Terephthyl-linked acyl hydrazone-based K⁺/Cl^- ion pair symporter: synthesis, mechanistic insights, and in vitro...

Cellular membranes rely on the precise transport of vital ions to regulate various physiological processes. Developing synthetic ion transporters offers a promising solution to overcome the dysfunction of natural transport phenomena. Moreover, this innovative approach may also unlock new avenues for cancer treatment, providing a groundbreaking opportunity to tackle this devastating disease. Hence, in this present work, we have synthesized a series of acyl hydrazone-based ion pair symporters L_a-L_c. The ¹H NMR titration study confirms the binding with of K⁺ and Cl^- to the sympoters. The ion transport experiments across the lipid bilayer membrane (both EYPC-LUVs⊃HPTS and EYPC-LUVs⊃Lucigenin) demonstrate that L_c exhibits the highest transport activity among the other congeners. From the Hill analysis, the EC50 value (7.26 μM), and the Hill coefficient value (n = 2) indicate the formation of a noncovalent dimer of the L_c as an active structure responsible for the ion transport activity. The detailed transport study unveils that Lc transports K⁺Cl^- ion pair via symport mechanism. The SCXRD analysis reveals the linear and planner geometry of the transporters. Whereas the DFT calculation study discloses the fact that during the ion-pair binding, the transporter molecule forms a self-assembled helical structure with a dimer formation. Ultimately, the anticancer activity of Lc is confirmed, demonstrating its efficacy in killing cancer cells. Notably, Lc induced cancer cell death through the apoptosis pathway, highlighting its potential as a targeted therapeutic agent.