pH regulation of divalent/monovalent Ca/K cation transport selectivity by a macrocyclic carrier molecule (macrocyclic polyether/synthetic ionophore/competitive calcium-potassium transport/proton pump) ANN HRICIGA AND JEAN-MARIE LEHN

The lipophilic dicarboxylic acid-dicarboxamide macrocycle 1 is an efficient carrier for calcium and potassium transport through a liquid membrane. The process involves competitive Ca2'/K' symport coupled to proton antiport in a pH gradient. It presents a very pronounced phenomenon of pH regulation of transport selectivity from preferential K+ transport to preferential Ca2' transport as the pH increases from 2 to 9 in the starting aqueous phase containing the metal ions. The results demonstrate how carrier design allows control of the rate and selectivity of divalent/monovalent M2+/M+ cation transport. Like molecular recognition and catalysis, the design of synthetic carrier molecules and of artificial transport processes represents a major area of research into the functional features of supramolecular systems (1, 2). Because they may, in principle, be modified at will, synthetic carriers offer the possibility to monitor the transport mechanism via the structure of the ligand and to analyze the effect of various structural units on the thermodynamic and kinetic parameters that determine transport rates and selectivities. The regulation of the ionic composition of cell rests on selective ion transport processes coupled to proton flow and to ATP-driven pumps (3-5). The active recent research on receptor molecules for inorganic (especially alkali and alkaline-earth) as well as organic cations gave rise to investigations on the ability of such substances to also act as membrane carrier agents. Thus, cation transport by natural as well as by synthetic macrocyclic ionophores has been extensively studied (refs. 1, 2, 6-11; also references included in ref. 9). Furthermore, systems may be set up that allow coupling cation transport to proton or redox pumps (see refs. 1 and 2 and references therein). Proton/monovalent cation antiport in a pH gradient has been realized with either natural or synthetic ionophores containing an ionizable carboxylic group (12-19). A particularly interesting problem in carrier design is to achieve control over the divalent/monovalent M2+/M+ cation transport selectivity. Because M + ions have much higher hydration energy than M+ ions, they are much more reluctant to enter into the membrane phase. Transport of Ca2' deserves special attention in view of the very important biological role of this cation (20). Noncyclic (6, 7, 21-26) and cyclopeptide (27) carboxylic ionophores have been found to carry calcium cations. We now report a system that displays (i) efficient transport of either calcium or potassium cations; (ii) coupling of cation transport to proton antiport; and (iii) pH regulation of Ca2+/K+ transport selectivity. Our approach to the design of an artificial carrier that might effect regulation of M2+/M+ transport selectivity consisted of fitting a macrocyclic ligand molecule possessing only a single cation binding site (monotopic receptor) with two anionic groups. Such a species may form a neutral complex in the membrane by extracting either one divalent cation or two monovalent ones; however, because a single cation receptor site is available, only one of the two M+ ions has the possibility to bind inside the macrocyclic cavity, the other being confined outside, whereas only inside binding occurs with a single M2" cation (see also figure 7 in ref. 2). Thus, binding and extraction of M2+ should be favored over 2M+, resulting in selective M2+/M+ transport. On the other hand, protonation of one of the two anionic groups should lead to preferential M+ take up and therefore invert the transport selectivity in favor of MW. The synthetic dicarboxylic acid-dicarboxamide [18]-06 macrocycle 1 presents such features and we describe here its carrier properties.