A series of ligustrazine platinum(IV) complexes with potent anti-proliferative and anti-metastatic properties that exert chemotherapeutic and immunotherapeutic effects.

The development of novel anticancer drugs with antiproliferative and antimetastatic activities is of great importance in the pharmaceutical field. Herein, a series of ligustrazine (LSZ) platinum(IV) complexes with chemotherapeutic and immunotherapeutic effects were designed, prepared and evaluated as antitumor agents for the first time. Complex 4 with potent antitumor activities both in vitro and in vivo was screened out as a candidate. Notably, it displays significantly more effective anti-metastatic activities than the platinum(II) drugs cisplatin and oxaliplatin. Mechanism detection discloses that it causes serious DNA damage and increases the expression of γ-H2AX and P53. Then, the apoptosis of tumor cells is promoted by activating the mitochondrial apoptotic pathway Bcl-2/Bax/caspase-3 and causing autophagy via modulating LC3-I/II and P62 expression. Furthermore, the immune therapeutic responses are significantly elevated by blocking HIF-1α, ERK 1/2 and COX-2 pathways to reduce PD-L1 expression, and further increasing CD3 + and CD8 + T cells to elevate T cell immunity in tumors. Tumor metastasis is blocked by the synergistic functions of DNA damage, hypoxia modulation and immune activation.