Eighteen 5,7-Dihalo-8-quinolinol and 2,2′-Bipyridine Co(II) Complexes as a New Class of Promising Anticancer Agents

[Image: see text] Here we first report the design of a series of bis-chelate Co(II) 5,7-dihalo-8-quinolinol-phenanthroline derivative complexes, [Co(py)(QL1)(2)] (Co1), [Co(py)(QL2)(2)] (Co2), [Co(Phen)(QL1)(2)] (Co3), [Co(Phen)(QL2)(2)] (Co4), [Co(DPQ)(QL1)(2)]·(CH(3)OH)(4) (Co5), [Co(DPQ)(QL2)(2)] (Co6), [Co(DPPZ)(QL1)(2)]·CH(3)OH (Co7), [Co(MDP)(QL1)(2)]·3H(2)O (Co8), [Co(ODP)(QL1)(2)]·CH(3)OH (Co9), [Co(PPT)(QL1)(2)]·CH(3)OH (Co10), [Co(ClPT)(QL1)(2)] (Co11), [Co(dpy)(QL3)(2)] (Co12), [Co(mpy)(QL1)(2)] (Co13), [Co(Phen)(QL4)(2)] (Co14), [Co(ODP)(QL4)(2)] (Co15), [Co(mpy)(QL4)(2)]I (Co16), [Co(ClPT)(QL4)(2)] (Co17), and [Co(ClPT)(QL5)(2)] (Co18), with 5,7-dihalo-8-quinolinol and 2,2′-bipyridine mixed ligands. The antitumor activity of Co1–Co18 has been evaluated against human HeLa (cervical) cancer cells in vitro (IC(50) values = 0.8 nM–11.88 μM), as well as in vivo against HeLa xenograft tumor growth (TIR = 43.7%, p < 0.05). Importantly, Co7 exhibited high safety in vivo and was more effective in inhibiting HeLa tumor xenograft growth (43.7%) than cisplatin (35.2%) under the same conditions (2.0 mg/kg). In contrast, the H-QL1 and DPPZ ligands greatly enhanced the activity and selectivity of Co7 in comparison to Co1–Co6, Co8–Co18, and previously reported cobalt(II) compounds. In addition, Co7 (0.8 nM) inhibited telomerase activity, caused G2/M phase arrest, and induced mitochondrial dysfunction at a concentration 5662.5 times lower than Co1 (4.53 μM) in related assays. Taken together, Co7 showed low toxicity, and the combination could be a novel Co(II) antitumor compound candidate.