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. 2019 Nov 6;10(12):1614–1619. doi: 10.1021/acsmedchemlett.9b00337

Novel Quinoline-based Ir(III) Complexes Exhibit High Antitumor Activity in Vitro and in Vivo

Yan Yang †,‡, Yi-Dong Bin †,‡, Qi-Pin Qin †,∥,*, Xu-Jian Luo †, Bi-Qun Zou §,∥,*, Hua-Xin Zhang ‡,*
PMCID: PMC6912864  PMID: 31857836

Abstract

graphic file with name ml9b00337_0007.jpg

Eight novel Ir(III) complexes listed as [Ir(H–P)2(P)]PF6 (PyP-Ir), [Ir(H–P)2(dMP)]PF6 (PydMP-Ir), [Ir(H–P)2(MP)]PF6 (PyMP-Ir), [Ir(H–P)2(tMP)]PF6 (PytMP-Ir), [Ir(MPy)2(P)]PF6 (MPyP-Ir), [Ir(MPy)2(dMP)]PF6 (MPydMP-Ir), [Ir(MPy)2(MP)]PF6 (MPyMP-Ir), [Ir(MPy)2((tMP)]PF6 (MPytMP-Ir) with 2-phenylpyri-dine (H–P) and 3-methyl-2-phenylpyridine (MPy) as ancillary ligands and pyrido-[3,2-a]-pyrido[1′,2′:1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido [3,2-a]-pyrido-[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (tMP) as main ligands, respectively, were designed and synthesized to fully characterize and explore the effect of their toxicity on cancer cells. Cytotoxic mechanism studies demonstrated that the eight Ir(III) complexes exhibited highly potent antitumor activity selectively against cancer cell lines NCI-H460, T-24, and HeLa, and no activity against HL-7702, a noncancerous cell line. Among the eight Ir(III) complexes, MPytMP-Ir exhibited the highest cytotoxicity with an IC50 = 5.05 ± 0.22 nM against NCI-H460 cells. The antitumor activity of MPytMP-Irin vitro could be contributed to the steric or electronic effect of the methyl groups, which induced telomerase inhibition and damaged mitochondria in NCI-H460 cells. More importantly, MPytMP-Ir displayed a superior inhibitory effect on NCI-H460 xenograft in vivo than cisplatin. Our work demonstrates that MPytMP-Ir could potentially be developed as a novel potent Ir-based antitumor drug.

Keywords: Ir(III) complexes, telomerase inhibition, antitumor activity, damaging mitochondria

The capacity of tumor cells to grow, invade, and metastasize to other organs is the driving forces in cancer development.1−3 Identifying and developing new anticancer drugs and exploring their putative antitumor mechanisms is an urgent need. Since the discovery of cisplatin, platinum compounds were the most successful representative drugs in clinical treatment.4 However, due to their undesired side effects, considerable efforts have been made to develop nonplatinum compounds.5,6 Recently, RuII/III, IrIII, RhIII, PdII, and AuIII, and other complexes have received significant attention because of their various cellular targets and mechanisms of action.7−13 The octahedral polypyridyl Ir(III) cyclometalated complexes could induce apoptosis via regulating protein kinases interactions,14−17 mitochondrial membrane disruption,18,19 or DNA binding.20−22

Heterocyclic compounds have been widely studied and developed as potent biological compounds.23 The 5,8-quinolinediones derived from 8-hydroxyquinoline have demonstrable anticancer activity23 and are used as anticancer, antifungal, and antimalarial agents.24−28 Additionally, several 7-aminoquinoline quinones, Streptonigrin, and clioquinol derivatives,29−31 and their Ni(II),32 Yb(III),33 Sm(III),34 and La(III)35 complexes have shown activity against senile dementia, intestinal amebiasis, and cancer.29−36

Inspired by the previous research and the high anticancer activity of quinoline derivatives, here we used easily acquired 8-hydroxylquinoline derivative 6,7- dichloro-5,8-quinolinequinone with an AI50 = 1.3 ± 0.9 μM and MIC = 6.3–12.5 μg/mL37 to modify and synthesize four quinoline derivatives as main ligands: pyrido-[3,2-a]-pyrido[1′,2′:1,2]imidazo[4,5-c]phenazine (P), 12,13-dimethyl pyrido-[3,2-a]-pyrido[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (dMP), 2-methylpyrido [3,2-a]-pyrido-[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (MP), and 2,12,13-trimethylpyrido-[3,2-a]-pyrido-[1′,2′:1,2]-imidazo-[4,5-c]-phenazine (tMP) (Chart S1). We studied and characterized their antineoplastic activity and explored the underlying mechanisms. Based on previously reported efficacy of [Ir(C^N)2(N^N)]+,38−41 we synthesized eight novel quinoline based organoiridium(III) complexes and fully characterized them (Figures S1–S48, structures shown in Chart 1). Furthermore, we also noted through HPLC experiments that MPydMP-Ir and MPytMP-Ir were stable for 48 h in Tris-HCl buffer (Figures S47 and S48).

Chart 1. Chemical Structures of the Eight IrIII Complexes.

Chart 1

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We studied the cytotoxic effects of the eight novel Ir(III) complexes and the free ancillary ligands against NCI-H460 (nonsmall lung), T-24 (bladder), HeLa (cervical), and HL-7702 (hepatocyte) using the MTT assay.42−44 The results are shown in Table S1. We found that the IC50 values of the free ancillary ligands against cancer cells were >50 μM except in HeLa cells. In contrast, the novel Ir(III) complexes exhibited much superior cytotoxic activities against all the tested human cancer cell lines except HL-7702 (noncancerous cells) compared to the free ancillary ligands and cisplatin (positive control). Significantly, their cytotoxic activity decreased in the following order: MPytMP-Ir, MPydMP-Ir, PytMP-Ir, PydMP-Ir, MPyMP-Ir, PyMP-Ir, MPyP-Ir, and PyP-Ir against all tested cancer cells except the noncancerous HL-7702. Furthermore, among the eight novel Ir(III) complexes, MPytMP-Ir exhibited significantly superior and sensitive cytotoxic activity with a much lower IC50 (5.05 ± 0.22 nM) against NCI-H460 cells. Of course, the methyl electron-donating group does enhance the cytotoxic activity via a combination of steric and electronic effects, such as polypyridyl, pyrazine, and pyrazole ring.4,16,40,45,46 Owing to its highly efficient and selective cytotoxic activity against the NCI-H460 cancer cells compared to cisplatin, we performed further in-depth studies using MPytMP-Ir.16,40 We also compared its effectiveness to another synthesized compound MPydMP-Ir and used the sensitive NCI-H460 cell line to further study the potential interactive mechanisms of its biological cytotoxic influences.40−51

Following the treatment of NCI-H460 cells with MPydMP-Ir and MPytMP-Ir at the corresponding IC50 concentration for 24 h (Figure 1), apoptosis induction was seen in 38.7% of the MPydMP-Ir treated cells, while 92.6% cells were apoptotic following treatment with MPytMP-Ir. These results underscore the greatly superior apoptosis induction capacity of MPytMP-Ir.

Figure 1.

Figure 1

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MPydMP-Ir (125 nM) and MPytMP-Ir (5 nM) induced NCI-H460 cell apoptosis after 24 h treatment.

A 24-h treatment of NCI-H460 cells with MPydMP-Ir and MPytMP-Ir resulted in 19.75% and 49.40% inhibition of telomerase activity, respectively (Figure 2). This clearly demonstrates that MPytMP-Ir could induce much stronger telomerase inhibition than MPydMP-Ir. This provides more evidence that increasing the methyl electron-donating groups could enhance the telomerase inhibition via a combination of steric and electronic effects.45,52−58 As expected, c-myc and/or hTERT proteins were effectively downregulated in MPydMP-Ir and MPytMP-Ir treated cells (Figure S1) and led to telomerase inhibition.52−58

Figure 2.

Figure 2

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Telomerase inhibition in NCI-H460 cells treated with MPydMP-Ir (125 nM) and MPytMP-Ir (5 nM).

Previous studies have shown that telomerase inhibition was related to cell cycle arrest in cancer cells.43,59−66 We observed that 68.70% of the untreated NCI-H460 tumor cells were in the G1 phase, while this increased to 84.09% after treatment with MPytMP-Ir (Figure 3). However, MPydMP-Ir treatment resulted in a 1.38% decrease in cells at the G1 phase. We could conclude that the antineoplastic activity of MPytMP-Ir was at least partly due to decreased proliferation as the cells were arrested in G1 phase.43,59−66 The expression level of CDK2, a key player in cell cycle progression, decreased slightly after treatment with MPydMP-Ir, while a slight increase in Cyclin D1 was observed due to G1 arrest (Figure S2). Of note, treatment with MPytMP-Ir resulted in a significant decrease in cyclin D1-CDK2 complex.66 These results are consistent with our previous expectations and investigation.

Figure 3.

Figure 3

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NCI-H460 cell cycle analysis following MPydMP-Ir (125 nM) and MPytMP-Ir (5 nM) treatment.

We next assessed the effect of MPytMP-Ir treatment on mitochondria using the JC-1 fluorescent mitochondrial probe. We saw that the green JC-1 fluorescence (damaged mitochondria, decrease in mitochondrial membrane potential [MMP]) was observed in 13.3% of NCI-H460 cells treated with MPydMP-Ir. Strikingly, 92.2% of the cells treated with MPytMP-Ir showed green fluorescence, i.e., damaged mitochondria (Figure 4). Thus, the high methyl electron-donating levels in MPytMP-Ir could dramatically increase the effectiveness of this compound on MMP and, in turn, on apoptosis induction.67−70

Figure 4.

Figure 4

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Degradation of MMP in MPydMP-Ir (125 nM) and MPytMP-Ir (5 nM) treated cells.

In addition, we observed that MPytMP-Ir resulted in a much more significant (Figure S2) accumulation of apaf-1 and cytochrome than MPydMP-Ir. Taken together, these results demonstrate that MPytMP-Ir could cause apoptosis in NCI-H460 cells by inducing mitochondrial dysfunction.64−78

Treatment with MPytMP-Ir (10.0 mg/kg per 2 days) led to a 47.1% tumor growth inhibition on day 12.0, significantly higher than that reported for cisplatin (25.5%) (Figure 5 and Tables S2–S4).71−77 Moreover, MPytMP-Ir treatment did not adversely affect body weight (average body weight pre- and post-treatment; control group, 18.47 ± 1.08 and 20.37 ± 0.52 g; treated group, 18.03 ± 1.28 and 20.28 ± 0.47g). Thus, MPytMP-Ir exhibited less toxicity and better safety profile than that reported for cisplatin.64,71−77 In summary, MPytMP-Ir displayed effective inhibition of tumor growth in NCI-H460 models.

Figure 5.

Figure 5

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Tumor volumes (A, mm3 ± SD), tumor weights (B, g ± SD), body weights (C, g ± SD), and photograph (D) of NCI-H460 xenograft following MPytMP-Ir treatment (n = 6). **p < 0.05 relative to control.

In conclusion, we first synthesized eight novel quinoline-based Ir(III) complexes and demonstrated their high cytotoxic activity. Based on the first set of cytotoxicity experiments, we chose two representative complexes to further explore the effect of their toxicity in selected cancer cell lines. MPytMP-Ir exhibited the most potent in vitro cytotoxicity against human cancer cells. MPytMP-Ir also showed the highest selective cytotoxic against NCI-H460 cancer cells and was most potent in inhibiting telomerase activity. MPytMP-Ir-induced cytotoxicity in the NCI-H460 tumor cells was exerted via G1 cell cycle arrest, leading to inhibition of cell proliferation. Additionally, MPytMP-Ir could induce cellular apoptosis by activating the mitochondrial dysfunction pathway in the NCI-H460 tumor cells. Last but not least, MPytMP-Ir displayed effective inhibition of tumor growth in NCI-H460 xenograft models and exhibited less toxicity and even better safety profile than cisplatin. Through this study, we have identified a novel potent antitumor drug, MPytMP-Ir and have demonstrated its superior efficacy compared to cisplatin.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.9b00337.

  • Experimental procedures for the quinoline-based Ir(III) complexes (PDF)

Author Contributions

⊥ These authors made an equal contribution to this work.

We thank the National Natural Science Foundation of China (Nos. 51463023, 51962035, 21867017, and 21461028), Guangxi Natural Science Foundation (No. 2018GXNSFBA138021), Yulin Normal University for High-level Talents (No. G2019ZK04), and the Innovative Team and Outstanding Talent Program of Colleges and Universities in Guangxi (2014-49 and 2017-38) for funding this work.

The authors declare no competing financial interest.

Supplementary Material

ml9b00337_si_002.pdf (2.6MB, pdf)

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