Benzyl Mono-P-Fluorophosphonate and Benzyl Penta-P-Fluorophosphate Anions Are Physiologically Stable Phosphotyrosine Mimetics and Inhibitors of Protein Tyrosine Phosphatases.
Benzyl Mono-P-Fluorophosphonate and Benzyl Penta-P-Fluorophosphate Anions Are Physiologically Stable Phosphotyrosine Mimetics and Inhibitors of Protein Tyrosine Phosphatases.
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DOI：
10.1002/chem.201701204
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发表时间：
2017-11
期刊：
影响因子：
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通讯作者：
Stefan Wagner;Matteo Accorsi;J. Rademann
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文献类型：
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作者：
Stefan Wagner;Matteo Accorsi;J. Rademann
α，α-二氟苄基膦酸盐是目前最流行的一类磷酸酪氨酸模拟物。它们在结构上来源于天然底物磷酸酪氨酸，构成了经典的生物同位体，并使蛋白酪氨酸磷酸酶（PTP）和磷酸酪氨酸识别位点（如SH2结构域）的有效抑制剂得以开发。然而，作为带两个负电荷的钠离子，膦酸盐不能穿透膜，因此在细胞中通常是无活性的，并且尚未成为治疗方法的成功起点。在这项工作中，通过用磷结合的氟原子取代磷结合的氧原子来修饰膦酸苄酯。令人惊讶的是，单p -氟膦酸盐在生理条件下是完全稳定的，从而可以研究它们对PTP的作用方式。测试了三种替代方案，并确定了单p -氟膦酸盐是稳定的可逆PTP1B抑制剂，尽管失去了一个负电荷，并且氟取代了一个氧原子作为氢键供体。为了扩展这一替代策略，合成了α，α-二氟苯基五对氟磷酸盐，并发现它们是一种新型的磷酸酪氨酸模拟物，对PTP1B的磷酸酪氨酸结合位点具有更好的亲和力。
α,α-Difluoro-benzyl phosphonates are currently the most popular class of phosphotyrosine mimetics. Structurally derived from the natural substrate phosphotyrosine, they constitute classical bioisosteres and have enabled the development of potent inhibitors of protein tyrosine phosphatases (PTP) and phosphotyrosine recognition sites such as SH2 domains. Being dianions bearing two negative charges, phosphonates, however, do not permeate membranes and thus are often inactive in cells and have not been a successful starting point toward therapeutics, yet. In this work, benzyl phosphonates were modified by replacing phosphorus-bound oxygen atoms with phosphorus-bound fluorine atoms. Surprisingly, mono-P-fluorophosphonates were fully stable under physiological conditions, thus enabling the investigation of their mode of action toward PTP. Three alternative scenarios were tested and mono-P-fluorophosphonates were identified as stable reversible PTP1B inhibitors, despite of the loss of one negative charge and the replacement of one oxygen atom as an H-bond donor by fluorine. In extending this replacement strategy, α,α-difluorobenzyl penta-P-fluorophosphates were synthesized and found to be novel phosphotyrosine mimetics with improved affinity to the phosphotyrosine binding site of PTP1B.