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2.B.109.  The α-AminOxy Serine Ion Carrier (AAOS-IC) Family 

Dan Yang and his co-workers developed small molecule-based ion transporters that eradicate cancer stem cells (Shen et al. 2020).  α-Aminoxy serine derivatives 42a–d were designed to transport cations. Ion transport studies showed selective transport of K+ over Cl by 42b (see figure below). The aminoxy amide-NH is critical for cation binding as the activity is completely gone upon replacing –NH with –NMe 42c. The α-effect of the oxygen atom adjacent to serine –NH is also key as the transport activity decreases in 42d without oxygen. 42b (pKa of 7.1) is in its deprotonated state at physiological pH to facilitate K+ transport. The transport mechanism involves extracellular deprotonation of the aminoxy amide-NH at pH 8.0, leading to K+ binding and diffusion across the membrane. An intracellular pH of 6.8 leads to protonation of the compound and release of K+. Deprotonation of the –NH proton and the pH gradient play an important role in K+ transport (see the figure below). Concentration-dependent ion transport studies of 42b showed low EC50 values of 4.04 and 0.30 mol% for K+ and H+ ion transport, respectively.

(a) α-Aminoxy serine derivatives 42a–d. (b) Mechanism of K+ transport mediated by α-aminoxy serine derivative 42b at the applied pH gradient.

References associated with 2.B.109 family:

Shen, F.F., S.Y. Dai, N.K. Wong, S. Deng, A.S. Wong, and D. Yang. (2020). Mediating K/H Transport on Organelle Membranes to Selectively Eradicate Cancer Stem Cells with a Small Molecule. J. Am. Chem. Soc. 142: 10769-10779. 32441923