1H-cyclopenta[b] benzofuran lignans from Aglaia species inhibit cell proliferation and alter cell cycle distribution in human monocytic leukemia celllines

Thirteen naturally occurring 1H-cyclopenta[b]benzofuran lignans of the roca glamide type as well as one naturally occurring aglain congener all of them isolated from three Aglaia species (Aglaia duperreana, A. oligophylla and A. spectabilis) collected in Vietnam were studied for their antiproliferati ve effects using the human monocytic leukemia cell lines MONO-MAC-1 and MON O-MAC-B. Only rocaglamide type compounds showed significant inhibition of [ H-3-]thymidine incorporation and the most active compound didesmethylrocagl amide inhibited cell growth in a similar concentration range as the well-kn own anticancer drug vinblastine sulfate. Detailed structure-activity analys is indicated that the OH-group at C-sb which is a common structural feature of most naturally occurring rocaglamide compounds is essential for the des cribed antiproliferative activity since replacement of this group by methyl ation led to a complete loss of the inhibitory activity for the resulting d erivative. Rocaglamide derivatives rapidly inhibited DNA as well as protein biosynthesis of MONO-MAC-6 cells at concentrations well below those of act inomycin D or cycloheximide which were used as positive controls in the res pective experiments. Didesmethylrocaglamide was furthermore able to induce growth arrest of MONO-MAC-1 cells in the G2/M and probably G0/G1-phase of t he cell cycle with no morphological indication of cellular damage. Our data suggests that 1H-cyclopenta[b]benzofuran lignans of the rocaglamide type a ct primarily by a cytostatic mechanism.