Mitochondria-localizing curcumin-cryptolepine Zn(II) complexes and their antitumor activity

Abstract

Many metal complexes are potent candidates as mitochondrial-targeting agents. In this study, four novel Zn(II) complexes, [Zn(BPQA)Cl₂] (Zn1), [Zn(BPQA)(Curc)]Cl (Zn2), [Zn(PQA)Cl₂] (Zn3), and [Zn(PQA)(Curc)]Cl (Zn4), containing N,N-bis(pyridin-2-ylmethyl)benzofuro[3,2-b]quinolin-11-amine (BPQA), N-(pyridin-2-ylmethyl)benzofuro[3,2-b]quinolin-11-amine (PQA), and curcumin (H-Curc) were synthesized. An MTT assay showed that Zn1-Zn4 had strong anticancer activities against SK-OV-3/DDP and T-24 tumor cells with IC₅₀ values of 0.03-6.19 μM. Importantly, Zn1 and Zn2 displayed low toxicities against normal HL-7702 cells. Mechanism experiments demonstrated that probe Zn2 showed appreciable fluorescence in the red region of the spectrum, and substantial accumulation of Zn2 occurred in the mitochondria after treatment, indicating increases in Ca²⁺ and reactive oxygen species levels, loss of the mitochondrial membrane potential, and consequent induction of mitochondrial dysfunction at low concentrations. In addition, the probe Zn2 effectively (50.7%) inhibited the growth of T-24 bladder tumor cells in vivo. The probe Zn2 shows potential for use in cancer therapy while retaining the H-Curc as an imaging probe.

Keywords: Cell apoptosis; Curcumin-cryptolepine; Mitochondrial dysfunction; Zn(II) complexes.