Discovery of a Novel EF24 Analogue-Conjugated Pt(IV) Complex as Multi-Target Pt(IV) Prodrugs Aims to Enhance Anticancer Activity and Overcome Cisplatin Resistance

Acquired resistance in cancer remains a significant challenge in oncology, posing obstacles to the efficacy of diverse therapeutic approaches. The nuclear factor-kappa B (NF-κB) signaling pathway plays an important role in the development of drug resistance in tumor cells. Herein, we employed NF-κB inhibitors and cisplatin to synthesize multitarget Pt(IV) antitumor prodrugs. Among them, the antiproliferation activity of complex <b>8</b> demonstrated a remarkable 146.92-time increase compared to cisplatin against A549/CDDP cells. Moreover, complex <b>8</b> could effectively induce DNA damage, promote ROS generation, induce autophagy, trigger the mitochondrial apoptosis pathway, and suppress cell proliferation through the NF-κB signaling pathway. Furthermore, complex <b>8</b> effectively downregulated the levels of VEGF and HIF-1α and exerted antiproliferative activity through the PI3K/AKT and STAT-3 pathway in A549/CDDP cells. Interestingly, complex <b>8</b> showed a superior in vivo antitumor activity than cisplatin, <b>5a</b>, or their combination, suggesting its potential as a promising candidate for further drug development in lung cancer treatment.