trans-2-Aminocyclohexanol as a pH-sensitive conformational switch in lipid amphiphiles

Abstract

Protonation-induced conformational change of lipid tails is reported as a novel strategy to render pH-sensitive lipid amphiphiles and lipid colloids.

trans-2-Aminocyclohexanol-based amphiphiles as highly efficient helper lipids for gene delivery by lipoplexes

“…The spin-spin coupling constants between several pairs of vicinal protons attached to the cyclohexane moiety are strongly conformationdependent, which allowed the assignment of a predominant conformation and the estimation of a position of the conformational equilibrium as described previously [21][22][23][24]31,32]. To characterize the pH-induced change of conformational equilibrium, a TACH-lipid was dissolved in CD 3 OD (0.02-0.03 M), and the changes of its 1 H NMR spectrum (600 MHz) were monitored during titration of the solution with d-trifluoroacetic acid (d-TFA) and with a base: 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU).…”

“…The amphiphiles 1-3, 6, and 9, and the corresponding intermediates were prepared as described earlier [21][22][23][24]. Other TACH-lipids ( Fig.…”

“…This impulse is mechanically transmitted via the conformational flip of the cyclohexane ring to force both ester groups into axial positions (BH + on Scheme 1), thereby drastically increasing the spatial separation of the lipid tails and perturbing the bilayer structure. After incorporation into liposome membranes, TACH-lipids significantly enhanced the release from both the traditional liposomes based on phospholipids and the sterically hindered liposomes containing mPEG2000-ceramide (PEG-ceramide) upon exposure to lowered pH [21][22][23][24]. To highlight the key role of the conformational flip in the pHtriggered liposome leakage, we introduced the terms "flipids" for the amphiphiles containing a pH-sensitive conformational switch and "fliposomes" for the liposomes comprising these amphiphiles [22][23][24].…”

“…We recently designed a novel type of amphiphiles based on trans-2-aminocyclohexanol (TACH) and introduced these TACH-lipids as a pHsensitive conformational switch of liposome bilayer [21][22][23][24] (Scheme 1). In the original conformational equilibrium A ⇆ B (Scheme 1), the amine and the hydroxy groups of TACH-lipid are predominantly in axial positions while both lipidic trans-ester groups adopt equatorial positions (A).…”

“…1). The analogous amphiphiles 9 [21,22] and 10 ( Fig. 1) were also synthesized as controls that do not perform pH-triggered conformational switch.…”