2.B.107.  The Sqaramide Derivative Porter (SDP) Family 

Thiosquaramide derivatives 21a–d that have pKa values in the range of ∼5.3–8.0 reported by the Jolliffe and Gale group transport chloride ions at pH 4 (see fig below) (Busschaert et al. 2014). Thiosquaramides are not planar structures like oxosquaramides, and they show a twist between the aromatic ring and the cyclobutene ring with torsional angles of 26–32° and 32–42° for 21a·DMSO and 21d·DMSO, respectively. The twisted conformation prevents the additional hydrogen bonding of aromatic C–H units. The acidity and lipophilicity of thiourea –NH are higher than those of –NH of urea, making them better anion transporters than squaramides. Anion transport studies showed that 21a and 21b are chloride carriers and are more efficient than 21c and 21d. Their activities are markedly increased at pH 4.0. The decrease in activity at pH 7.2 is due to partial deprotonation of the molecules (Fig. 22b). Mechanistic studies show that Cl is mainly transported via a Cl/NO3 antiport mechanism, but it can be switched to H+/Cl symport by applying a suitable pH gradient across the lipid bilayer. Similarly, for oxothiosquaramide 22 with a pKa of 6.6, chloride efflux is increased when the pH is switched from 7.2 to 4.0.28


(a) Thiosquaramide-based chloride ion transporters 21a–d and oxothiosquaramide 22. (b) pH-dependent ion transport by thiosquaramide.

 Wang et al. 2021 demonstrated the effect of various functional groups on the pH-dependent ion transport of squaramido-tethered bis-benzimidazole (see figure below). Ion transport studies at pH 7.0 show that 28 is the most efficient transporter in the series. The effect of pH on chloride transport was studied using a chloride-selective electrode. The highest pH switch was observed for transporters 31 and 30 (∼32 and ∼17 fold increase, respectively). Interestingly, 25 with an electron-releasing substituent also showed higher activity (∼9 fold) at pH 4.0. The observed changes corroborate the electron-withdrawing/releasing ability of the substituents. Derivative 36 exhibited a negligible rate of anion transport, indicating that both arms need to be functionalized for ion transport.


Squaramide-attached benzimidazole 23–36 chloride transporters.

 

References:

Busschaert, N., R.B. Elmes, D.D. Czech, X. Wu, I.L. Kirby, E.M. Peck, K.D. Hendzel, S.K. Shaw, B. Chan, B.D. Smith, K.A. Jolliffe, and P.A. Gale. (2014). Thiosquaramides: pH switchable anion transporters. Chem Sci 5: 3617-3626.

Wang, Z.K., X.Q. Hong, J. Hu, Y.Y. Xing, and W.H. Chen. (2021). Synthesis and biological activity of squaramido-tethered bisbenzimidazoles as synthetic anion transporters. RSC Adv 11: 3972-3980.