synthesis of new trans-dehydrocrotonin nitrogenated derivatives and their cytotoxic and dna-topoisomerase i inhibitory activities

A new series of 19-nor-clerodane diterpene derivatives was synthesized from the natural trans-dehydrocrotonin obtained from stem barks of croton cajucara (euphorbiaceae), a native medicinal plant of the brazilian amazon. the new derivatives were obtained by changes in the ketone moiety of trans-dehydrocrotonin leading to nitrogenated derivatives which are: three substituted hydrazine diterpenes, oxime, and methyloxime. the cytotoxic effect of the diterpene derivatives was evaluated by mtt (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay against ehrlich carcinoma and k562 human leukemia cells. the cytotoxic activity of the hydrazine and oxime semi-synthetic derivatives was better than the one of the natural product trans-dehydrocrotonin. moreover, all diterpenes were tested for their dna topoisomerase i inhibitory activity, and the most effective one, in general, was observed to the phenyl-hydrazone derivative. results indicated that the topoisomerase i inhibitory effect is correlated with the cytotoxic activity.