MICROBIAL CONVERSION OF EM574 AND EM523, GASTROINTESTINAL MOTOR STIMULATING AGENTS

EM574 exerts gastrointestinal motor stimulating (GMS) activity even af ter being converted to its metabolites P1 and P2 in dogs. These metabo lites were isolated from dog liver using a series of chromatographic p rocedures. Their structures were determined to be the 15- and 14-hydro xyl derivatives of EM574, respectively, by spectral analysis. Large sc ale preparation by microbial transformation was investigated for furth er evaluation of the metabolites, because the amounts obtained by oxid ation with dog liver homogenate were limited. Three strains of actinom ycetes, Amycolatopsis tolypophorus IFO 13151, Dactylosporangium varies porum IFO 14104 and Nocardia capreola IFO 12847, were found to have th e aiming oxidative potency. HPLC analysis of the crude extracts from t hese three cultures showed that the bioactive metabolites, EM574 P1 an d P2 were produced. They were isolated From the culture broth with the other bioactive products EM574 P3 and P4. These bioactive products we re prepared by large scale cultivation. EM574 P3 and P4 showed GMS act ivity comparable to that of EM574 P1 and P2. The structures of EM574 P 3 and P4 were elucidated by spectral analysis and found to be the 3''- O-demethyl derivatives of EM574 P2 and EM574, respectively. Moreover, the absolute configuration at the C14 position of P2 was determined to be R by spectral analysis of the 6-membered cyclic carbonate of EM574 P2.