Madindoline, a novel inhibitor of IL-6 activity from Streptomyces sp K93-0711 .1. Taxonomy, fermentation, isolation and biological activities

Selective growth inhibition against IL-6-dependent cells was detected in fermentation extracts of a microbial strain, K93-0711, which was characterized as Streptomyces species. Active metabolite, termed madindoline A and B, were isolated, and the structure was determined to be 3a-hydroxyindoline with diketocyclopentene at the N position. Madindoline A and B displayed dose-dependent inhibition of MH60 cells, an IL-6-dependent cell line, in presence of 0.1 U/ml IL-6. The IC50 for madindoline A and B against this cell line was 8 mu M and 30 mu M, respectively. These compounds did not inhibit the growth of cell lines which are not IL-6 dependent and the growth inhibition bf the MH60 cell line was reversed by addition of excess, 0.4 U/ml of IL-6 to the culture media. These compounds did not show any antimicrobial activity at a concentration Of 1,000 mu g/ml.