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

摘要

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)].(CH3OH)(4) (Co5), [Co(DPQ)(QL2)(2)] (Co6), [Co(DPPZ)(QL1)(2)].CH3OH (Co7), [Co(MDP)(QL1)(2)].3H(2)O (Co8), [Co(ODP)(QL1)(2)].CH3OH (Co9), [Co(PPT)(QL1)(2)].CH3OH (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 (IC50 values = 0.8 nM-11.88 mu M), 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 mu M) in related assays. Taken together, Co7 showed low toxicity, and the combination could be a novel Co(II) antitumor compound candidate.