TRANSFORMATION OF NATURAL-PRODUCTS INTO MORE POTENT COMPOUNDS - CHEMICAL MODIFICATION OF MONENSIN

Monensin (1) is a representative compound of polyether ionophore antib iotics, which selectively transport Na+ ions. In order to obtain poten t Na+ ionophores, the modification of the carboxyl group of monensin w as carried out to yield monensylamino acids (2) and monensylamino acid -1,29-lactones (3). The Na+ permeability of ion through the erythrocyt e membrane of 2 and 3 was evaluated by the Na-23-NMR method. Compound 2 showed less Na+ ion transport activity than monensin, probably due t o the lower lipophilicity caused by the conformational change of the c hain moiety of the molecules. Although 3 showed higher lipophilisity t han 1, 3 had no Na+ ion permeability, probably due to loss of the carb oxyl group. As more lipophilic compounds possessing a carboxyl group w as supposed to have more ion transport activity, 7-O-acylnonensins (8) and 7-O-alkylmonensins (11) were synthesized. Among these compounds, the value of Na+ ion permeability of 7-O-benzylmonensin (lie) was 1.4 time that of 1. Further investigation was carried out by preparing var ious 7 -O-(substituted benzyl)monensins (13), and 7-O-(p-ethylbenzyl)m onensin (13b) exhibited the largest Na+ ion permeability, about twice the value of 1. In order to convert monensin (1) to Ca2+ ionophore, 7- carboxylmethylmonensin (18) via protected 7-oxomonensin (15), and 25-c arboxylmonensin (26) were prepared. In the course of the synthesis, 15 was clarified as a useful intermediate to give 7-amino and 7-alkyl de rivatives. Ca2+ ion transport activities of 18 and 26 were determined by a CHCl3 liquid membrane system. 25 -carboxylmonensin (26) showed 70 % of the activity of Ca2+ ionophore, lasalocid A, and compound 26 coul d be the lead compound for the preparation of a new Ca2+ ionophore.