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 models