Tyrosine specific kinases involving cell signal transduction pathway play a crucial role in cell proliferation or differentiation, and are important target molecules for cancer chemotherapy. We found that Microbispora rosea subsp. hibaria isolated form soil sample produced v-src tyrosin kinase inhibitor, and the active principles were named hibarimicins. Hibarimicins were extracted from fermented broth of the producing microorganism, and purified by Diaion HP20, ODS-silica gel column chromatography, ODS- TLC and HPLC. Hibarimicins were determined to be glycosides of octacyclic aglycons by spectroscopic analyses. Combination of three kinds of aglycon (R, P, Y) and four kinds of deoxy sugars gives more than ten species of hibarimicins. Asymmetric carbons were located in both ends of the aglycon and the carbohydrate moiety, and their absolute configurations were determined by improved Mosher's method. Absolute configuration of axial chirality at C2-C2' bond was determined to be Sa for hibarimicin A〜K by circular dichroism exciton chirality method. Feeding experiments with labeled acetate indicated that hibarimicin aglycon was biosynthesized through polyketide pathway, dimerization and glycosylation. Hibarimicins selectively inhibited tyrosin kinase in multiple protein kinase assay system using v-src transformed NIH3T3 cells.
