2.B.65.  The Pitenin-mediated Chloride/Proton Transport (Pitenin) Family 

The anticancer agents, PITENINs, have an efficient transmembrane Cl- ion transport activity, and each of them strongly binds a Cl- ion.  In addition to their lipophilicity, the presence of both acylthiourea and phenolic OH moieties of the compounds plays a crucial role in the transport of Cl- ions. Among the tested compounds, PIT-1 and DM-PIT-1 showed higher Cl- ion selectivity and transport efficiency. Mechanistic studies demonstrated that the potent compounds follow the H+/Cl- transport pathway. Cellular activity studies showed that disruption of Cl- ion homeostasis by PIT-1 or DM-PIT-1 preferentially promotes apoptotic cell death (Biswas et al. 2020).

PITENINs 38a and 39b show weak chloride binding with binding constants of 21.8 ± 1.7 M−1 and 23.4 ± 3.7 M−1, respectively. PITENINs interact with chloride ions via thiourea-N–H and phenolic O–H. At pH 7.0, 38a, 38b and 39b are better chloride transporters than other PITENINs. Compound 39b shows EC50 values of 0.65 and 0.031 μM at pH 7.0 and 5.5, respectively. PITENIN 38a does not show an increase in chloride transport at pH 5.5. The pH sensitivity of 39b is attributed to the pKa (6.43) of its phenolic OH (Fig. 24b). Compound 38a does not show remarkable pH dependence because the pKa of its phenolic group is 5.02.

 

(a) Anticancer agents PITENINs 37–39. (b) Decrease in chloride transport of PITENINs at pH 7.2 due to the phenoxide ion.

 

References:

Biswas, O., N. Akhtar, Y. Vashi, A. Saha, V. Kumar, S. Pal, S. Kumar, and D. Manna. (2020). Chloride Ion Transport by PITENINs across the Phospholipid Bilayers of Vesicles and Cells. ACS Appl Bio Mater 3: 935-944.