Design, Synthesis, and Evaluation of Antitumor Activity of Novel Phenylahistin Derivatives with Double F-Substitution via Dual Inhibition of Microtubule and P53/BCL-2/BAX Signaling Pathways

Plinabulin, a derivative of phenylahistin, is a microtubule-protein inhibitor that is being studied as a potential antitumor agent. In this study, 33 novel derivatives were designed and synthesized. The results showed that most derivatives have significant inhibitory effects on the proliferation of tumor cells at the nanomolar level. Among them, compound 45 showed robust antiproliferative activity against H460 lung cancer cells. Further studies demonstrated that compound 45 not only disrupted the microtubule network and induced G2/M phase arrest but also enhanced p53 protein expression, thereby inhibiting the function of the antiapoptotic BCL-2 protein. This led to mitochondrial dysfunction and a significant increase in reactive oxygen species (ROS) levels in tumor cells, ultimately inducing tumor cell apoptosis. Importantly, compound 45 not only surpassed docetaxel in inhibiting tumor growth in the mouse allograft model using LLC cells but also demonstrated a good safety profile.