Synthesis of antitumor-active betulinic acid-derived hydroxypropargylamines by copper-catalyzend mannich reactions.

Several novel betulin derivates were prepared using Mannich reactions as a key step. Starting from 3-ethynyl-3-hydroxy-lup-20(29)-ene derivatives, copper-catalyzed Mannich reactions yielded hydroxypropargyl ammonium hydrochlorides or their corresponding methiodides. All compounds were screened in a sulforhodamine B assay for their antitumor activity using a panel of 9 human cancer cell lines. Some of these compounds showed significant cytotoxicity; they act by triggering apoptotic cell death as shown by additional acridine orange/propidium iodide assays, Trypan blue tests, DNA laddering experiments, and investigations of the cell cycle.