Studies on the chemical modification of monensin. III. Synthesis and sodium ion transport activity of macrocyclic monensylamino acid-1,29-lactones.

Monensylglycine (2a) was lactonized to macrocyclic monensylglycine-1,29-lactone (3a) by Corey's method. Lactonization of monensylamino acids (2b--d) to monensylamino acid-1,29-lactones (3b--d) was carried out by utilizing the template effect of K+ ion. Monobenzyl esters of dicarboxylic monensylamino acids (5e--f) also were lactonized followed by debenzylation to yield carboxylic monensylamino acid-1,29-lactones (3e--f). Sodium ion transport activity of monensin (1) and the lactones (3) was measured in a liquid membrane and in guinea pig erythrocyte membrane. Monensylaspartic acid-1,29-lactone (3e) exhibited 2.5 times higher activity than 1 in the liquid membrane. Monensylalanine-1,29-lactone (3b), monensylphenylalanine-1,29-lactone (3c), and monensyltyrosine-1,29-lactone (3d), having smaller Na+ ion transport activity than 3e, showed weak antibacterial activity, while 3e was inactive in biological tests, probably due to the lower lipophilicity.