Abstract
<jats:p>Cancer is the second leading cause of death worldwide, with breast cancer and leukemia among the most prevalent types. Some chemotherapy options are becoming obsolete due to multidrug-resistant cells and new tumor initiation mechanisms. We aimed to investigate semisynthetic natural products as potential scaffolds for novel antitumoral agents. Eleven derivatives (2-12) were synthesized from 29-hydroxyfriedelan-3-one (1), an abundant friedelane-type triterpene isolated from Cheiloclinium cognatum aerial parts extracts. Nine products presented oxime, lactone or lactam moieties on C-3. The reaction yields ranged from 18 to 87%. Their cytotoxic activity against breast cancer and leukemia (MDA-MB-231 and K-562, respectively) cells were assessed. Compounds 6, 7, 10, and 12 were more potent (IC50 = 32-63 µM) against these cell lines than 1 (IC50 = 58-80 µM). All derivatives showed low cytotoxicity towards the non-cancerous WI-26 VA4 cells. Eight compounds fitted at least two drug-like empirical rules. Self-organizing map analysis showed that properties related to intermolecular interactions were most strongly associated with biological activities. These results open perspectives for the investigation of new friedelane triterpenes as potential anticancer agents with higher cytotoxic potency and optimized physicochemical properties.</jats:p>