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首页> 外文期刊>Ukrainian Biochemical Journal >Calixarene methylene bisphosphonic acids as promising effectors of biochemical processes
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Calixarene methylene bisphosphonic acids as promising effectors of biochemical processes

机译：杯芳烃亚甲基双膦酸作为生化过程的有前途的效应器

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This interdisciplinary study, performed with participation of research workers of Palladin Institute of Biochemistry and Institute of Organic Chemistry of NAS of Ukraine, is devoted to analysis of biochemical effects of some calixarene methylene bisphosphonic acids (cyclic phenol oligomers) on two well-known biological phenomenons – Mgsup2+/sup-dependent ATP hydrolysis (myosin subfragment-1 of myometrium smooth muscle was used as an example) and fibrin polymerization. Calix[4]arene С-97 (calix[4]arene methylene bisphosphonic acids) is a macrocyclic substance, which contains intramolecular highly ordered lipophilic cavity formed by four aromatic rings, one of which is functionalized at the upper rim with methylene bisphosphonic group. At concentration of 100 μM, this substance was shown to effectively inhibit ATPase activity of pig myometrium myosin subfragment-1 (inhibition coefficient ?sub0.5/sub = 83 ± 7 μM). At the same time, this calix[4]arene causes significant (vs. control) increase of myosin subfragment-1 hydrodynamic diameter, which may indicate formation of an intermolecular complex between calixarene and myosin head. Computer simulation methods (docking and molecular dynamics with addition of grid technologies) enabled to elucidate the grounds of intermolecular interactions between calix[4]arene С-97 and myometrium myosin subfragment-1, that involve hydrophobic, electrostatic and π-π-stacking interactions, some of which are close to the ATPase active centre. In view of the ability of calixarenes to penetrate into the cell and their low toxicity, the results obtained may be used as a basis for further development of a new generation of supramolecular effectors (starting from the above mentioned substances, in particular calix[4]arene С-97) for regulation of smooth muscle contractile activity at the level of ATP dependent actin-myosin interaction. Calix[4]arenes bearing two or four methylenebisphosphonic acid groups at the macrocyclic upper rim have been studied with respect to their effects on fibrin polymerization. The most potent inhibitor proved to be calix[4]arene tetrakis-methylene-bis-phosphonic acid (C-192), in which case the maximum rate of fibrin polymerization in the fibrinogen + thrombin reaction decreased by 50% at concentrations of 0.52·10sup-6/sup M (ICsub50/sub). At this concentration, the molar ratio of the compound to fibrinogen was 1.7 : 1. For the case of desAB fibrin polymerization, the ICsub50/sub was 1.26·10sup-6/sup M at a molar ratio of C-192 to fibrin monomer of 4 : 1. Dipropoxycalix[4]-arene bis-methylene-bis-phosphonic acid (C-98) inhibited fibrin desAB polymerization with an ICsub50/sub = 1.31·10sup-4/sup M. We hypothesized that C-192 blocks fibrin formation by combining with polymerization site ‘A’ (Aa17–19), which ordinarily initiates protofibril formation in a ‘knob-hole’ manner. This suggestion was confirmed by an HPLC assay, which showed a host–guest inclusion complex of C-192 with the synthetic peptide Gly-Pro-Arg-Pro, an analogue of site ‘A’. Further confirmation that the inhibitor was acting at the initial step of the reaction was obtained by electron microscopy, with no evidence of protofibril formation being evident. Calixarene C-192 also doubled both the prothrombin time and the activated partial thromboplastin time in normal human blood plasma at concentrations of 7.13·10sup-5/sup and 1.10·10sup-5/sup M, respectively. These experiments demonstrate that C-192 is a specific inhibitor of fibrin polymerization and blood coagulation and can be used for the design of a new class of antithrombotic agents.
机译：这项跨学科研究由Palladin生物化学研究所和乌克兰NAS的有机化学研究所的研究人员共同完成，致力于分析某些杯芳烃亚甲基双膦酸（环状酚低聚物）对两种众所周知的生物现象的生化作用。 – Mg 2 + 依赖的ATP水解（以肌层平滑肌的肌球蛋白亚片段1为例）和血纤蛋白聚合。杯[4]芳烃С-97（杯[4]芳烃亚甲基双膦酸）是一种大环物质，其包含由四个芳环形成的分子内高度有序的亲脂性腔，其中一个在上边缘被亚甲基双膦基官能化。在浓度为100μM时，该物质可有效抑制猪肌层肌球蛋白亚片段1的ATPase活性（抑制系数α 0.5 = 83±7μM）。同时，此杯[4]芳烃导致肌球蛋白亚片段1流体动力学直径显着（相对于对照）增加，这可能表明杯芳烃和肌球蛋白头之间形成了分子间复合物。计算机模拟方法（对接和分子动力学以及网格技术的加入）能够阐明杯[4]芳烃С-97和肌层肌球蛋白亚片段1之间的分子间相互作用的基础，其中涉及疏水，静电和π-π堆积相互作用，其中一些靠近ATPase活性中心。考虑到杯芳烃的渗透能力和低毒性，所得结果可作为进一步开发新一代超分子效应子的基础（从上述物质，特别是杯[4]开始）芳烃С-97）用于调节ATP依赖性肌动蛋白-肌球蛋白相互作用水平的平滑肌收缩活性。已经研究了在大环上边缘带有两个或四个亚甲基双膦酸基团的杯[4]芳烃对它们对纤维蛋白聚合的影响。事实证明，最有效的抑制剂是杯[4]亚芳基四烷基-亚甲基-双膦酸（C-192），在这种情况下，浓度为0.52·时，血纤蛋白原+凝血酶反应中血纤蛋白的最大聚合速率降低了50％。 10 -6 M（IC 50 ）。在此浓度下，化合物与纤维蛋白原的摩尔比为1.7：1。对于desAB纤维蛋白聚合，IC 50 在1.26·10 -6 M C-192与血纤蛋白单体的摩尔比为4：1。双丙氧基杯[4]-芳烃双亚甲基双膦酸（C-98）抑制血纤蛋白desAB聚合，IC 50 = 1.31·10 -4 M。我们假设C-192通过与聚合位点“ A”（Aa17-19）结合阻止纤维蛋白的形成，聚合位点通常以“旋钮孔”方式引发原纤维的形成。 HPLC分析证实了这一建议，该分析显示了C-192与合成肽Gly-Pro-Arg-Pro（'A'位点的类似物）的客体-客体包涵体。通过电子显微镜进一步证实了抑制剂在反应的初始阶段起作用，没有明显的原纤维形成的迹象。在正常人血浆中浓度为7.13·10 -5 和1.10·10 -5 M的情况下，杯芳烃C-192的凝血酶原时间和活化的部分凝血活酶时间也翻倍。 ， 分别。这些实验证明，C-192是纤维蛋白聚合和凝血的特异性抑制剂，可用于设计新型抗血栓药。

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