Anti-proliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm

Nine indolocarbazole alkaloids of the staurosporine. type, including three new derivatives, were evaluated for their potential as inhibitors of cell proliferation and macromolecule synthesis. Four derivatives were tested as inhibitors of cell proliferation with twelve human leukemia cell lines and demonstrated powerful antiproliferative activities, with 3-hydroxystaurosporine being the most potent. IC50 values were determined using the cell line MONO-MAC-6 and with an IC50 of 13 ng/ml, 3-hydroxystaurosporine turned out to be one of the most active staurosporine-type inhibitors described so far. All derivatives, except 3-hydroxy-3'-demethoxy-3'-hydroxystaurosporine and 4'-N-methylstaurosporine very strongly reduced RNA and DNA synthesis with 3-hydroxystaurosporine again being the strongest inhibitor. Analysis of structure-activity relationships demonstrated that hydroxylation of staurosporine at position 3 of the indolocarbazole moiety caused an increase in anti-proliferative activity, while hydroxylation at carbon 11 resulted in a decrease in activity. Our results suggest that not only the presence or absence of hydrophilic substitutions, but also the position of the alteration within the molecule, is important in the antiproliferative properties of the various staurosporine analogues. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.