Design and synthesis of new hybrids from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid and O-2-(2,4-dinitrophenyl) diazeniumdiolate for intervention of drug-resistant lung cancer

To search for new drugs for intervention of drug-resistant lung cancer, a series of hybrids 4-15 from 2-cyano-3,12-dioxooleana-9-dien-28-oic acid (CDDO) and O-2-(2,4-dinitrophenyl) diazeniumdiolate were designed, synthesized and biologically evaluated. The most active compound 7 produced relatively high levels of nitric oxide (NO) and reactive oxygen species (ROS) in drug-resistant lung cancer A549/Taxol cells which over-express glutathione S-transferase pi (GST pi), and significantly inhibited the cells' proliferation (IC50 = 0.349 +/- 0.051 mu M), superior to the positive controls CDDO-Me, JS-K and Taxol. The inhibitory activity of 7 could be attenuated by an NO scavenger, ROS scavenger or GST pi inhibitor. In addition, 7 suppressed the Lon protease expression as well as induced cell apoptosis and cycle arrest in A549/Taxol cells more strongly than CDDO-Me or JS-K. Together, our findings suggest that 7 may be worth studying further for intervention of drug-resistant lung cancer. (C) 2018 Elsevier Masson SAS. All rights reserved.