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

Citation
P. Schupp et al., Anti-proliferative effects of new staurosporine derivatives isolated from a marine ascidian and its predatory flatworm, CANCER LETT, 174(2), 2001, pp. 165-172
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
CANCER LETTERS
ISSN journal
0304-3835 → ACNP
Volume
174
Issue
2
Year of publication
2001
Pages
165 - 172
Database
ISI
SICI code
0304-3835(200112)174:2<165:AEONSD>2.0.ZU;2-Z
Abstract
Nine indolocarbazole alkaloids of the staurosporine. type, including three new derivatives, were evaluated for their potential as inhibitors of cell p roliferation and macromolecule synthesis. Four derivatives were tested as i nhibitors of cell proliferation with twelve human leukemia cell lines and d emonstrated powerful antiproliferative activities, with 3-hydroxystaurospor ine 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 an d 4'-N-methylstaurosporine very strongly reduced RNA and DNA synthesis with 3-hydroxystaurosporine again being the strongest inhibitor. Analysis of st ructure-activity relationships demonstrated that hydroxylation of staurospo rine at position 3 of the indolocarbazole moiety caused an increase in anti -proliferative activity, while hydroxylation at carbon 11 resulted in a dec rease in activity. Our results suggest that not only the presence or absenc e of hydrophilic substitutions, but also the position of the alteration wit hin the molecule, is important in the antiproliferative properties of the v arious staurosporine analogues. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.