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.

Antitumor activity; Oleanolic acid; Oleanolic acid derivatives; Structural modification; c-Kit.