Side chain-functionalized aniline-derived ursolic acid derivatives as multidrug resistance reversers that block the nuclear factor-kappa B (NF-κB) pathway and cell proliferation.
Huang RZ, Hua SX, Liao ZX, Huang XC, Wang HS.
A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing functionalized aniline or amide side chains were synthesized and evaluated for inhibition of NF-κB as well as their antitumor effects. These compounds exhibited significant inhibition activity toward NF-κB with IC<sub>50</sub> values at micromolar concentrations in the NCI-H460 lung adenocarcinoma cell line. A docking study of the most active compound <b>5Y8</b> revealed key interactions between <b>5Y8</b> and the active site of NF-κB in which the functionalized amide moiety at the C-28 position and an ester group at the C-3 position were important for improving the activity. In particular, compound <b>5Y8</b> appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive <i>versus</i> drug-resistant cancer cell lines, at least partly, by blocking the NF-κB signaling pathway and inducing apoptosis. Mechanistically, compound <b>5Y8</b> might trigger the apoptotic signaling pathway. Thus, the rational design of UA derivatives with functionalized aniline or amide side chains offers significant potential for the discovery of a new class of NF-κB inhibitors with the ability to induce apoptosis and reverse multidrug resistance in the NCI-H460 lung adenocarcinoma cell line.