MICROBIAL CONVERSION PRODUCTS OF LEPTOMYCIN-B

Leptomycin B (LMB), a secondary metabolite produced by Streptomyces sp , strain ATS 1287, with known antifungal and antitumor effects, inhibi ts the nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 regulatory protein Rev and exhibits significant antiproli ferative activity. Since LMB itself turned out to be distinctly cytoto xic, a bioconversion screening with a selected set of 29 bacterial and 72 fungal strains was performed in order to obtain metabolites of LMB with reduced antiproliferative effects, Several derivatives of LMB, m ore polar than the parent compound and produced in yields of >5%, were detected, Liquid chromatography-mass spectroscopy analysis indicated the type of bioconversion, Fermentations (1-liter scale) of those stra ins with high rates of transformation were suitable for isolation and characterization of the most prominent metabolites, Thus, bioconversio n of LMB with Aspergillus flavus ATCC 9170 and Emericella unguis ATCC 13431 served for isolation of the novel derivatives 26-hydroxy-LMB (30 % was the concentration metabolite [with respect to LMB] used for bioc onversion) and LMB-24-glutaminamide (90%), respectively, Streptomyces rimosus ATCC 28893 converted LMB into 4,11-dihydroxy-LMB (13%) and 2,3 -dihydro-LMB (55%). Although the antiproliferative effects of the LMB metabolites could be reduced through microbial conversion, none of the se metabolites inhibited the nuclear export of Rev better than LMB its elf.