Research paper
Cyclometalated Ir(III)-8-oxychinolin complexes acting as red-colored probes for specific mitochondrial imaging and anticancer drugs

https://doi.org/10.1016/j.ejmech.2020.112192Get rights and content

Highlights

  • Fourteen luminescent IrIII anti-tumor Ir-1Ir-14 complexes have been prepared.

  • Ir-1Ir-14 show highest antiproliferative activities toward HeLa cells.

  • Ir-1Ir-14 acted as red-color probes and targeted mitochondria.

  • Ir-1Ir-14 induces mitochondria dysfunction.

Abstract

A new class of luminescent IrIII antitumor agents, namely, [Ir(CP1)(PY1)2] (Ir-1), [Ir(CP1)(PY2)2] (Ir-2), [Ir(CP1)(PY4)2] (Ir-3), [Ir(CP2)(PY1)2] (Ir-4), [Ir(CP2)(PY4)2] (Ir-5), [Ir(CP3)(PY1)2]⋅CH3OH (Ir-6), [Ir(CP4)(PY4)2]⋅CH3OH (Ir-7), [Ir(CP5)(PY2)2] (Ir-8), [Ir(CP5)(PY4)2]⋅CH3OH (Ir-9), [Ir(CP6)(PY1)2] (Ir-10), [Ir(CP6)(PY2)2]⋅CH3OH (Ir-11), [Ir(CP6)(PY3)2] (Ir-12), [Ir(CP6)(PY41)2] (Ir-13), and [Ir(CP7)(PY1)2] (Ir-14), supported by 8-oxychinolin derivatives and 1-phenylpyrazole ligands was prepared. Compared with SK-OV-3/DDP and HL-7702 cells, the Ir-1Ir-14 compounds exhibited half maximal inhibitory concentration (IC50) values within the high nanomolar range (50 nM−10.99 μM) in HeLa cells. In addition, Ir-1 and Ir-3 accumulated and stained the mitochondrial inner membrane of HeLa cells with high selectivity and exhibited a high antineoplastic activity in the entire cervical HeLa cells, with IC50 values of 1.22 ± 0.36 μM and 0.05 ± 0.04 μM, respectively. This phenomenon induced mitochondrial dysfunction, suggesting that these cyclometalated IrIII complexes can be potentially used in biomedical imaging and Ir(III)-based anticancer drugs. Furthermore, the high cytotoxicity activity of Ir-3 is correlated with the 1-phenylpyrazole (H-PY4) secondary ligands in the luminescent IrIII antitumor complex.

Introduction

Since the introduction of Pt(II/IV)-based antineoplastic drugs [[1], [2], [3]] and other transition metal complexes (e.g., Ru, Au, Os, Ir, and Co), metal compounds have been explored for their potential use in tumor treatment [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]. Mitochondrial damage is associated with cancer cell death regulation [[21], [22], [23], [24]]; thus, compounds targeting the mitochondria have elicited considerable attention in imaging, cancer therapy, and medicinal chemistry [[25], [26], [27], [28], [29], [30], [31]]. In particular, luminescent IrIII antitumor compounds have been studied for biomedical imaging and various therapies [[32], [33], [34], [35], [36], [37]]. These compounds include [Ir(CˆN)2(NˆN)]+ (CˆN = 1-phenylisoquinoline, NˆN = 4,4-dimethoxy-2,2-bipyridyl) [5], planar diimine ligands IrIII complexes [21], bis-N-heterocyclic carbene (NHC) Ir(III) complexes [38], [(η5-C5Me5)IrCl(L)]PF6 (L = 9-ethyl-N-(pyridine-2-yl methylene)-9Hcarbazole-3-amine, C5Me5 = pentamethylcyclopentadienyl) [39], hydrophobic acyl Ir(III) complex–peptide hybrids [40], 1,4-substituted 2-pyridyl-N-phenyl triazoles organoiridium(III) complexes [41], thiabendazole Ir(III) biscyclometallated complexes [42], a pyrazole-appended quinoline-based Ir(III) complex [43], half-sandwich [(Cp∗Ir(S2C2B10H10))3(tris(2-(3-methylimidazol-2-ylidene)ethyl)amine)] and [(η5-Cp∗)Ir(2-(R′-phenyl)-R-pyridine)Cl] complexes [44,45], [IrCp∗Cl2]2 [46,47], pentamethylcyclopentadienyl Ir(III) complexes [48], [1-methyl-3-(pentamethylbenzyl)-imidazol-2-ylidene] Ir(I) complex [49], [Ir(COD)(IMes)(pdz)]Cl (pdz = pyridazine) and [Ir(COD)(IMes)(phth)]Cl (phth = phthalazine) [50], lidocaine and (pyren-1-yl)ethynyl Ir(III) complexes [51], luminescent heterobimetallic Ir(III)–Ru(II) complex [52], and [Ir(η5-Cpxbiph)(bpy)Cl]PF6 [53].

In addition, different 8-oxychinolin and its corresponding analogues have been designed as ligands to produce a new series of metal complexes [16,[54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91]] with high in vitro and in vivo antiproliferation properties [16,[54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91]]. Interestingly, 8-hydroxyquinoline–phthalocyanines Zn(II) complexes have demonstrated high cellular uptake and photocytotoxicity on hepatocarcinoma cells, with half maximal inhibitory concentration (IC50) values of 0.02–0.05 μM (λex = 670 nm) [91]. A series of quinoline–coumarin organoplatinum(II) complexes (Pt1Pt11) exhibits a green-colored luminescent function (λex = at 490–495 nm) and induces mitochondrial damage and A549/DDP cell apoptosis [29]. Nevertheless, Ir(III) complexes with 8-oxychinolin derivatives and 1-phenylpyrazole ligands have been rarely studied, and the antiproliferation mechanisms and biomedical imaging of these mixed complexes remain unexplored.

Here, we first described a novel series of cyclometalated Ir(III)-8-oxychinolin complexes, namely, [Ir(CP1)(PY1)2] (Ir-1), [Ir(CP1)(PY2)2] (Ir-2), [Ir(CP1)(PY4)2] (Ir-3), [Ir(CP2)(PY1)2] (Ir-4), [Ir(CP2)(PY4)2] (Ir-5), [Ir(CP3)(PY1)2]⋅CH3OH (Ir-6), [Ir(CP4)(PY4)2]⋅CH3OH (Ir-7), [Ir(CP5)(PY2)2] (Ir-8), [Ir(CP5)(PY4)2]⋅CH3OH (Ir-9), [Ir(CP6)(PY1)2] (Ir-10), [Ir(CP6)(PY2)2]⋅CH3OH (Ir-11), [Ir(CP6)(PY3)2] (Ir-12), [Ir(CP6)(PY41)2] (Ir-13), and [Ir(CP7)(PY1)2] (Ir-14), with 5,7-dichloro-2-methyl-8-quinolinol (H-CP1), 5,7-dibromo-2-methyl-8-quinolinol (H-CP2), 5,7-diiodo-8-hydroxyquinoline (H-CP3), 5,7-dichloro-8-quinolinol (H-CP4), 5,7-dibromo-8-quinolinol (H-CP5), 5-chloro-8-hydroxy-quinoline (H-CP6), or 8-hydroxy-2-methylquinoline (H-CP7) as the primary ligands, and 2-phenylpyridine (H-PY1), 3-methyl-2-phenylpyridine (H-PY2), 7,8-benzoquinoline (H-PY3), and 1-phenylpyrazole (H-PY4) as the secondary ligands (Scheme 1). Moreover the effects of the Ir-1Ir-14 probes on the mitochondria were explored in HeLa cancer cells. These probes demonstrated high antiproliferation activity.

Section snippets

Synthesis and stability

Four [Ir(CˆN)2Cl]2 (CˆN = deprotonated H-PY1−H-PY4) complexes were synthesized following the method of Qin and Watts (Scheme 1) [92,93]. Then, 14 cyclometalated Ir(III)-8-oxychinolin complexes of type [Ir(OˆN)(CˆN)2], where OˆN is a deprotonated 8-oxychinolin ramification of H-CP1−H-CP7, were synthesized with good yields (85.1%–93.4%) using the reaction of Cl bridging [Ir(CˆN)2Cl]2 complexes in CH2Cl2 (0.2 mL) and CH3OH (5.0 mL). The synthesized Ir-1Ir-14 probes were fully characterized (

Conclusions

In conclusion, 14 luminescent IrIII antitumor compounds, namely, Ir-1Ir-14, with different 8-oxychinolin derivatives and 1-phenylpyrazole ligands are prepared. The newly synthesized Ir-1Ir-14 compounds exhibit higher antiproliferative activities (50 nM−10.99 μM) against HeLa cells and SK-OV-3/DDP cells than cisplatin. Notably, Ir-1 and Ir-3 can be fleetly taken into HeLa cells and then localized to MIM to induce mitochondrial dysfunction. This study demonstrates that these cyclometalated IrIII

Synthesis

Four [Ir(CˆN)2Cl]2 (CˆN = deprotonated H-PY1−H-PY4) complexes were synthesized following the method of Qin and Watts (Scheme 1) [92,93]. The brown block products (Ir-1Ir-14) were prepared by treating with 2.0 mmol of H-CP1−H-CP7 with 1.0 mmol of [Ir(OˆN)(CˆN)2] in CH2Cl2 (0.2 mL) and CH3OH (5.0 mL) solution at 80 °C for 12 h. The yields were within the range of 85.1%–93.4%.

Data of Ir-1. Yield: 85.1%. ESI–MS m/z: 727.6 [M+H]+. Elemental analysis calcd (%) for C32H22Cl2IrN3O: C 52.82, H 3.05, N

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

We would like to thank the National Natural Science Foundation of China (Nos. 21771043, 51572050, 21601038, 21867017, and 21261025), the Guangxi Natural Science Foundation (Nos. 2016GXNSFAA380085, 2015GXNSFDA139007, and 2018GXNSFBA138021), the Guangxi Key Laboratory of Electrochemical and Magnetochemical Functional Materials (EMFM20162107), the Key Foundation Project of Colleges and Universities in Guangxi (No. ZD2014108), the State Key Laboratory for Chemistry and Molecular Engineering of

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