Synthesis and anticancer mechanisms of zinc(II)-8-hydroxyquinoline complexes with 1,10-phenanthroline ancillary ligands

Abstract

Twenty new zinc(II) complexes with 8-hydroxyquinoline (H-Q1-H-Q6) in the presence of 1,10-phenanthroline derivatives (D1-D10) were synthesized and formulated as [Zn(Q1)₂(D1)] (DQ1), [Zn(Q2)₂(D2)]·CH₃OH (DQ2), [Zn(Q1)₂(D3)] (DQ3), [Zn(Q1)₂(D4)] (DQ4), [Zn(Q3)₂(D5)] (DQ5), [Zn(Q3)₂(D4)] (DQ6), [Zn(Q4)₂(D5)]·CH₃OH (DQ7), [Zn(Q4)₂(D6)] (DQ8), [Zn(Q4)₂(D3)]·CH₃OH (DQ9), [Zn(Q4)₂(D1)]·H₂O (DQ10), [Zn(Q5)₂(D4)] (DQ11), [Zn(Q6)₂(D6)]·CH₃OH (DQ12), [Zn(Q5)₂(D2)]·5CH₃OH·H₂O (DQ13), [Zn(Q5)₂(D7)]·CH₃OH (DQ14), [Zn(Q5)₂(D8)]·CH₂Cl₂ (DQ15), [Zn(Q5)₂(D9)] (DQ16), [Zn(Q5)₂(D1)] (DQ17), [Zn(Q5)₂(D5)] (DQ18), [Zn(Q5)₂(D10)]·CH₂Cl₂ (DQ19) and [Zn(Q5)₂(D3)] (DQ20). They were characterized using multiple techniques. The cytotoxicity of DQ1-DQ20 was screened using human cisplatin-resistant SK-OV-3/DDP ovarian cancer (SK-OV-3CR) cells and normal hepatocyte (HL-7702) cells. Complex DQ6 showed low IC₅₀ values (2.25 ± 0.13 μM) on SK-OV-3CR cells, more than 3.0-8.0 times more cytotoxic than DQ1-DQ5 and DQ7-DQ20 (≥6.78 μM), and even 22.2 times more cytotoxic than the standard cisplatin, the corresponding free H-Q1-H-Q6 and D1-D10 alone (>50 μM). As a comparison, DQ1-DQ20 displayed nontoxic rates against healthy HL-7702 cells. Furthermore, DQ6 and DQ11 induced significant apoptosis via mitophagy pathways. DQ6 also significantly inhibited tumor growth in an in vivo SK-OV-3-xenograft model (ca. 49.7%). Thus, DQ6 may serve as a lead complex for the discovery of new antitumor agents.