Exploration of trans‐2‐(azaarylsulfanyl)‐cyclohexanols as potential pH‐triggered conformational switches

Abstract

A series of trans‐2‐(azaarylsulfanyl)‐cyclohexanols, structurally similar to previously studied trans‐2‐aminocylohexanols, have been synthesized and explored as conformational pH triggers. 1H NMR spectroscopy was used to estimate the position of the chair‐chair conformational equilibrium and its acid‐induced shift towards the conformer with the azaarylsulfanyl and hydroxy groups in equatorial positions due to an intramolecular hydrogen bond and electrostatic interactions. Such acid‐induced transition may be used to control the geometry‐dependent molecular properties. The 1H NMR titration curves were used for estimation of the pKa values of protonated compounds that varied from 2.8 to 4.3 (in d4‐methanol) depending on the structure of the azaarylsulfanyl group.

Ring-System-Based Conformational Switches and their Applications in Sensing and Liposomal Drug Delivery

“…The recent study found that novel conformational switches, i.e., trans-2-(azaarylsulfanyl)cyclohexanols, can trigger the ring flip in a relatively low pH range (2.8 to 4.3). 45 Apart from changing the pH sensitivity, the higher polarity or larger size of the lipid head-group tends to decrease the size of the liposomes, while higher basicity of the head-group causes release of the liposomes to be triggered at higher pH values. 41 Moreover, longer lipid tails yield liposomes with higher encapsulation capacity, while shorter lipid tails lead to a faster leakage of the liposome in response to lowered pH.…”