A Rationally Designed Bimetallic Platinum (II)‐Ferrocene Antitumor Agent Induces Non‐Apoptotic Cell Death and Exerts in Vivo Efficacy

Despite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)‐ferrocene hybrids that display multi‐pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi‐modal mechanism of action of these hybrid agents lead to non‐apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo. A heterobimetallic platinum (II)‐ferrocene hybrid 2 circumvents apoptosis and multifactorial cisplatin resistance, exhibits multi‐pronged action in cancer cells ‐ promoting necroptosis and paraptosis, and exerts in vivo anticancer efficacy in mice xenograft model.