Trans-2-aminocyclohexanols as pH-triggered molecular switches

Abstract

Cyclohexane-based conformationally controlled ionophores, the emerging new class of molecular switches, provide a new and promising approach to allosteric systems with negative cooperativity. Protonation of trans-2-aminocyclohexanols leads to dramatic conformational changes: due to an intramolecular hydrogen bond, a conformer with equatorial position of ammonio-and hydroxy-groups becomes predominant. Thus, these structures can serve as powerful conformational pH-triggers. The trans-2-aminocyclohexanol moiety has been used for pH-triggered conformational switching of a crown ether and a podand, and their complexes with potassium ion.

Fliposomes: pH-controlled Release from Liposomes Containing New trans-2-Morpholinocyclohexanol-based Amphiphiles that Perform a Conformational Flip and Trigger an Instant Cargo Release upon Acidification

“…Thus, the elongation and branching of the hydrocarbon chains did not produce any conformational effects in the polar heads of these structures. In accordance with the previous observations for various trans-2-morpholinocyclohexanols [13,14,[23][24][25][26], the molecules of 1-3 strongly prefer the conformation B (Scheme 3) in a nonpolar solvent (CDCl 3 ) thanks to the stabilizing intramolecular hydrogen bond OH…N. The hydrogen bonds of this type were found to be strong enough to convert a chair ring into a twist-boat conformation in aminohydroxy steroids [29,30].…”

“…[B + BH + ] (Scheme 3) were calculated as described before for (amino)cyclohexanol derivatives [13,14,[22][23][24][25][26][27] from an averaged signal width (W = ΣJ HH ) measured as the distance between terminal peaks of a multiplet in the 1 H NMR spectrum: W observed = W A •n A + W B •n B [28] (Table 1). We used mainly the signal of H4 (geminal to the hydroxy group, Scheme 3), which was usually better resolved and located in a region apart from other signals.…”

“…We used mainly the signal of H4 (geminal to the hydroxy group, Scheme 3), which was usually better resolved and located in a region apart from other signals. The limiting parameter W B was assumed to equal W BH+ , that is the value observed in the presence of excess acid (ΣJ HH = 25.6 Hz for 1, 25.5 Hz for 2, and 25.3 Hz for 3; Table 1), and the parameter W A was estimated as 9.0 Hz from reported data [13,[22][23][24][25][26][27] for the related conformationally biased (amino)cyclohexanols. The estimated share of the conformer A (n A ) includes both the nonprotonated form A and the protonated form A•H + (the latter being apparently the minor one due to conversion into B•H + ).…”

Toward Engineering Intra-Receptor Interactions into Bis(crown ethers)

“…NMR spectroscopy did not allow determination of the ratio of meso-2 and rac-2 in the product mixture thus obtained because both diastereoisomers give rise to indistinguishable NMR spectra, even in the presence of salts such as KBr whose cation can bind to these bis(crown ethers) [15]. HPLC, on the other hand, allowed determination of the diastereomeric ratio provided that the mobile phase contains KBr [see ESI].…”

Systems for the delivery of chemotherapeutic drugs, new approaches and perspective

“…For the preparation of pH-sensitive liposomes [3,11,[75][76][77], some researchers have used a polyacrylic acid, polyethylene glycol-ortho ester-distearoyl glycerol conjugate (POD), trans-2-aminocyclohexanols [78], N-hemisuccinate-dioleoyl-phosphatidylethanolamine [79]. Nancy L. Bomane et al [80] in the research with large unilamellar vesicle (LUV) showed that increasing the (saturated) the length of the acyl chain of phosphatidylcholine molecule increased the internal buffer capacity and made lower internal pH; all these lead to increased drugs retention time (VCR).…”