Design, synthesis, and antitumor activity study of novel oleanolic acid structural derivatives targeting c-Kit.

Oleanolic acid (OA) is a pentacyclic triterpenoid, which inhibits tumor cell proliferation. In this study, OA was selected as the lead compound, and computer-aided drug design was used to develop novel derivatives. Structural modifications were made at the C-1, C-2, C-3, and C-28 positions based on the previously established structure-activity relationship. This led to the synthesis of two classes of OA derivatives with high predicted binding affinity to the c-Kit receptor (2-anilino) ethyl 1-ene-3-oxooleanolic acid esters (I1-I14) and 1-ene-3-(E)-oxime-oleanolic acid esters (II1-II11). MTT assays revealed that these compounds exhibited significant inhibitory activity against HepG-2 and MCF-7 cell lines, with compounds I9 and II9 showing IC50 values comparable to those of the reference drugs gefitinib and sorafenib. Additionally, Western blot analysis revealed that treatment with compound I9 led to a concentration-dependent downregulation of c-Kit expression, indicating that its antitumor activity may be mediated, at least in part, through inhibition of c-Kit signaling.