Synthesis of benzimidazole derivatives as antiallergic agents with 5-lipoxygenase inhibiting action

Syntheses were conducted of novel benzimidazole derivatives that suppress histamine release from mast cells, inhibit 5-lipoxygenase, and possess antioxidative action. Among the compounds synthesized, 1-[2-[2-(4-hydroxy- 2,3,5-trimethylphenoxy)ethoxy]ethyl]-2-(4-methyl-1- homopiperazino)benzimidazole (22) potently suppressed histamine release from rat peritoneal mast cells triggered by the antigen-antibody reaction, inhibited 5-lipoxygenase in rat basophilic leukemia-1 (RBL-1) cells, and prevented the NADPH-dependent lipid peroxidation induced by Fe(3+)-ADP in rat liver microsomes, in addition to an antagonizing the contraction of guinea pig ileum caused by histamine.     

Quantitative structure-activity relationship of coumarin derivatives. Involvement of partition between aqueous and membrane phase

In order to understand the substrate behaviour of several 7-alkoxycoumarins and 7-alkoxy-4-alkylcoumarins towards the liver microsomal monooxygenase system, their lipophilic properties have been examined. As a model for the lipophilicity the reversed-phase liquid chromatographic retention parameter log kw has been used. In a system with methanol-water as the mobile phase and RP-18 (octadecylsilica) as the stationary phase, we found a quadratic relationship between the volume fraction of the organic solvent and the logarithm of the capacity factor (log k'). The extrapolation to a pure aqueous phase reveals a linear relationship of the theoretical capacity factor log kw with the chain length. This holds for 1-12 carbon atoms in the alkoxy chain and for zero to three carbon atoms in the alkyl chain. Moreover, the incremental effect of the methylene residues on the lipophilicity of the compounds (delta log kw/delta CH2) is found to be 0.60 +/- 0.01. If the coumarin derivatives are used as substates for the liver microsomal monooxygenase system, no systematic dependence of the enzymic data (Michaelis-Menten constant Km) on the lipophilic data (log kw) can be demonstrated. The metabolism of these compounds by the microsomal monooxygenase system seems not to be limited by the partition between the membrane and the aqueous phase. Whether other factors, e.g. the lateral diffusion of the substrates versus the membrane-bound enzyme system or enzyme active-site characteristics, govern the metabolism remains to be investigated.     

三苯基丙烯腈衍生物的定量结构-活性关系研究

应用半经验量子化学AMl方法得到了24种三苯基丙烯腈衍生物的优势构象，利用AMl方法和分子图形学技术获得其电子结构、几何结构及拓扑结构参数，并将这些参数与三苯基丙烯腈衍生物对乳腺癌细胞(MCF-7)的生物活性相关联．结果表明，三苯基丙烯腈衍生物对MCF-7的活性与羟基指示数、分子表面积和B环上原子净电荷之和之间存在良好的多元线性相关性，成功地建立了三苯基丙烯腈衍生物的构效关系式．     

Quantitative structure-activity relationship studies using Gaussian processes.

A Gaussian process method (GPM) is described and applied to the production of some QSAR models. These models have the potential to solve a number of problems which arise in QSAR modeling in that no parameters have to be supplied and only one hyperparameter is used in finding the optimal solution. The application of the method to QSAR is illustrated using data sets of compounds active at the benzodiazepine and muscarinic receptors as well as the data set of the toxicity of substituted benzenes to the ciliate, Tetrahymena Pyriformis.     

Antioxidative and 5-lipoxygenase inhibiting activities of novel bis(4-hydroxy-2,3,5-trimethylphenoxy)alkyl derivatives

Novel bis(4-hydroxy-2,3,5-trimethylphenoxy)alkyl derivatives were synthesized and evaluations were made of their inhibiting action on Fe3+-ADP induced lipid peroxidation in rat liver microsome and reducing action on alpha,alpha-diphenyl-beta-picrilhydrazyl (DPPH), a stable radical, in addition to their inhibiting action on 5-lipoxygenase (5-LO), an enzyme that synthesizes leukotrienes. We performed a structure-activity correlation study on these derivatives. A strong Fe3+-ADP induced lipid peroxidation preventing activity was observed for the derivatives with an odd number of methylene groups including 1,3-bis(4-hydroxy-2,3,5-trimethylphenoxy)propane (3b) and 3a. No change in the DPPH reducing activity was found with change in the number of methylene groups. 5-LO inhibiting activity among the derivatives was the highest for 1,6-bis(4-hydroxy-2,3,5-trimethylphenoxy)hexane (3e). MM2 calculations were performed to find a stable steric structure for the derivatives, and 1,5-bis(4-hydroxy-2,3,5-trimethylphenoxy)pentane (3d) showed a strong activity in both antioxidative action and 5-LO inhibiting action.     

Quantitative structure-activity relationships of H1-antihistaminic benzimidazole derivatives

The quantitative structure-activity relationships (QSAR) of 2-(4-substituted-1-piperazinyl)benzimidazole derivatives for antihistaminic activity were examined. Taking into consideration the specific conformations of some derivatives, a significant correlation was obtained using Verloop's STERIMOL parameters B3 and L of the substituent at the 1-position of the benzimidazole nucleus. The results indicated that the derivatives having a substituent with a small breadth and an appropriate length at the 1-position showed potent activity. From the results, a model of the binding site is proposed. The QSAR of side effects (anticholinergic activity and central nervous system depressive effect) were also examined and the results showed that a sterically small substituent at the 1-position was required to decrease side effects.     

Synthesis of ureidomuraymycidine derivatives for structure-activity relationship studies of muraymycins

One of the key constituents of the muraymycins is the 6-membered cyclic guanidine, (2S,3S)-muraymycidine (or epi-capreomycidine). In order to diversify the structure of the oligopeptide moiety of the muraymycins for thorough structure-activity relationship studies, we have developed a highly stereoselective synthesis of ureidomuraymycidine derivatives with the lactone 4a.     

Synthesis and structure-activity relationship of rhodomyrtone derivatives as antibacterial agent

To study structure-activity relationship of rhodomyrtone against Gram-positive bacteria,structural modification of rhodo-myrtone was carried out to afford its 10 analogues.All compounds were assayed for their antibacterial potency using broth microdilution method.The results indicated that rhodomyrtone exhibited higher antibacterial activity against all Gram-positive bacteria than its analogues,with the exception of rhodomyrtone 6,8-diacetate(3) and oxime analogues 6 and 7 which demonstrated similar activity as the parent compound against Bacillus subtilis and Staphylococcus epidermidis with minimum inhibitory concentration and minimum bactericidal concentration ranged from 1 to 4μg/mL and 2 to 4μg/mL,respectively.In contrast,all analogues displayed no activity against Acinetobacter baumannii.Hydroxyl and ketone groups of rhodomyrtone were elucidated to be essential for the antibacterial property.     

PDK1的吲哚酮类抑制剂定量构效关系研究

3'磷酸肌醇依赖的激酶1(3'-phosphoinositide-dependent kinase1,PDK1)是--个63kDa的丝氨酸/苏氨酸(Ser/Thr)蛋白酶,它是Akt1的上游活化激酶~([1,2]).PDK1可在磷酸化的Akt1的Thr308位点使Akt1的活性增加30倍以上.但这种活化以依赖PIP3或PIP2的方式完成,PDK1也就因此而得名~([3]).     

石房蛤毒素(STX)衍生物的电子结构与毒性-结构关系研究

本文对十个石房蛤毒素(Saxitoxin,STX)衍生物进行了量子化学(INDO)计算,得到了多种电子结构信息。据此研究了它们的电子结构特征,确定了它们的活性部位。通过构效关系研究,发现某些电子结构指数与毒性之间存在较好的相关关系。这些结果为讨论该类化合物的作用机理、与受体之间的相互作用及进一步的分子设计提供了有价值的信息。     

姜黄素衍生物与类似物的构效关系研究进展

根据目前对姜黄素衍生物与类似物的结构与药理作用的关系的研究现状,论述了姜黄素衍生物与类似物的结构与其抗氧化、抗炎和抗肿瘤的药理作用的关系,包括对姜黄素及其衍生物与类似物的结构修饰与其活性之间的关系的论述。大量的实验结果显示姜黄素衍生物与类似物的药理作用与其结构中所具有的官能团有着密切的关系,这为新药开发提供了一个很好的方向。