Design, Synthesis, and Evaluation of Bibenzyl Analogues against Hepatocellular Carcinoma by Targeting Pyruvate Carboxylase.

Pyruvate carboxylase (PC) replenishes tricarboxylic acid cycle intermediates, driving cancer metabolic reprogramming. To improve the metabolic stability of erianin, a potent PC inhibitor from Dendrobium chrysotoxum Lindl, we designed and synthesized 55 derivatives, culminating in the identification of CIB-Q22, which exhibited potent PC inhibition (IC50 = 1.74 nM) and suppressed HCC cell viability (IC50 = 25.18 nM), comparable to erianin. Notably, CIB-Q22 demonstrated significantly improved in vivo stability, with a half-life (T1/2 = 1.21 h) much longer than erianin (T1/2 ∼ 0.1 h). Mechanistically, CIB-Q22 suppressed HCC proliferation and metastasis by inducing apoptosis and ferroptosis. Moreover, it promoted mitochondrial oxidative stress and inhibited glycolysis, thereby sensitizing cells to glutamine deprivation. In vivo, CIB-Q22 exhibited comparable antitumor efficacy but improved safety compared to sorafenib. With its potent PC inhibition and favorable drug-like properties, CIB-Q22 represented a promising therapeutic candidate for HCC treatment.