Development of six novel dinuclear calcium(II) complexes based on 8-hydroxyquinoline as anticancer agents

This study reports the synthesis and antitumor evaluation of six novel dinuclear calcium(II) complexes with the general formula [Ca₂(μ₂-O)₂(QM^x)₄(QH^y)₂], designated as CaQ1 through CaQ6. These complexes incorporate various deprotonated 8-hydroxyquinoline ligands (H-QM¹-H-QM⁴) and 1,10-phenanthroline derivatives (QH²), synthesized using Ca(NO₃)₂·4H₂O. The specific compositions are as follows: CaQ1: H-QM¹ = 5,7-dibromo-8-hydroxyquinoline (x = 1), QH¹ = bathophenanthroline; CaQ2: H-QM² = 5,7-dichloro-8-quinolinol (x = 2), QH¹ = bathophenanthroline; CaQ3: H-QM³ = 5,7-diiodo-8-hydroxyquinoline (x = 3), QH² = 1,10-phenanthroline; CaQ4: H-QM² = 5,7-dichloro-8-quinolinol (x = 2), QH² = 1,10-phenanthroline; CaQ5: H-QM⁴ = clioquinol (x = 4), QH² = 1,10-phenanthroline; CaQ6: H-QM¹ = 5,7-dibromo-8-hydroxyquinoline (x = 1), QH² = 1,10-phenanthroline. Cytotoxicity was assessed using the cell counting kit-8 assay, and the results showed that CaQ1-CaQ6 exhibited greater selectivity toward cisplatin-resistant SK-OV-3/DDP ovarian (cis-SK3) cancer cells compared to both nontumorigenic HL-7702 liver cells and parental SK-OV-3 ovarian cancer cells. Notably, CaQ1 and CaQ2, which contain the active H-QM¹, H-QM², and QH¹ ligands, showed the most potent cytotoxicity, with IC₅₀ values of 3.59 ± 0.67 μM and 2.73 ± 0.25 μM, respectively, against cis-SK3 cells. Apoptosis induced by CaQ1 and CaQ2 was mediated by mitophagy activation and adenosine triphosphate depletion, with CaQ2 being more effective than CaQ1-likely due to the presence of QM² and QH¹ ligands in the CaQ2 complex. In conclusion, these findings suggest that the synthesized 8-hydroxyquinoline-based binuclear calcium(II)-1,10-phenanthroline complexes (CaQ1-CaQ6) represent promising Ca(II)-based anticancer drug candidates.