Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells

Ursolic acid (UA) is a pentacyclic triterpenoid with recognized anticancer properties. We prepared a series of new A-ring cleaved UA derivatives and evaluated their antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines using 2D and 3D culture models. Compound 17, bearing a cleaved A-ring with a secondary amide at C-3, was found to be the most active compound, with potency in 2D systems. Importantly, even in 3D systems, the effect was maintained albeit a slight increase in the IC50. The molecular mechanism underlying the anticancer activity was further investigated. Compound 17 induced apoptosis via activation of caspase-8 and caspase-7 and via decrease of BcI-2. Moreover, induction of autophagy was also detected with increased levels of Beclin-1 and LC3A/B-II and decreased levels of mTOR and p62. DNA synthetic capacity and cell cycle profiles were not affected by the drug, but total RNA synthesis was modestly but significantly decreased. Given its activity and mechanism of action, compound 17 might represent a potential candidate for further cancer research. (C) 2016 Elsevier Masson SAS. All rights reserved.