Zinc(II) Complexes of SIRTi1/2 Analogues Transmetallating with Copper Ions and Inducing ROS Mediated Paraptosis

As the SIRTi analogue series (HL1–HL6) show potent antitumor activity in vitro, we synthesized their corresponding zinc­(II) complexes (ZnL1–ZnL6) and investigated their potential as anticancer agents. The Zn­(II) complexes showed substantially greater cytotoxicity than HL1–HL6 alone in several cancer cell-types. Notably, distinct structure–activity relationships confirmed the significance of tert-butyl (ZnL2) pharmacophore inclusion in their activity. ZnL2 complexes were found to transmetalate with copper ions inside cells, causing the formation of redox-active copper complexes that induced reactive oxygen species (ROS) production, mitochondrial membrane depolarization, ATP decay, and cell death. This is the first study to exhibit Zn­(II) complexes that mediate their activity via transmetalation with copper ions to undergo paraptosis cell death pathway. To further confirm if the SIRT1/2 inhibitory property of SIRTi analogues is conserved, a docking simulation study is performed. The binding affinity and specific interactions of the Cu­(II) complex obtained after transmetalation with ZnL2 were found to be higher for SIRT2 (K i = 0.06 μM) compared to SIRT1 (K i = 0.25 μM). Thus, the concurrent regulation of several biological targets using a single drug has been shown to have synergistic therapeutic effects, which are crucial for the effective treatment of cancer.