Benzyl Mono-P-Fluorophosphonate and Benzyl Penta-P-Fluorophosphate Anions Are Physiologically Stable Phosphotyrosine Mimetics and Inhibitors of Protein Tyrosine Phosphatases

4 years ago

Benzyl Mono-P-Fluorophosphonate and Benzyl Penta-P-Fluorophosphate Anions Are Physiologically Stable Phosphotyrosine Mimetics and Inhibitors of Protein Tyrosine Phosphatases

Stefan Wagner, Jörg Rademann, Matteo Accorsi

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. Through decades, phosphonates like 3 have constituted classical inhibitors of protein tyrosine phosphatases mimicking the favorable interactions of phenyl phosphate substrates while being non-hydrolyzable. Despite their popularity, phosphonates were not developed as drugs, yet, mainly due to severe issues in cell penetration. Here, modifications of this traditional class of inhibitors are presented by substituting P-bonded oxygen atoms with one (6) or five fluorine atoms (13).

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701204