Equipe de Chimie Bio-Organique, COBRA-CNRS UMR 6014 & FR 3038, rue Tesnière, 76130 Mont-Saint-Aignan, France.
Chemistry. 2010 Mar 15;16(11):3510-23. doi: 10.1002/chem.200902986.
A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.
一种新的针对高通量筛选分析（HTS）的荧光探针，旨在选择性和有效地切割有机磷神经毒剂的 P-S 键，并通过这种方式提供无毒的膦酸，已经被设计和合成。之前描述的荧光探针是基于传统的 P-O 键的活化断裂，而我们的方法则使用自耗性连接子策略，允许对非活化的 P-S 键的膦酸酯酶活性进行检测。此外，我们还开发并优化了一种高通量筛选测定法，用于选择能够有效水解高度毒性 V 型神经毒剂的解毒剂（化学或生化清除剂）。在一个小型的α-亲核试剂库上进行的初步筛选，使我们能够识别出一些初步的“命中”化合物，其中吡啶醛肟、α-氧代肟、羟肟酸，以及活性较低但更具创新性的偕胺肟，是最有前途的。通过使用 PhX 作为底物，进一步证实了它们对磷酰硫酯酶的选择性，这为合成更有效的 V 型神经毒剂清除剂提供了新的前景。
