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

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)]·CH 3 OH ( 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)]·CH 3 OH ( DQ7 ), [Zn(Q4) 2 (D6)] ( DQ8 ), [Zn(Q4) 2 (D3)]·CH 3 OH ( DQ9 ), [Zn(Q4) 2 (D1)]·H 2 O ( DQ10 ), [Zn(Q5) 2 (D4)] ( DQ11 ), [Zn(Q6) 2 (D6)]·CH 3 OH ( DQ12 ), [Zn(Q5) 2 (D2)]·5CH 3 OH·H 2 O ( DQ13 ), [Zn(Q5) 2 (D7)]·CH 3 OH ( DQ14 ), [Zn(Q5) 2 (D8)]·CH 2 Cl 2 ( DQ15 ), [Zn(Q5) 2 (D9)] ( DQ16 ), [Zn(Q5) 2 (D1)] ( DQ17 ), [Zn(Q5) 2 (D5)] ( DQ18 ), [Zn(Q5) 2 (D10)]·CH 2 Cl 2 ( 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 IC 50 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. DQ1-DQ20 exhibit selective cytotoxicity to SK-OV-3/DDP. They inhibit cell growth via mitophagy pathways. Importantly, DQ6 displays high in vivo antitumor activity.