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. 2019 Oct 30;10(12):1603–1608. doi: 10.1021/acsmedchemlett.9b00356

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

Ting Meng †, Qi-Pin Qin †,‡,*, Hua-Hong Zou †,*, Kai Wang †,§, Fu-Pei Liang †,§,*
PMCID: PMC6912862  PMID: 31857834

Abstract

graphic file with name ml9b00356_0008.jpg

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]·3H2O (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 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.

Keywords: 5,7-Dihalo-8-quinolinol; Co(II) complex; antitumor activity; telomerase activity; mitochondrial dysfunction

Pt-based drugs were extensively used to treat a large number of tumors in the clinic.1−10 However, cisplatin (cis-[PtCl2(NH3)2]) and its derivatives were limited by drug resistance and some severe side effects,11,14 and consequently, the Ru, Ti, Au, Co, Ir, Os, Rh, Fe, Cu, etc., complexes have been designed and attracted attention.16−38 In addition, cobalt has emerged as a key of vitamin B12 (cobalamin) metabolism and its metal complexes have been reported as DNA cleavage agents, antiviral, antifungal, antitumor antiproliferative, antioxidant, and have shown antimicrobial activity, such as oxoisoaporphine,15 shydroxamic acids prodrugs,16,17 2-benzimidazole derivatives,18 acetylenehexacarbonyldicobalt,19 2-acetylpyridine and malonic acid dihydrazide,20 antiulcer drug famotidine,21 sparfloxacin,23 valine-derived Schiff bases,24N-benzoyl-N′-dialkylthiourea derivatives,25 nonsteroidal anti-inflammatory drugs,28 nonsteroidal anti-inflammatory drug tolfenamic acid,30 2-acetoxy-(2-propynyl)benzoate]hexacarbonyldicobalt,31 a fluorescent coumarin,32 and tetradentate phenolate-based ligand35 cobalt(II/III) complexes.

Recently, many novel hydroxyquinoline metal compounds, such as Zn, Cu, Ni, Ir, Os, Rh, Au, Co, Fe, Sn, Ru, Pt, Pd, and Ln metal complexes,39−60 have proved to be promising anticancer drugs in vitro and in vivo. Among them, a small amount of copper(II) complexes of hydroxyquinolines were designed and preliminarily identified as anticancer drugs.50−60 However, to date, Co(II) complexes bearing 5,7-dihalo-2-methyl-8-quinolinol and o-phenanthroline derivative mixed ligands have not been reported.

To gain the mixed chelating cobalt(II) complexes with high anticancer activity in vitro and in vivo, we first designed 18 novel Co(II) complexes Co1–Co18 with 2,2′-bipyridine (py), 1,10-phenanthroline (Phen), 5,7-dichloro-2-methyl-8-quinolinol (H-QL1), dipyridoquinoxaline (DPQ), 5,7-dibromo-2-methyl-8-quinolinol (H-QL2), dipyridophenazine (DPPZ), 5,6-dimethyl-10-phenanthroline (MDP), 4,4′-dimethoxy-2,2′-bipyridyl (ODP), 4,7-diphenyl-10-phenanthroline (PPT), 4,7-dichloro-1,10-phenanthroline (ClPT), 5-chloro-7-iodo-8-hydroxy-quinoline (H-QL3), 5,5-dimethyl-2,2-dipyridine (dpy), 5,7-diiodo-8-hydroxyquinoline (H-QL4), 4,4′-dimethyl-2′-bipyridine (mpy), and 5,7-dibromo-8-quinolinol (H-QL5). Additionally, the biological properties of Co1–Co18 have been evaluated.

First, the mononuclear complexes Co1–Co18 were prepared by CH3CN–CH3OH (3.5 mL/1.5 mL) reflux of H-QL1 (or H-QL2, H-QL3, H-QL4, H-QL5) and py, Phen, DPQ, DPPZ, MDP, ODP, PPT, ClPT, dpy, and mpy with cobalt(II) acetate (2:1:1) at 80 °C for 24 h, respectively (Scheme 1). These 18 new Co(II) complexes were structurally fully characterized (Figures 1 and S1–S45).

Scheme 1. General Synthetic Pathway for Co1–Co18.

Scheme 1

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Figure 1.

Figure 1

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Crystal structures of Co1 and Co7.

The Co(II) atoms in Co1–Co18 were six-coordinated and surrounded by two deprotonated QL ligands (N∧O-ligand) and one second ligand molecule (N∧N-ligand) showing a distorted octahedral geometry (Figures 1 and S1–S16). In addition, a diagram of Co1–Co18 is shown in Figures 1 and S1–S16, and selected bond distances (Å) and angles (deg) are listed in Tables S1–S54, and the bond lengths (Å) of Co1–Co18 remained normal.

MTT assay was carried out to gauge the in vitro anticancer activity of Co1–C o18, H-QL1, H-QL2, py, Phen, DPQ, DPPZ, MDP, ODP, PPT, ClPT, H-QL3, dpy, H-QL4, CoCl2·6H2O, mpy, and H-QL5 using BEL-7404 (hepatocellular), Hep-G2 (hepatocellular), HeLa (cervical), MCF-7 (breast) cancer cells, and normal HL-7702 (hepatocyte) cells. As a general observation (Table S55), Co7 was more active (IC50 values = 0.80 nM) than the Co1–Co6, Co8–Co18, cisplatin, H-QL1, H-QL2, py, Phen, DPQ, DPPZ, MDP, ODP, PPT, ClPT, H-QL3, dpy, H-QL4, CoCl2·6H2O, mpy, and H-QL5 in all tested cells, and the cytotoxicity of Co1–Co18 against HeLa cells followed the order Co7 > Co5 > Co8 > Co11 > Co3 > Co10> Co9 > Co13 > Co1 > Co6 > Co4> Co2 > Co12 > Co18 > cisplatin > Co15 > Co17 > Co14 > Co16. The higher in vitro anticancer activity for Co7 may be due to the H-QL1 and DPPZ ligands. Such observed, different antitumor effects may be due to the electronic effect of the methyl group and the halogenated and more extended planar ligand of H-QL1 and DPPZ. Interestingly, Co1–Co18 showed low toxicity (IC50 > 60.0 μM) to normal HL-7702 (hepatocyte) cells. Compared with previously reported 8-hydroxyquinoline metal complexes (IC50 ≥ 1.00 nM),39−60Co7 exhibited higher cytotoxicity against HeLa cells (IC50 = 0.80 ± 0.21 nM).

Thus, ICP-MS assay showed that the Co(II) concentrations of Co7 ((22.96 ± 0.15 nmol of Co)/106 cells) and Co1 ((18.06 ± 0.05 nmol of Co)/106 cells) were significantly above those of control groups and cisplatin ((4.11 ± 0.59 nmol of Pt)/106 cells),15 with Co7 (0.80 nM) showing the highest cell accumulation of Co ((22.96 ± 0.15 nmol of Co)/106 cells) and a high extent in HeLa nuclear fraction (Table S56). Thus, Co7 (0.80 nM) showed higher toxicity on the HeLa (cervical) cancer cells possibly due to its better cellular uptake.

Thus, the induction of the level of c-myc, hTERT, and thus, telomerase in HeLa cells by Co1 (4.53 μM) and Co7 (0.80 nM) was investigated using a TRAP-silver staining assay and Western blot. As shown in Figure 2, Co7 (0.80 nM) showed a more inhibitory effect on c-myc, hTERT, and telomerase activity than that of Co1 (4.53 μM), suggesting that Co1 (4.53 μM) and Co7 (0.80 nM) inhibited c-myc and hTERT, and thus, telomerase levels were related to a variety of malignant cancers.61−65 Importantly, inhibition of telomerase in Co7 (0.80 nM)-treated cells was 44.10%, while that caused by Co1 (4.53 μM) only reached 7.13%.

Figure 2.

Figure 2

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Level of telomerase (A) and related factors (B,C) in HeLa cells induced by Co1 (4.53 μM) and Co7 (0.80 nM) at 24 h.

Furthermore, a G2/M population of 22.89% was observed in Co7 (0.80 nM)-treated cells, while the other corresponding G2/M populations of 20.27% and 12.35% were observed in the Co1 (4.53 μM) treated and control cells (Figure 3), suggesting that Co1 (4.53 μM) and Co7 (0.80 nM) caused G2/M cycle arrest. In addition, Co7 (0.80 nM) and Co1 (4.53 μM) could inhibit the expression of cyclin B1 and CDK1 in HeLa (cervical) cells (Figure S46), mainly due to the G2/M phase arrest (Figure 3) that they cause and their ability to inhibit telomerase.66−68 Further, immunofluorescence (Figure S47) and Western blot assays (Figure S46) were carried out. Clearly, Co7 (0.80 nM) and Co1 (4.53 μM) could up-regulate the H2A.X and cleaved-PARP levels, indicating that Co7 (0.80 nM) and Co1 (4.53 μM) remarkably induced DNA damage (Figures S46 and S47) and caused G2/M phase arrest following the order of Co7 > Co1.

Figure 3.

Figure 3

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Co7 (0.80 nM) and Co1 (4.53 μM) caused G2/M phase arrest for 24 h.

In addition, Co7 (0.80 nM) mainly accumulated in a nuclear fraction (Table S56) but also was distributed in the mitochondria. Thus, Co7 (0.80 nM) and Co1 (4.53 μM) caused obviously up-regulated reactive oxygen species (ROS, Figure S48), intracellular [Ca2+] (Figure 4), and caspase-3/9 levels (Figure S49 and S50), and down-regulated mitochondrial membrane potential (ΔΨm) (Figure S51) in HeLa cells, illustrating that the ΔΨm, ROS generation, intracellular [Ca2+], and caspase-3/9 played a key role in cancer mitochondrial function damage and apoptosis.15,69−72

Figure 4.

Figure 4

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Effects of Co7 (0.80 nM) and Co1 (4.53 μM) on the [Ca2+] level in HeLa cells at 24 h.

Therefore, to clarify the antimigration effects of Co7 (0.80 nM) and Co1 (4.53 μM) in HeLa cells (Figure 5a–d), the trans-well migration assay was carried out. It was found that Co7 (0.80 nM) could significantly induce cell migration at 0.80 nM than that of Co1 (4.53 μM).

Figure 5.

Figure 5

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Antimigration (a–d) and apoptosis (e–g) effect of Co7 (0.80 nM) and Co1 (4.53 μM) on HeLa cells for 24 h.

For this, to further investigate the ability of Co7 (0.80 nM) and Co1 (4.53 μM) to induce HeLa cell apoptotic by flow cytometry (FCM). As shown in Figure 5e–g, the percentages of apoptotic cells treated with Co7 (0.80 nM) and Co1 (4.53 μM) were 95.68% and 34.42%, respectively, suggesting that Co complexes could cause cell death at higher rates than other 8-quinolinate metal complexes.39−60

Furthermore, treatment of HeLa xenografts by Co7 (2.0 mg/kg/q2d) was related to significant reduction (TIR = 43.7%, p < 0.05) in tumor growth (Figure 6 and Tables S57–S59), which represents approximately 1.3-fold reduction compared with cisplatin-treated groups (IR = 35.2 ± 5.8%, p < 0.05).51,55,56,72−74 In addition, Co7 (2.0 mg/kg/q2d)-treated mice displayed no obvious signs of toxicity (Figure 6 and Tables S57–S59) as indicated by a relatively stable mouse body weight (mend= 20.5 ± 1.3 g) compared to solvent control (mend= 20.7 ± 1.4 g).

Figure 6.

Figure 6

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Tumor volume (A, mm3 ± SD) and images (B) of the HeLa tumors of Co7 (n = 6) for 21.0 days.

In conclusion, we have shown Co1–Co18 complexes containing mixed 5,7-dihalo-8-quinolinol (H-QL1–H-QL5) and 2,2′-bipyridine derivative-based ligands as potential Co(II) complexes with superior cytotoxicity compared with previously reported Co compounds. MTT studies have demonstrated that Co7 was ca. 300.6 times more cytotoxic than cisplatin (15.03 ± 1.05 μM), with IC50 values of 0.80 ± 0.21 nM while maintaining a high extent in HeLa nuclear fraction and targeting telomerase; thus, it was considerably less cytotoxic to normal HL-7702 (hepatocyte) cells. In addition, the antitumor activity of Co7 has been evaluated in vivo against HeLa xenograft growth (TIR = 43.7%, p < 0.05). It also inhibited telomerase activity, caused G2/M phase arrest, and induced mitochondrial dysfunction at a 104.6-fold lower concentration than Co1 (4.53 μM) in related assays. Thus, the superior cytotoxicity (IC50 = 0.80 ± 0.21 nM) and selectivity index of Co7 in comparison to cisplatin could make it a novel antitumor cobalt(II)-based drug.

Acknowledgments

We acknowledge professor Peng-Fei Yao for helping to perform the structure analysis of Co1–Co18.

Glossary

ABBREVIATIONS

SD

standard deviation

TIR

tumor growth inhibition rate

Biographies

Qi-Pin Qin received his Ph.D. degree from Guangxi Normal University in 2017 under the guidance of Prof. Zhen-Feng Chen and Hong Liang. Subsequently, he joined the faculty at Yulin Normal University in 2017 as a professor. His current research interest is focused on metal-based anticancer complexes, nanodrugs, and bioimaging agents. He has designed and synthesized over 300 new coordination compounds. The results have been published in over 70 research papers.

Hua-Hong Zou obtained his Ph.D. from Guangxi Normal University under the supervision of Prof. Fu-Pei Liang in 2015. Currently, he works at the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University. His research is focused on the design and mechanism of action of metal-based anticancer complexes, and assembly process and mechanism of polynuclear clusters in solution. He has published more than 120 papers related to the above research areas.

Fu-Pei Liang received his Ph.D. degree from the University of Zurich in 2001 and completed postdoctoral research at the University of Zurich in 2002. He is currently a Professor of the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry & Pharmacy of Guangxi Normal University. His research interests include the design and mechanism of action of metal-based anticancer complexes, multifunctional complexes, and synthesis and properties of high-nuclearity lanthanide clusters.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.9b00356.

  • Detailed experiments of Co1–Co18 (PDF)

Author Contributions

The manuscript was written through contributions of all authors.

We thank the National Natural Science Foundation of China (Nos. 21771043, 51572050, 21867017, and 21601038), the Natural Science Foundation of Guangxi (Nos. 2018GXNSFBA138021, 2015GXNSFDA139007, and 2016GXNSFAA380085), the Key Foundation Project of Colleges and Universities in Guangxi (No. ZD2014108), and the Innovative Team & Outstanding Talent Program of Colleges and Universities in Guangxi (2014–49) for their financial support.

The authors declare no competing financial interest.

Notes

The CCDC numbers for Co1–Co18 are 1916696–1916700, 1916702, 1916703, 1917994, 1917997, 1917998, 1918000, 1918001, 1918004, 1918006, 1918007, 1918010, 1918012, and 1918014.

Supplementary Material

ml9b00356_si_002.pdf (2.6MB, pdf)

References

  1. Gandioso A.; Shaili E.; Massaguer A.; Artigas G.; González-Cantó A.; Woods J. A.; Sadler P. J.; Marchán V. An integrin-targeted photoactivatable Pt(IV) complex as a selective anticancer pro-drug: synthesis and photoactivation studies. Chem. Commun. 2015, 51, 9169–9172. 10.1039/C5CC03180J. [DOI] [PubMed] [Google Scholar]
  2. Wang X.-Y.; Wang X.-H.; Guo Z.-J. Functionalization of platinum complexes for biomedical applications. Acc. Chem. Res. 2015, 48, 2622–2631. 10.1021/acs.accounts.5b00203. [DOI] [PubMed] [Google Scholar]
  3. Zheng Y.-R.; Suntharalingam K.; Johnstone T. C.; Lippard S. J. Encapsulation of Pt(IV) prodrugs within a Pt(II) cage for drug delivery. Chem. Sci. 2015, 6, 1189–1193. 10.1039/C4SC01892C. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Wong D. Y. Q.; Lau J. Y.; Ang W. H. Harnessing chemoselective imine ligation for tethering bioactive molecules to platinum(IV) prodrugs. Dalton Trans. 2012, 41, 6104–6111. 10.1039/c2dt30264k. [DOI] [PubMed] [Google Scholar]
  5. Noh J.; Kwon B.; Han E.; Park M.; Yang W.; Cho W.; Yoo W.; Khang G.; Lee D. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nat. Commun. 2015, 6, 6907. 10.1038/ncomms7907. [DOI] [PubMed] [Google Scholar]
  6. Hurley L. H. DNA and its associated processes as targets for cancer therapy. Nat. Rev. Cancer 2002, 2, 188–200. 10.1038/nrc749. [DOI] [PubMed] [Google Scholar]
  7. Pinato O.; Musetti C.; Sissi C. Pt-based drugs: the spotlight will be on proteins. Metallomics 2014, 6, 380–395. 10.1039/C3MT00357D. [DOI] [PubMed] [Google Scholar]
  8. Fang L.; Qin X.; Zhao J.; Gou S. Construction of dual stimuli-responsive platinum(IV) hybrids with NQO1 targeting ability and overcoming cisplatin resistance. Inorg. Chem. 2019, 58, 2191–2200. 10.1021/acs.inorgchem.8b03386. [DOI] [PubMed] [Google Scholar]
  9. Qin Q.-P.; Wang Z.-F.; Wang S.-L.; Luo D.-M.; Zou B.-Q.; Yao P.-F.; Tan M.-X.; Liang H. In vitro and in vivo antitumor activities of three novel binuclear platinum(II) complexes with 4′-substituted-2,2′:6′,2″-terpyridine ligands. Eur. J. Med. Chem. 2019, 170, 195–202. 10.1016/j.ejmech.2019.03.014. [DOI] [PubMed] [Google Scholar]
  10. Pettinari R.; Marchetti F.; Condello F.; Pettinari C.; Lupidi G.; Scopelliti R.; Mukhopadhyay S.; Riedel T.; Dyson P. J. Ruthenium(II)-arene RAPTA type complexes containing curcumin and bisdemethoxycurcumin display potent and selective anticancer activity. Organometallics 2014, 33, 3709–3715. 10.1021/om500317b. [DOI] [Google Scholar]
  11. Zutphen S.; Reedijk J. Targeting platinum anti-tumour drugs: Overview of strategies employed to reduce systemic toxicity. Coord. Chem. Rev. 2005, 249, 2845–2853. 10.1016/j.ccr.2005.03.005. [DOI] [Google Scholar]
  12. Jung Y.; Lippard S. J. Direct cellular responses to platinum-induced DNA damage. Chem. Rev. 2007, 107, 1387–1407. 10.1021/cr068207j. [DOI] [PubMed] [Google Scholar]
  13. Romero-Canelon I.; Salassa L.; Sadler P. J. The contrasting activity of iodido versus chlorido ruthenium and osmium arene azo-and imino-pyridine anticancer complexes: control of cell selectivity, cross-resistance, p53 dependence, and apoptosis pathway. J. Med. Chem. 2013, 56, 1291–1300. 10.1021/jm3017442. [DOI] [PubMed] [Google Scholar]
  14. Zeng L.; Gupta P.; Chen Y.; Wang E.; Ji L.-N.; Chao H.; Chen Z.-S. The development of anticancer ruthenium(II) complexes: from single molecule compounds to nanomaterials. Chem. Soc. Rev. 2017, 46, 5771–5804. 10.1039/C7CS00195A. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Qin Q.-P.; Qin J.-L.; Meng T.; Lin W.-H.; Zhang C.-H.; Wei Z.-Z.; Chen J.-N.; Liu Y.-C.; Liang H.; Chen Z.-F. High in vivo antitumor activity of cobalt oxoisoaporphine complexes by targeting G-quadruplex DNA, telomerase and disrupting mitochondrial functions. Eur. J. Med. Chem. 2016, 124, 380–392. 10.1016/j.ejmech.2016.08.063. [DOI] [PubMed] [Google Scholar]
  16. Hall M. D.; Failes T. W.; Yamamoto N.; Hambley T. W. Bioreductive activation and drug chaperoning in cobalt pharmaceuticals. Dalton Trans. 2007, 3983–3990. 10.1039/b707121c. [DOI] [PubMed] [Google Scholar]
  17. Failes T. W.; Hambley T. W. Models of hypoxia activated prodrugs: Co(III) complexes of hydroxamic acids. Dalton Trans. 2006, 1895–1901. 10.1039/b512322d. [DOI] [PubMed] [Google Scholar]
  18. Lopez-Sandoval H.; Londono-Lemos M. E.; Garza-Velasco R.; Poblano-Melendez I.; Granada-Macias P.; Gracia-Mora I.; Barba-Behrens N. Synthesis, structure and biological activities of cobalt(II) and zinc(II) coordination compounds with 2-benzimidazole derivatives. J. Inorg. Biochem. 2008, 102, 1267–1276. 10.1016/j.jinorgbio.2008.01.016. [DOI] [PubMed] [Google Scholar]
  19. Ott I.; Abraham A.; Schumacher P.; Shorafa H.; Gastl G.; Gust R.; Kircher B. Synergistic and additive antiproliferative effects on human leukemia cell lines induced by combining acetylenehexacarbonyldicobalt complexes with the tyrosine kinase inhibitor imatinib. J. Inorg. Biochem. 2006, 100, 1903–1906. 10.1016/j.jinorgbio.2006.06.013. [DOI] [PubMed] [Google Scholar]
  20. Eshkourfu R.; Cobeljic B.; Vujcic M.; Turel I.; Pevec A.; Sepcic K.; Zec M.; Radulovic S.; Srdic-Radic T.; Mitic D.; Andjelkovic K.; Sladic D. Synthesis, characterization, cytotoxic activity and DNA binding properties of the novel dinuclear cobalt(III) complex with the condensation product of 2-acetylpyridine and malonic acid dihydrazide. J. Inorg. Biochem. 2011, 105, 1196–1203. 10.1016/j.jinorgbio.2011.05.024. [DOI] [PubMed] [Google Scholar]
  21. Miodragovic D. U.; Bogdanovic G. A.; Miodragovic Z. M.; Radulovic M. Đ.; Novakovic S. B.; Kaludjerovic G. N.; Kozlowski H. Interesting coordination abilities of antiulcer drug famotidine and antimicrobial activity of drug and its cobalt(III) complex. J. Inorg. Biochem. 2006, 100, 1568–1574. 10.1016/j.jinorgbio.2006.05.009. [DOI] [PubMed] [Google Scholar]
  22. Nomiya K.; Yoshizawa A.; Tsukagoshi K.; Kasuga N. C.; Hirakawa S.; Watanabe J. Synthesis and structural characterization of silver(I), aluminium(III) and cobalt(II) complexes with 4-isopropyltropolone (hinokitiol) showing noteworthy biological activities. Action of silver(I)-oxygen bonding complexes on the antimicrobial activities. J. Inorg. Biochem. 2004, 98, 46–60. 10.1016/j.jinorgbio.2003.07.002. [DOI] [PubMed] [Google Scholar]
  23. Efthimiadou E. K.; Karaliota A.; Psomas G. Structure, antimicrobial activity and DNA-binding properties of the cobalt(II)–sparfloxacin complex. Bioorg. Med. Chem. Lett. 2008, 18, 4033–4037. 10.1016/j.bmcl.2008.05.115. [DOI] [PubMed] [Google Scholar]
  24. Lv J.; Liu T.; Cai S.; Wang X.; Liu L.; Wang Y. Synthesis, structure and biological activity of cobalt(II) and copper(II) complexes of valine-derived schiff bases. J. Inorg. Biochem. 2006, 100, 1888–1896. 10.1016/j.jinorgbio.2006.07.014. [DOI] [PubMed] [Google Scholar]
  25. Weiqun Z.; Wen Y.; Liqun X.; Xianchen C. N-Benzoyl-N′-dialkylthiourea derivatives and their Co(III) complexes: structure, and antifungal. J. Inorg. Biochem. 2005, 99, 1314–1319. 10.1016/j.jinorgbio.2005.03.004. [DOI] [PubMed] [Google Scholar]
  26. Bottcher A.; Takeuchi T.; Hardcastle K. I.; Meade T. J.; Gray H. B. Spectroscopy and electrochemistry of cobalt(III) Schiff base complexes. Inorg. Chem. 1997, 36, 2498–2504. 10.1021/ic961146v. [DOI] [Google Scholar]
  27. Takeuchi T.; Bottcher A.; Quezada C. M.; Meade T. J.; Gray H. B. Inhibition of thermolysin and human α-thrombin by cobalt(III) Schiff base complexes. Bioorg. Med. Chem. 1999, 7, 815–819. 10.1016/S0968-0896(98)00272-7. [DOI] [PubMed] [Google Scholar]
  28. Dimiza F.; Papadopoulos A. N.; Tangoulis V.; Psycharis V.; Raptopoulou C. P.; Kessissoglou D. P.; Psomas G. Biological evaluation of non-steroidal anti-inflammatory drugs-cobalt(II) complexes. Dalton Trans. 2010, 39, 4517–4528. 10.1039/b927472c. [DOI] [PubMed] [Google Scholar]
  29. Dimiza F.; Papadopoulos A. N.; Tangoulis V.; Psycharis V.; Raptopoulou C. P.; Kessissoglou D. P.; Psomas G. Biological evaluation of cobalt(II) complexes with non-steroidal anti-inflammatory drug naproxen. J. Inorg. Biochem. 2012, 107, 54–64. 10.1016/j.jinorgbio.2011.10.014. [DOI] [PubMed] [Google Scholar]
  30. Tsiliou S.; Kefala L.-A.; Perdih F.; Turel I.; Kessissoglou D. P.; Psomas G. Cobalt(II) complexes with non-steroidal anti-inflammatory drug tolfenamic acid: Structure and biological evaluation. Eur. J. Med. Chem. 2012, 48, 132–142. 10.1016/j.ejmech.2011.12.004. [DOI] [PubMed] [Google Scholar]
  31. Ott I.; Schmidt K.; Kircher B.; Schumacher P.; Wiglenda T.; Gust R. Antitumor-active cobalt-alkyne complexes derived from acetylsalicylic acid: Studies on the mode of drug action. J. Med. Chem. 2005, 48, 622–629. 10.1021/jm049326z. [DOI] [PubMed] [Google Scholar]
  32. Yamamoto N.; Renfrew A. K.; Kim B. J.; Bryce N. S.; Hambley T. W. Dual targeting of hypoxic and acidic tumor environments with a cobalt(III) chaperone complex. J. Med. Chem. 2012, 55, 11013–11021. 10.1021/jm3014713. [DOI] [PubMed] [Google Scholar]
  33. Tabrizi L.; McArdle P.; Erxleben A.; Chiniforoshan H. Nickel(II) and cobalt(II) complexes of lidocaine: Synthesis, structure and comparative in vitro evaluations of biological perspectives. Eur. J. Med. Chem. 2015, 103, 516–529. 10.1016/j.ejmech.2015.09.018. [DOI] [PubMed] [Google Scholar]
  34. Kawade V. A.; Kumbhar A. A.; Kumbhar A. S.; Näther C.; Erxleben A.; Sonawane U. B.; Joshi R. R. Mixed ligand cobalt(II) picolinate complexes: synthesis, characterization, DNA binding and photocleavage. Dalton Trans. 2011, 40, 639–650. 10.1039/C0DT01078B. [DOI] [PubMed] [Google Scholar]
  35. Garai A.; Pant I.; Banerjee S.; Banik B.; Kondaiah P.; Chakravarty A. R. Photorelease and cellular delivery of mitocurcumin from its cytotoxic cobalt(III) complex in visible light. Inorg. Chem. 2016, 55, 6027–6035. 10.1021/acs.inorgchem.6b00554. [DOI] [PubMed] [Google Scholar]
  36. Shahabadi N.; Kashanian S.; Darabi F. DNA binding and DNA cleavage studies of a water soluble cobalt(II) complex containing dinitrogen Schiff base ligand: The effect of metal on the mode of binding. Eur. J. Med. Chem. 2010, 45, 4239–4245. 10.1016/j.ejmech.2010.06.020. [DOI] [PubMed] [Google Scholar]
  37. Munteanu C. R.; Suntharalingam K. Advances in cobalt complexes as anticancer agents. Dalton Trans. 2015, 44, 13796–13808. 10.1039/C5DT02101D. [DOI] [PubMed] [Google Scholar]
  38. Obermoser V.; Baecker D.; Schuster C.; Braun V.; Kircher B.; Gust R. Chlorinated cobalt alkyne complexes derived from acetylsalicylic acid as new specific antitumor agents. Dalton Trans. 2018, 47, 4341–4351. 10.1039/C7DT04790H. [DOI] [PubMed] [Google Scholar]
  39. Deka B.; Sarkar T.; Banerjee S.; Kumar A.; Mukherjee S.; Deka S.; Saikia K. K.; Hussain A. Novel mitochondria targeted copper(II) complexes of ferrocenyl terpyridine and anticancer active 8-hydroxyquinolines showing remarkable cytotoxicity, DNA and protein binding affinity. Dalton Trans. 2017, 46, 396–409. 10.1039/C6DT03660K. [DOI] [PubMed] [Google Scholar]
  40. Havrylyuk D.; Howerton B. S.; Nease L.; Parkin S.; Heidary D. K.; Glazer E. C. Structure-activity relationships of anticancer ruthenium(II) complexes with substituted hydroxyquinolines. Eur. J. Med. Chem. 2018, 156, 790–799. 10.1016/j.ejmech.2018.04.044. [DOI] [PubMed] [Google Scholar]
  41. Afzal O.; Kumar S.; Haider M. R.; Ali M. R.; Kumar R.; Jaggi M.; Bawa S. A review on anticancer potential of bioactive heterocycle quinolone. Eur. J. Med. Chem. 2015, 97, 871–910. 10.1016/j.ejmech.2014.07.044. [DOI] [PubMed] [Google Scholar]
  42. Jia X.; Yang F.-F.; Li J.; Liu J.-Y.; Xue J.-P. Synthesis and in vitro photodynamic activity of oligomeric ethylene glycol–quinoline substituted zinc(II) phthalocyanine derivatives. J. Med. Chem. 2013, 56, 5797–5805. 10.1021/jm400722d. [DOI] [PubMed] [Google Scholar]
  43. Oliveri V.; Viale M.; Aiello C.; Vecchio G. New 8-hydroxyquinoline galactosides. The role of the sugar in the antiproliferative activity of copper(II) ionophores. J. Inorg. Biochem. 2015, 142, 101–108. 10.1016/j.jinorgbio.2014.09.017. [DOI] [PubMed] [Google Scholar]
  44. Tang Q.; Ni W.-X.; Leung C.-F.; Man W.-L.; Lau K.K.-K.; Liang Y.; Lam Y.-W.; Wong W.-Y.; Peng S.-M.; Liu G.-J.; Lau T.-C. Synthesis and antitumor activity of a series of osmium(VI) nitrido complexes bearing quinolinolato ligands. Chem. Commun. 2013, 49, 9980–9982. 10.1039/c3cc42250j. [DOI] [PubMed] [Google Scholar]
  45. Martin Santos C.; Cabrera S.; Rios-Luci C.; Padron J. M.; Lopez Solera I.; Quiroga A. G.; Medrano M. A.; Navarro-Ranninger C.; Aleman J. Novel clioquinol and its analogous platinum complexes: importance, role of the halogen substitution and the hydroxyl group of the ligand. Dalton Trans. 2013, 42, 13343–13348. 10.1039/c3dt51720a. [DOI] [PubMed] [Google Scholar]
  46. Correia I.; Adao P.; Roy S.; Wahba M.; Matos C.; Maurya M. R.; Marques F.; Pavan F. R.; Leite C. Q. F.; Avecilla F.; Pessoa J. C. Hydroxyquinoline derived vanadium(IV and V) and copper(II) complexes as potential anti-tuberculosis and anti-tumor agents. J. Inorg. Biochem. 2014, 141, 83–93. 10.1016/j.jinorgbio.2014.07.019. [DOI] [PubMed] [Google Scholar]
  47. Tardito S.; Barilli A.; Bassanetti I.; Tegoni M.; Bussolati O.; Franchi-Gazzola R.; Mucchino C.; Marchio L. Copper-dependent cytotoxicity of 8-hydroxyquinoline derivatives correlates with their hydrophobicity and does not require caspase activation. J. Med. Chem. 2012, 55, 10448–10459. 10.1021/jm301053a. [DOI] [PubMed] [Google Scholar]
  48. Barilli A.; Atzeri C.; Bassanetti I.; Ingoglia F.; Dall’Asta V.; Bussolati O.; Maffini M.; Mucchino C.; Marchio L. Oxidative stress induced by copper and iron complexes with 8-hydroxyquinoline derivatives causes paraptotic death of HeLa cancer cells. Mol. Pharmaceutics 2014, 11, 1151–1163. 10.1021/mp400592n. [DOI] [PubMed] [Google Scholar]
  49. Yang L.; Zhang J.; Wang C.; Qin X.; Yu Q.; Zhou Y.; Liu J. Interaction between 8-hydroxyquinoline ruthenium(II) complexes and basic fibroblast growth factors (bFGF): inhibiting angiogenesis and tumor growth through ERK and AKT signaling pathways. Metallomic 2014, 6, 518–531. 10.1039/C3MT00237C. [DOI] [PubMed] [Google Scholar]
  50. Gobec M.; Kljun J.; Sosic I.; Mlinaric-Rascan I.; Ursis M.; Gobec S.; Turel I. Structural characterization and biological evaluation of a clioquinol-ruthenium complex with copper-independent antileukaemic activity. Dalton Trans. 2014, 43, 9045–9051. 10.1039/C4DT00463A. [DOI] [PubMed] [Google Scholar]
  51. Qin Q.-P.; Wang Z.-F.; Huang X.-L.; Tan M.-X.; Zou B.-Q.; Liang H. Strong in vitro and vivo cytotoxicity of novel organoplatinum(II) complexes with quinoline-coumarin derivatives. Eur. J. Med. Chem. 2019, 184, 111751. 10.1016/j.ejmech.2019.111751. [DOI] [PubMed] [Google Scholar]
  52. Liu Y.-C.; Wei J.-H.; Chen Z.-F.; Liu M.; Gu Y.-Q.; Huang K.-B.; Li Z.-Q.; Liang H. The antitumor activity of zinc(II) and copper(II) complexes with 5, 7-dihalo-substituted-8-quinolinoline. Eur. J. Med. Chem. 2013, 69, 554–563. 10.1016/j.ejmech.2013.08.033. [DOI] [PubMed] [Google Scholar]
  53. Zou H.-H.; Meng T.; Chen Q.; Zhang Y.-Q.; Wang H.-L.; Li B.; Wang K.; Chen Z.-L.; Liang F.-P. Bifunctional mononuclear dysprosium complexes: single-ion magnet behaviors and antitumor activities. Inorg. Chem. 2019, 58, 2286–2298. 10.1021/acs.inorgchem.8b02250. [DOI] [PubMed] [Google Scholar]
  54. Ferraz K. S. O.; Reis D. C.; Da Silva J. G.; Souza-Fagundes E. M.; Baran E. J.; Beraldo H. Investigation on the bioactivities of clioquinol and its bismuth(III) and platinum(II, IV) complexes. Polyhedron 2013, 63, 28–35. 10.1016/j.poly.2013.07.008. [DOI] [Google Scholar]
  55. Qin Q.-P.; Wang Z.-F.; Tan M.-X.; Huang X.-L.; Zou H.-H.; Zou B.-Q.; Shi B.-B.; Zhang S.-H. Complexes of lanthanides(III) with mixed 2, 2′-bipyridyl and 5, 7-dibromo-8-quinolinoline chelating ligands as a new class of promising anti-cancer agents. Metallomics 2019, 11, 1005–1015. 10.1039/C9MT00037B. [DOI] [PubMed] [Google Scholar]
  56. Meng T.; Qin Q.-P.; Chen Z.-L.; Zou H.-H.; Wang K.; Liang F.-P. Discovery of a high in vitro and in vivo antitumor activities of organometallic ruthenium(II)-arene complexes with 5,7-dihalogenated-2-methyl-8-quinolinol. Dalton Trans. 2019, 48, 5352–5360. 10.1039/C9DT00866G. [DOI] [PubMed] [Google Scholar]
  57. Filak L. K.; Kalinowski D. S.; Bauer T. J.; Richardson D. R.; Arion V. B. Effect of the piperazine unit and metal-Binding Site Position on the Solubility and anti-proliferative activity of ruthenium(II)-and osmium(II)-arene complexes of isomeric indolo [3, 2-c] quinoline Piperazine Hybrids. Inorg. Chem. 2014, 53, 6934–6943. 10.1021/ic500825j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Heidary D. K.; Howerton B.; Glazer E. C. Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents. J. Med. Chem. 2014, 57, 8936–8946. 10.1021/jm501043s. [DOI] [PubMed] [Google Scholar]
  59. Chen D.; Cui Q. C.; Yang H.; Barrea R. A.; Sarkar F. H.; Sheng S.; Yan B.; Reddy G. P.; Dou Q. P. Clioquinol, a therapeutic agent for Alzheimer’s disease, has proteasome-inhibitory, androgen receptor–suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts. Cancer Res. 2007, 67, 1636–1644. 10.1158/0008-5472.CAN-06-3546. [DOI] [PubMed] [Google Scholar]
  60. Yu H.; Zhou Y.; Lind S. E.; Ding W.-Q. Clioquinol targets zinc to lysosomes in human cancer cells. Biochem. J. 2009, 417, 133–139. 10.1042/BJ20081421. [DOI] [PubMed] [Google Scholar]
  61. Molphy Z.; Prisecaru A.; Slator C.; Barron N.; McCann M.; Colleran J.; Chandran D.; Gathergood N.; Kellett A. Copper phenanthrene oxidative chemical nucleases. Inorg. Chem. 2014, 53, 5392–5404. 10.1021/ic500914j. [DOI] [PubMed] [Google Scholar]
  62. Reed J. E.; Arnal A. A.; Neidle S.; Vilar R. Stabilization of G-quadruplex DNA and inhibition of telomerase activity by square-planar nickel(II) complexes. J. Am. Chem. Soc. 2006, 128, 5992–5993. 10.1021/ja058509n. [DOI] [PubMed] [Google Scholar]
  63. De Cian A.; DeLemos E.; Mergny J.-L.; Teulade-Fichou M.-P.; Monchaud D. Highly efficient G-quadruplex recognition by bisquinolinium compounds. J. Am. Chem. Soc. 2007, 129, 1856–1857. 10.1021/ja067352b. [DOI] [PubMed] [Google Scholar]
  64. Choudhury J. R.; Guddneppanavar R.; Saluta G.; Kucera G. L.; Bierbach U. Tuning the DNA conformational perturbations induced by cytotoxic platinum-acridine bisintercalators: effect of metal cis/trans isomerism and DNA threading groups. J. Med. Chem. 2008, 51, 3069–3072. 10.1021/jm8003569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Zheng X.-H.; Chen H.-Y.; Tong M.-L.; Ji L.-N.; Mao Z.-W. Platinum squares with high selectivity and affinity for human telomeric G-quadruplexes. Chem. Commun. 2012, 48, 7607–7609. 10.1039/c2cc32942e. [DOI] [PubMed] [Google Scholar]
  66. Taggart A. K. P.; Teng S.-C.; Zakian V. A. Est1p as a cell cycle-regulated activator of telomere-bound telomerase. Science 2002, 297, 1023–1026. 10.1126/science.1074968. [DOI] [PubMed] [Google Scholar]
  67. Yu Q.; Liu Y.; Zhang J.; Yang F.; Sun D.; Liu D.; Zhou Y.; Liu J. Ruthenium(II) polypyridyl complexes as G-quadruplex inducing and stabilizing ligands in telomeric DNA. Metallomics 2013, 5, 222–231. 10.1039/c3mt20214c. [DOI] [PubMed] [Google Scholar]
  68. Celli G. B.; de Lange T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat. Cell Biol. 2005, 7, 712–718. 10.1038/ncb1275. [DOI] [PubMed] [Google Scholar]
  69. Krainz T.; Gaschler M. M.; Lim C.; Sacher J. R.; Stockwell B. R.; Wipf P. A Mitochondrial-Targeted Nitroxide Is a Potent Inhibitor of Ferroptosis. ACS Cent. Sci. 2016, 2, 653–659. 10.1021/acscentsci.6b00199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Xun Z.; Rivera-Sanchez S.; Ayala-Pen S.; Lim J.; Budworth H.; Skoda E. M.; Robbins P. D.; Niedernhofer L. J.; Wipf P.; McMurray C. T. Targeting of XJB-5–131 to Mitochondria Suppresses Oxidative DNA Damage and Motor Decline in a Mouse Model of Huntington’s Disease. Cell Rep. 2012, 2, 1137–1142. 10.1016/j.celrep.2012.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Wei M. C.; Zong W.-X.; Cheng E. H. Y.; Lindsten T.; Panoutsakopoulou V.; Ross A. J.; Roth K. A.; MacGregor G. R.; Thompson C. B.; Korsmeyer S. J. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001, 292, 727–730. 10.1126/science.1059108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Qin Q.-P.; Zou B.-Q.; Wang Z.-F.; Huang X.-L.; Zhang Y.; Tan M.-X.; Wang S.-L.; Liang H. High in vitro and in vivo antitumor activities of luminescent platinum(II) complexes with jatrorrhizine derivatives. Eur. J. Med. Chem. 2019, 183, 111727. 10.1016/j.ejmech.2019.111727. [DOI] [PubMed] [Google Scholar]
  73. Wang J.-Q.; Zhang P.-Y.; Ji L.-N.; Chao H. A ruthenium(II) complex inhibits tumor growth in vivo with fewer side-effects compared with cisplatin. J. Inorg. Biochem. 2015, 146, 89–96. 10.1016/j.jinorgbio.2015.02.003. [DOI] [PubMed] [Google Scholar]
  74. Qin Q. P.; Wang Z. F.; Huang X. L.; Tan M. X.; Shi B. B.; Liang H. High in Vitro and in Vivo Tumor-Selective Novel Ruthenium(II) Complexes with 3-(2′-Benzimidazolyl)-7-fluoro-coumarin. ACS Med. Chem. Lett. 2019, 10, 936–940. 10.1021/acsmedchemlett.9b00098. [DOI] [PMC free article] [PubMed] [Google Scholar]

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