Fluorinated synthetic anion carriers: experimental and computational insights into transmembrane chloride transport

Abstract

A series of fluorinated tripodal tris-thioureas function as highly active anion transporters across lipid bilayers and cell membranes.

Development of a Library of Thiophene‐Based Drug‐Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity

“…As illustrated in Figure , irrespective of the starting scenario, with the counting of hydrogen bonds between 15 and Cl − , phosphate head groups, sn‐ 1 and sn‐ 2 ester groups, and water molecules as a function of the position of the transporter along the bilayer normal ( z ‐axis), the N−H⋅⋅⋅Cl − interactions are mainly replaced by hydrogen‐bonding interactions with the phosphate head groups (see Figures S130–S135 for other MD runs). The high affinity of our small molecules for these hydrogen‐bond acceptors (see below) might play an important role in their ability to promote transmembrane chloride transport, given that the anion uptake necessarily occurs at the water/lipid interface level, as we have previously demonstrated …”

“…In the course of this energetic and structural analysis, only the computed binding arrangements with thiophene and benzo[ b ]thiophene derivatives adopting conformation A will be used to rationalize their binding and transport properties. Following our previous work with thiourea‐ and squaramide‐based transporters, the maximum of the electrostatic potential surface ( V S,max ) is again taken as a binding descriptor. The V S,max of 1 – 17 is located in the binding region confined by the urea binding units, as illustrated in red in Figure for 4 , 15 , and 17 and in Figures S6 and S7 for the remaining thiophene and benzo[ b ]thiophene derivatives.…”

“…Molecule used to rationalize their binding and transport properties. Following our previous work with thiourea- [27] and squaramidebased [16b, 28] transporters, the maximum of the electrostatic potential surface( V S,max )i sa gain taken as ab inding descriptor. The V S,max of 1-17 is located in the binding region confined by the urea binding units, as illustrated in red in Figure 3f Table 1) indicate that fluorination of the central phenyls pacer, either with two electron-withdrawingf luoro substituents or with at rifluoromethyl substituent, leads to an increaseo fa round8 .6 kcal mol À1 .O nt he other hand, peripheralf luorination of the a-benzo[b]thiophene derivatives 8 and 9,w ith the appendage of a trifluoromethylg roup at the phenyl-fusedr ing at positions C 9 and C 9' (12 and 13)i ncreased V S,max by about 3.1 kcal mol À1 ,b ut attachment at the C 10 and C 10' positions (10 and 11)a fforded a greater gain of about 8.…”

“…The high affinity of our smallm olecules for these hydrogen-bond acceptors( see below)m ight play an important role in their ability to promote transmembrane chloride transport, given that the anion uptake necessarily occurs at the water/lipid interfacel evel, as we have previously demonstrated. [27,28] The counting of NÀH···Cl À hydrogen bonds throughout the MD runs carriedo ut in scenario L indicates that 3, 4, 8, 9, 14, 16,a nd 17 typically release the anion within the first 50 ns of simulation. In contrast, in one of the initial MDr uns with 15, dissociation of the complex occurs almost at the end of the MD simulation (ca.…”

Enzyme-catalyzed C–F bond formation and cleavage

“…Incorporation of fluorine into organic compounds usually endows organofluorines with unique chemical and physical properties, a strategy that has been successfully applied in agrochemicals, materials science, and pharmaceutical chemistry (Phelps 2004;Müller et al 2007;Shah and Westwell 2007;Hagmann 2008;Nenajdenko et al 2015;Zhang et al 2016;Lowe et al 2017). Especially in medicinal chemistry, the unique elemental properties of fluorine have been proved to enhance metabolic stability and alter pharmacokinetic characteristics without increasing the apparent spatial volume; thus, more than 20% of drugs are organofluorines (Zhou et al 2016;Gillis et al 2015;Spooner et al 2019). The wide application of organofluorines has motivated fast methodology development for fluorine incorporation (Purser et al 2008;Berger et al 2011).…”