The First Multimodal Anticancer Manganese(II) Complex of an Asymmetric Anthrahydrazone Triggers Apoptosis, Autophagy and Ferroptosis

A new nonsymmetric anthrahydrazone ligand (AAIH) was designed and synthesized, affording novel manganese(II) and cobalt(II) complexes, AAIH-Mn and AAIH-Co. Both complexes crystallized in the same centrosymmetric dinuclear coordination mode, however, AAIH-Mn exhibited much higher in vitro cytotoxicity (IC50 = 1.64 μM against MGC-803 cells) than AAIH-Co (IC50 = 10.05 μM) and AAIH (IC50 = 18.82 μM), signifying the importance of the Mn(II) center. Furthermore, AAIH-Mn exerted anticancer activity via multiple pathways: S-phase cell cycle arrest, cell apoptosis, autophagy and notably, the emerging process of ferroptosis. AAIH-Mn also effectively inhibited 56% of tumor growth in vivo on MGC-803 xenografts at 16 mg/kg, without causing obvious toxicity. Low toxicity was further supported by zebrafish models, along with its anti-inflammatory activity and low cardiotoxicity. As the first Mn(II) complex inducing ferroptosis, AAIH-Mn provides a valuable example of a low-toxicity metal center to generate highly cytotoxic nonplatinum anticancer complex.