Discovery of novel dehydroabietylamine–pyrimidine hybrids: design, synthesis and anti-tumor evaluation

Abstract

Challenges in cancer treatment lie in the identification and development of novel agents with potent anti-tumor activity. A series of novel dehydroabietylamine–pyrimidine derivatives 3a–3s were designed and synthesized based on the principles of molecular hybridization. The inhibitory activities of the target compounds against the proliferation of four different human cancer cell lines (HepG2, A549, HCT116 and MCF-7) were evaluated. Among them, compound 3r, which contains a bicyclic quinuclidine ring, was identified as a potent apoptotic inducer, with a better IC₅₀ value of 1.15 ± 0.31 μM on MCF-7 cells and a favorable selectivity index (SI = 27.7) on human normal mammary epithelial cells (MCF-10A). Cell clonogenic and migration assays further demonstrated that 3r not only effectively inhibited colony formation but also suppressed the cell migratory capacity. Further mechanistic studies revealed that 3r significantly elevates reactive oxygen species (ROS) levels and reduces mitochondrial membrane potential (MMP), thereby inducing cancer cell apoptosis and causing G2 phase cell cycle arrest.