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.