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2.B.85.  The Synthetic Sulfonamide NH-containing Compound Ion Transporter (SSNH-IT) Family 

Shinde and Talukdar 2018 synthesized HCl cotransporters containing an acidic sulfonamide NH group (compounds 30a–30g shown in the figure below. A variety of assays including pH dissipation assays using HPTS encapsulated within vesicles were used to elucidate the transport mechanism facilitated by these systems (Davis et al. 2020). These compounds function by transporting chloride across a lipid bilayer and then decomplex and deprotonate, allowing the anionic form of the deprotonated sulfonamide to diffuse back across the membrane to bind another equivalent of HCl. The anion transport activity of the series was found to be 30d > 30b > 30e > 30f > 30c > 30a > 30g (see below).

Anion transporters 30a–g containing an acidic sulfonamide group.

Roy et al. 2017 studied related compounds. The sulfonamide-based pH switchable transporters 18 show an inversion of selectivity with pH. The transporters with pKa values in the range of 6.8–7.39 exist in their anionic form at pH 7. Based on the crystal structures of 18c and 18e, an intramolecular NH⋯O bond is proposed between two sulfonamide groups. Compounds 18a–e at pH 7.0 show chloride transport with EC50 values of 40, 43, 14, 211 and 10 μM, respectively. The highest transport rate was observed for 18e with the CF3 substituent. The compound showed ion selectivity with the trend Cl > F ≈ Br ≈ I for anions, and K+ > Rb+ ≈ Cs+ > Na+ > Li+ for cations. At a pH of 7 and below, compound 18e is selective for anions. The selectivity switches towards cations at pH 8 (Fig. 19).

Enhanced cation selectivity of sulfonamide transporters 18a–e due to deprotonation of sulfonamide.

As noted above, Shinde and Talukdar 2019 have reported the sulfonamide-based chloride receptor 19 (see figure below) The sulfonamide-NH receptors 19 can be deprotonated under physiological conditions as their pKa ranges from 7.28 to 7.44. The molecule 19b with a CH3 substitutent on the aromatic ring has an EC50 value of 2.33 μM and operates via a H+/Cl symport mechanism. The ability of the transporters to accomplish intracellular acidification has been applied to cancer therapy.

Sulfonamide receptor 19 undergoes deprotonation to show H+/Cl co-transport.

References associated with 2.B.85 family:

Davis, J.T., P.A. Gale, and R. Quesada. (2020). Advances in anion transport and supramolecular medicinal chemistry. Chem Soc Rev. [Epub: Ahead of Print] 32692794
Roy, A., O. Biswas, and P. Talukdar. (2017). Bis(sulfonamide) transmembrane carriers allow pH-gated inversion of ion selectivity. Chem Commun (Camb) 53: 3122-3125. 28245016
Shinde, S.V. and P. Talukdar. (2019). Transmembrane H/Cl cotransport activity of bis(amido)imidazole receptors. Org Biomol Chem 17: 4483-4490. 30984952
Shinde, S.V., and P. Talukdar,. (2018). An anion receptor that facilitates transmembrane proton-anion symport by deprotonating its sulfonamide N-H proton. Chem Commun (Camb) 54: 10351-10354. 30151528