Oleanolic acid (OA) and Lupeol (LU) belong to the class of natural triterpenes and are endowed with a wide range of biological activities, including cytotoxicity toward several cancer cell lines. In this context, we investigated a set of compounds obtained from the two natural precursors for the cytotoxicity against leukemia HL60 cells and the multidrug-resistant (MDR) variant HL60R. Six new semi-synthetic triterpenes have been synthetized, fully characterized, and were investigated together with other triterpenes compounds for their pharmacological mechanism of action. The interaction of the more cytotoxic compounds with the nuclear factor kappa B (NF-κB) pathway has been also evaluated with the aid of docking. The lupane-like compounds were more active than the precursor, while the oleane-like compounds showed more complex behavior. Both OA and LU derivatives possess a similar interaction pattern with the p65 subunit of NF-κB, justifying the similar trend in their ability to inhibit the binding of p65 to DNA. Further, some of the derivatives tested were able to increase IκB-α levels preventing the translocation of NF-κB to the nucleus. In conclusion, this study offers a deeper insight on the pharmacological action of triterpenes toward leukemia cells, and it improves the background useful for the development of new anti-cancer drugs.

Lupeol, a naturally occurring pentacyclic triterpenoid widely distributed in various medicinal plants, has attracted significant attention due to its diverse pharmacological properties. In this study, we report the synthesis and structural modification of 14 lupeol derivatives through selective functionalizations at C3 and C30 positions of the lupane skeleton, via the sequential chemoselective introduction of carbonyl moieties and the addition of organometallics. Emphasis has been given to the stereoselective alkylation at C3 using a range of carbanions, including organolithiums, organomagnesiums and organoindiums. The C30 position was modified through oxidative pathways to introduce several functionalities.