibitors. Moreover, diiodo-AMI analogues inhibited 5'-T4 deiodination more strongly than their corresponding monoiodo- or deiodinated derivatives. CONCLUSION: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.     

Structure–activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity

The aim of this study was to investigate the possible influence of halogenated compounds on thyroid hormone metabolism via inhibition of iodotyrosine deiodinase (IYD) activity. The structure-activity relationships of 44 halogenated compounds for IYD-inhibitory activity were examined in vitro using microsomes of HEK-293 T cells expressing recombinant human IYD. The compounds examined were 17 polychlorinated biphenyls (PCBs), 15 polybrominated diphenyl ethers (PBDEs), two agrichemicals, five antiparasitics, two pharmaceuticals and three food colorants. Among them, 25 halogenated phenolic compounds inhibited IYD activity at the concentration of 1 × 10^?4 M or 6 × 10^?4 M. Rose bengal was the most potent inhibitor, followed by erythrosine B, phloxine B, benzbromarone, 4′-hydroxy-2,2′,4-tribromodiphenyl ether, 4-hydroxy-2,3′,3,4′-tetrabromodiphenyl ether, 4-hydroxy-2′,3,4′,5,6′-pentachlorobiphenyl, 4′-hydroxy-2,2′,4,5′-tetrabromodiphenyl ether, triclosan, and 4-hydroxy-2,2′,3,4′,5-pentabromodiphenyl ether. However, among PCBs and PBDEs without a hydroxyl group, including their methoxylated metabolites, none inhibited IYD activity. These results suggest that halogenated compounds may disturb thyroid hormone homeostasis via inhibition of IYD, and that the structural requirements for IYD-inhibitory activity include halogen atom and hydroxyl group substitution on a phenyl ring.     

Acetylcholinesterase inhibition: does it explain the toxicity of organophosphorus compounds?

The hypothesis that acetylcholinesterase (AChE) inhibition is the mechanism of toxicity of organophosphorus (OP) compounds was examined by mathematically modeling the in vivo lethal effects of OP compounds and determining the amount of variation in OP toxicity that is explained by AChE inhibition. Mortality dose–response curves for several OP compounds (i.e., VX, soman, cyclosarin, sarin, tabun, diisopropylfluorophosphate and paraoxon) exhibited steep probit slopes (> 9.6) in guinea pigs. Steep probit slopes were also observed when the mortality dose–response curves for soman were examined in mice, rats, rabbits and non-human primates. The consistently steep probit slopes of the dose–response curves for highly toxic OP compounds suggested that these compounds have a single specific mechanism of toxicity regardless of the OP compound or the species in which it was tested. Regression analysis indicated that 93% of the 3,280-fold variation in the median lethal doses (i.e., LD₅₀) of OP compounds in rats was explained by the variation in their in vitro rate constants for inhibition of AChE. Conversely, 91% of the 23-fold variation in the ability of the oximes pralidoxime and obidoxime to protect against the toxicity of OP compounds in guinea pigs was explained by the variation in the in vitro ability of oximes to reactivate OP-inhibited AChE. The best explanation for this variety of observations was that the primary mechanism of in vivo toxicity for highly toxic OP compounds is the inhibition of AChE, and the residual unexplained variation in OP toxicity that might be explained by other mechanisms represents < 10% of the total variation in OP toxicity.     

 Simulation Study on the Entrance of

d fund industries.The research indicates that the entrance of commercial banks into the property insurance and fund industries can increase their revenue and return per unit of risk,and significantly reduce their probability of bankruptcy.The results also indicate that appropriate proportion of nonbanking assets is indispensable for achieving the optimal effect of diversification.In addition,a comparative study shows that the simultaneous diversification into the property insurance and fund industries generates higher divers2;P<0.01)C与胰岛素水平、C反应蛋白、类风湿因子(RF)、肿胀指数、压痛指数、晨僵时间、病程、年龄、性别等无关;瘦素及瘦素受体在RA患者滑膜中的表达明显高于正常对照组。结论:瘦素可能通过在靶器官的高表达而起到调节炎症的作用;可能在炎性反应中参与急性时相蛋白的合成与调节而影响疾病的发展过程。     

Study on the Equivalent Conformation of Retinoids

具有诱导细胞分化作用及癌和皮肤病化学治疗作用的维甲类化合物，不仅要求分子一端有疏水性、另一端为极性羧基和整个分子的共轭性，而且分子的构象也起重要作用。本文合成的Ｎ（４羧基苯基）３，５双叔丁基４羟基苯甲酰胺（２）具有与全反式维甲酸（ＡＴＲＡ，１）相似性质的基团配置和构象，表现有维甲酸的生物活性。然而Ｎ甲基化合物３，由于构象的完全不同，丧失了活性。用Ｘ线晶体学、紫外和核磁共振等方法研究了化合物２、３和ＡＴＲＡ的结构异同。     

Synthesis and structure-activity relationships of novel compounds for the inhibition of TNF-α production

This study describes the synthesis, in vitro evaluation and molecular modeling study of novel compounds for the inhibition of TNF-alpha production. Among these compounds, 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-isoindolinone (9) was selected as a lead compound and its pyridine derivative 10 was more potent in activity and safer than rolipram.     

Inhibitory effect of curcumin analogs on tissue factor procoagulant activity and their preliminary structure–activity relationships

With the aim to explore the multifunctional behaviors of curcumin analogs and to discover new small molecular tissue factor inhibitors, twelve mono carbonyl curcumin analogs of three classes were synthesized and their effect on tissue factor procoagulant activity was evaluated in the human monoblastic leukemia THP-1 cells stimulated by LPS. The most potent compounds 2a exhibited the dramatically enhanced activity with the IC₅₀ values of 0.053 nM. Their preliminary structure–activity relationship was also discussed.