Novel synthetic pyridyl analogues of CDDO-Im with improved stability and their potential use in cancer prevention

Synthetic oleanane triterpenoids are non­cytotoxic, multifunctional drugs with a broad spectrum of applications for prevention and treatment of cancer and for many other chronic diseases. CDDO­Im, 1[2­Cyano­3,12­dioxooleana­1,9(11­dien­28­oyl] imidazole, synthesized more than a decade ago, is one of the most potent triterpenoids known to date with marked antiinflammatory, cytoprotective, antiproliferative, differentiative and proapoptotic activity on various human and murine tumor cell lines. However, pharmacokinetics of CDDO­Im are not optimal. Therefore, three new pyridyl analogues of CDDO­Im, namely CDDO­3P­Im, CDDO­2P­Im and CDDO­4P­Im, have been synthesized and screened for their possible use as chemopreventive or chemotherapeutic drugs. At low nanomolar concentrations, they were equivalent to CDDO­Im for induction of differentiation in U937 leukemia cells and at higher doses they induced apoptosis. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase expression in RAW264.7 macrophage­like cells and significantly induced heme oxygenase­1 and NADPH quinone reductase mRNA and protein levels in lung cancer cells as well as in various mouse tissues. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo revealed superior stability for each new analogue. While CDDO­Im was almost completely degraded after 30 min (< 12 % of starting material remaining) in human plasma, the new compounds were more stable with > 50 % still detectable. Six hours after gavage, much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney in contrast to CDDO­Im. Thus, the new pyridyl analogues have better bioavailability, and because of their potent anti­inflammatory activity and improved stability, they will be tested in vivo in relevant carcinogenesis model