Bušić Valentina, Katalinić Maja, Šinko Goran, Kovarik Zrinka, Gašo-Sokač Dajana
Josip Juraj Strossmayer University of Osijek, Faculty of Food Technology, Kuhačeva 20, HR-31000 Osijek, Croatia.
Institute for Medical Research and Occupational Health, Ksaverska c. 2, HR-10001 Zagreb, Croatia.
Toxicol Lett. 2016 Nov 16;262:114-122. doi: 10.1016/j.toxlet.2016.09.015. Epub 2016 Sep 29.
Organophosphorus (OP) nerve agents (sarin, tabun VX and soman) inhibit the enzyme acetylcholinesterase (AChE, EC 3.1.1.7) by binding to its active site while preventing neurotransmission in the cholinergic synapses. The protection and treatment of this kind of poisoning are still a challenge as we are yet to discover an antidote that would be effective in all cases of poisoning. To aid the search for more efficient antidotes, we evaluated the ability of nine pyridoxal oxime derivatives, prepared by a novel synthetic pathway, to reactivate recombinant human AChE and the related purified human plasma butyrylcholinesterase (BChE, EC 3.1.1.8) inhibited by VX, tabun and paraoxon. Oximes are derivatives of vitamin B6 bearing a phenacyl moiety attached to the quaternary nitrogen atom and having various substituents on the phenyl ring. As the results have shown, the tested oximes were in general more efficient in the reactivation of OP-inhibited BChE than AChE. The highest observed rate was in the case of VX-inhibited BChE reactivation, where k was 0.0087min and the reactivation maximum of 90% was achieved within 5h. The cholinesterases displayed a binding affinity for these derivatives in a μmolar range no matter the substituent on their rings which was in accordance with the molecular modelling results showing a similar binding pattern for all oximes within the active site of both AChE and BChE. Such a positioning reveals also that hydroxy and a metoxy substituents at the vicinity of the oxime moiety present a possible steric hindrance explaining the reactivation results.
有机磷（OP）神经毒剂（沙林、塔崩、VX和梭曼）通过与乙酰胆碱酯酶（AChE，EC 3.1.1.7）的活性位点结合来抑制该酶，同时阻止胆碱能突触中的神经传递。这类中毒的防护和治疗仍然是一个挑战，因为我们尚未发现一种能在所有中毒情况下都有效的解毒剂。为了有助于寻找更有效的解毒剂，我们评估了通过一种新型合成途径制备的九种吡哆醛肟衍生物对重组人AChE以及被VX、塔崩和对氧磷抑制的相关纯化人血浆丁酰胆碱酯酶（BChE，EC 3.1.1.8）的重新激活能力。肟是维生素B6的衍生物，在季氮原子上带有一个苯甲酰基部分，并且在苯环上有各种取代基。结果表明，所测试的肟一般在重新激活被OP抑制的BChE方面比AChE更有效。观察到的最高速率出现在VX抑制的BChE重新激活的情况下，其中k为0.0087min，并且在5小时内实现了90%的最大重新激活率。无论这些衍生物环上的取代基如何，胆碱酯酶对它们都表现出微摩尔范围内的结合亲和力，这与分子模拟结果一致，该结果显示所有肟在AChE和BChE活性位点内的结合模式相似。这样的定位还表明，肟部分附近的羟基和甲氧基取代基可能存在空间位阻，这解释了重新激活的结果。
