Design and synthesis of new hybrids from 2-cyano-3,12-dioxooleana- 9-dien-28-oic acid and O2-(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 O²-(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 π (GSTπ), and significantly inhibited the cells' proliferation (IC₅₀ = 0.349 ± 0.051 μM), 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 GSTπ 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.

CDDO; Drug resistance; Nitric oxide; O(2)-(2,4-dinitrophenyl) diazeniumdiolate; ROS.