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Design and Synthesis of Phosphate Specific Transmembrane Transporters

par Norvaisa, Karolis ;Cataldo, Alessio ;Halgreen, Lau ;Bodman, Samantha E.;Bartik, Kristin ;Butler, Stephen J.;Valkenier, Hennie
Référence International Symposium on Macrocyclic and Supramolecular Chemistry 2023
Publication Publié, 2023-06-25

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Résumé :

To date, no efficient carriers have been reported that can capture the size and geometry of phosphates and transport them through the lipid bilayer. Achieving selectivity for oxyanions over more simple spherical anions (e.g. chlorides, fluorides) is yet a challenging task. Because of the strong hydration (which makes extraction from the aqueous phase into the apolar interior of the lipid bilayer more difficult), the speciation of organic phosphates (RHPO4 and RPO42), and multiple negative charges of organic polyphosphates (e.g. triphosphate RH2P3O102−, RHP3O103−) extraction and transport of phosphorylated compounds are particularly difficult.The key to transporting and extracting such highly hydrated anions is the formation of multiple H-bonds to the anion. With the rapid expansion of the synthetic transmembrane transporters field over the past few decades, “strapped” calix[4]pyrroles as developed by the Sessler and Gale laboratories have emerged as carrier systems with excellent transmembrane transport properties. The presence of additional cooperative binding sites on the straps in strapped calix[4]pyrroles enhances preorganization and substrate affinity, resulting in what may be termed a "strap effect".We envisage that by controlling the rigidity of the multiple H-bond donor strap component, we will be able to construct phosphate-specific supramolecular structures based on calix[4]pyrroles. Thus, here we introduce a “semi-rigid” design that consists of two separate ion binding sites fixed at the desirable distance for more favourable binding towards oxoanions (such as phosphate) over the monoatomic anions (like chloride). We have synthesized semi-rigid strap system 1 enabling cooperative binding events for selective phosphate binding. Volume-specific sites with multivalent interactions in 1 allowed the extraction of strongly hydrated H2PO4- into the lipid bilayer while shielding its charges from the lipophilic bilayer interior and transferring them through the membrane.