Synthesis and Evaluation of in vitro and in vivo Anticancer Activities of 8-Hydroxyquinoline-modified Platinum(II) Polypyridyl Complexes

doi:10.6023/A25090300

Abstract

To overcome the problems of high toxicity and poor selectivity of cisplatin-based drugs, a novel 8-hydroxyquinoline-modified platinum(II) polypyridine complex, [Pt(IQ-O)(Py)]Cl (PyPt), was synthesized using 5,7-diiodo-8-hydroxyquinoline platinum(II) complex [Pt(IQ-O)(DMSO)Cl] (PtIQ) as an intermediate and 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)quinolin-8-ol (Py) as an auxiliary ligand. The structures of PyPt and PtIQ were characterized by nuclear magnetic resonance (NMR), ultraviolet-visible spectrophotometry (UV-vis), infrared spectroscopy (IR) and elemental analysis. Density functional theory calculations showed that the energy gaps between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of PyPt and PtIQ were 2.3 eV and 3.2 eV, respectively, indicating that there were differences in the anticancer activities of PyPt and PtIQ. Comparing with human lung cancer cells (A549) and human lung cancer cisplatin-resistant cells (A549/DDP), PyPt exhibited better inhibitory effects on human breast cancer cells (MDA-MB-231), with an IC₅₀ value of (0.05±0.04) μmol/L, which was superior to cis-[PtCl₂(DMSO)₂] (>50.0 μmol/L), PtIQ [(9.0±0.1) μmol/L], IQ-OH (>50.0 μmol/L), Py (>50.0 μmol/L) and the clinical drug cisplatin [(11.1±0.3) μmol/L]. Additionally, PyPt had little toxicity to normal liver cells (HL-7702), indicating that PyPt had better selectivity for MDA-MB-231 cancer cells. Flow cytometry and microscopic imaging showed that PyPt could significantly induce apoptosis [ca. (48.0±0.9)%] and senescence [IOD value=(1.9±0.1)×10⁶] in cells, which was superior to PtIQ [apoptosis rate=(44.2±0.6)%, senescence IOD value=(1.8±0.1)×10⁶] and the blank control group (apoptosis rate=(6.1±0.6)%, senescence IOD value=(2.1±0.1)×10⁵). Molecular docking results indicated that the binding energy of PyPt with the DNA strand in telomerase reverse transcriptase (hTERT) was –53.0 kJ/mol, which was significantly stronger than that of PtIQ (–30.2 kJ/mol). Comet assay, immunofluorescence assay, real time-PCR detection (RT-qPCR) and western blotting experiments showed that PyPt induced apoptosis and senescence in MDA-MB-231 cancer cells by inhibiting hTERT expression, activating caspase3/7 proteins and inducing DNA damage, and its induction ability was stronger than that of PtIQ. In vivo experiments showed that PyPt had a good inhibitory effect on MDA-MB-231 solid tumors with an inhibition rate of 44.4%, and did not affect the survival rate (n=6) and body weight of mice. In conclusion, a novel 8-hydroxyquinoline-modified platinum(II) polypyridine anticancer metal drug targeting DNA and hTERT was developed.

Key words: platinum(II) complexes, 8-hydroxyquinoline derivatives, anticancer activity, DNA damage, human telomerase reverse transcriptase (hTERT) inhibition

Cite this article

Qipin Qin, Qiuming Li, Jumei Zhang, Mingxiong Tan, Hong Liang. Synthesis and Evaluation of in vitro and in vivo Anticancer Activities of 8-Hydroxyquinoline-modified Platinum(II) Polypyridyl Complexes[J]. Acta Chimica Sinica, 2026, 84(1): 109-118.

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Fig. & Tab. 11

Figure 1. Synthesis of PyPt and PtIQ

Figure 2. The DFT calculated HOMO-LUMO gap of PyPt and PtIQ

Entry^a	A549	A549/DDP	MDA-MB- 231	HL-7702	SI^b
Py	>50.0	>50.0	>50.0	>50.0	ca. 1.0
IQ-OH	>50.0	>50.0	>50.0	>50.0	ca. 1.0
cis-[PtCl₂- (DMSO)₂]	>50.0	>50.0	>50.0	>50.0	ca. 1.0
PtIQ	7.2±0.5	6.1±0.9	9.0±0.1	35.5±0.4	4.0
PyPt	1.0±0.2	0.9±0.3	0.05±0.04	>50.0	>980.4
PtIQ+Py	7.0±0.5	6.0±0.1	8.8±0.4	36.2±0.7	4.2
顺铂	13.0±0.6	>50.0	11.1±0.3	15.6±0.2	1.4

Table 1. The IC50 values of cisplatin, PyPt and PtIQ against MDA-MB-231 and HL-7702 cells

Figure 3. Apoptosis of MDA-MB-231 cells induced by PyPt (0.05 μmol/L) and PtIQ (9.0 μmol/L)

Figure 4. Cellular senescence of MDA-MB-231 cells induced by PyPt (0.05 μmol/L) and PtIQ (9.0 μmol/L) Image multiple: 20 μm

Figure 5. Induction of DNA damage in MDA-MB-231 cells by PyPt (0.05 μmol/L) and PtIQ (9.0 μmol/L) for 48 h using neutral comet assay Image multiple: 100 μm.

Figure 6. TRF2 foci and γ-H2AX quantification detected by immunofluorescence on MDA-MB-231 cells treated with PyPt (0.05 μmol/L) and PtIQ (9.0 μmol/L) for 48 h (n=3) Image multiple: 10 μm.

Figure 7. Molecular docking analysis of PyPt and PtIQ against the target hTERT DNA

Figure 8. The hTERT RNA expression in MDA-MB-231 cells treated with PyPt (0.05 μmol/L) and PtIQ (9.0 μmol/L) for 48 h was determined using RT-PCR

Figure 9. Complexes PyPt (0.05 μmol/L) and PtIQ (9.0 μmol/L) triggered DNA damage and apoptosis response pathways in MDA-MB-231 cells after treatment for 48 h

Figure 10. In vivo antitumor activity of PyPt (5.0 mg/kg every 2.0 days) in the MDA-MB-231-bearing xenograft mouse model. p value<0.05

References 28

[1]	Štarha, P.; Křikavová, R. Coordin. Chem. Rev. 2024, 501, 215578. doi: 10.1016/j.ccr.2023.215578
[2]	Cai, L.; Chen, H.; Wang, Y.; Zhang, J.; Song, D.; Tan, Y.; Guo, Z.; Wang, X. J. Med. Chem. 2025, 68, 9162. doi: 10.1021/acs.jmedchem.4c02509
[3]	Liang, B.-B.; Liu, Q.; Liu, B.; Yao, H.-G.; He, J.; Tang, C.-F.; Peng, K.; Su, X.-X.; Zheng, Y.; Ding, J.-Y.; Shen, J.; Cao, Q.; Mao, Z.-W. Angew. Chem., Int. Ed. 2023, 62, e202312170. doi: 10.1002/anie.v62.44
[4]	Chen, S.; Zhou, Q.; Ng, K.-Y.; Xu, Z.; Xu, W.; Zhu, G. Inorg. Chem. Front. 2024, 11, 3085. doi: 10.1039/D4QI00459K
[5]	Sun, P.; Wang, J.-Q.; Xie, Q.; Ren, X.-L.; Qiao, X.; Xu, J.-Y. Inorg. Chem. Front. 2024, 11, 2914. doi: 10.1039/D4QI00386A
[6]	(a) Mo, X.; Chen, K.; Chen, Z.; Chu, B.; Liu, D.; Liang, Y.; Xiong, J.; Yang, Y.; Cai, J. Y.; Liang, F. P. Inorg. Chem. 2021, 60, 16128. doi: 10.1021/acs.inorgchem.1c01763 pmid: 25575314
	(b) Qin, Q.-P.; Wang, S.-L.; Tan, M.-X.; Liu, Y.-C.; Meng, T.; Zou, B.-Q.; Liang, H. Eur. J. Med. Chem. 2019, 161, 334. doi: S0223-5234(18)30921-8 pmid: 25575314
	(c) Qin, Q.-P.; Chen, Z.-F.; Qin, J.-L.; He, X.-J.; Li, Y.-L.; Liu, Y.-C.; Huang, K.-B.; Liang, H. Eur. J. Med. Chem. 2015, 92, 302. doi: 10.1016/j.ejmech.2014.12.052 pmid: 25575314
[7]	Shao, T.-M.; Wei, Z.-Z.; Luo, X.-L.; Qin, Q.-P.; Tan, M.-X.; Zeng, J.-J.; Liang, C.-J.; Liang, H. New J. Chem. 2022, 44, 19885. doi: 10.1039/D0NJ04753H
[8]	Yang, Y.; Du, L.-Q.; Huang, Y.; Liang, C.-J.; Qin, Q.-P.; Liang, H. J. Inorg. Biochem. 2023, 241, 112152. doi: 10.1016/j.jinorgbio.2023.112152
[9]	Wu, R.-C.; Zhang, J.-M.; Huang, X.-Q.; Li, Q.-M.; Zhou, Z.; Liang, H.; Tan, M.-X.; Qin, Q.-P. New J. Chem. 2025, 49, 6561. doi: 10.1039/D4NJ04292A
[10]	(a) Zhang, M.; Li, L.; Li, S.; Liu, Z.; Zhang, N.; Sun, B.; Wang, Z.; Jia, D.; Liu, M.; Wang, Q. J. Med. Chem. 2023, 66, 3393. doi: 10.1021/acs.jmedchem.2c01895 pmid: 36891739
	(b) Meng, T.; Tang, S.-F.; Qin, Q.-P.; Liang, Y.-L.; Wu, C.-X.; Wang, C.-Y.; Yan, H.-T.; Dong, J.-X.; Liu, Y.-C. Med. Chem. Commun. 2016, 7, 1802. doi: 10.1039/C6MD00201C pmid: 36891739
	(c) Ferraz, K.S.O.; Reis, D. C.; Da Silva, J. G.; Souza-Fagundes, E. M.; Baran, E. J.; Beraldo, H. Polyhedron 2013, 63, 28. doi: 10.1016/j.poly.2013.07.008 pmid: 36891739
[11]	Santos, C. M.; Cabrera, S.; Rios-Luci, C.; Padron, J. M.; Solera, I. L.; Quiroga, A. G.; Medrano, M. A.; Navarro-Ranninger, C.; Aleman, J. Dalton Trans. 2013, 42, 13343. doi: 10.1039/c3dt51720a
[12]	Živković, M. D.; Kljun, J.; Ilic-Tomic, T.; Pavic, A.; Veselinović, A.; Manojlović, D. D.; Nikodinovic-Runic, J.; Turel, I. Inorg. Chem. Front. 2018, 5, 39. doi: 10.1039/C7QI00299H
[13]	Low, K. H.; Xu, Z. X.; Xiang, H. F.; Chui, S. S. Y.; Roy, V. A. L.; Che, C. M. Chem. Asian J. 2011, 6, 3223. doi: 10.1002/asia.v6.12
[14]	Zhou, C.-H.; Zhao, X. J. Organomet. Chem. 2011, 696, 3322. doi: 10.1016/j.jorganchem.2011.07.003
[15]	(a) Qin, L.-Q.; Wei, Z.-Z.; Yang, L.; Qin, Q.-P.; Zeng, J.-J.; Tan, M.-X.; Liang, H. Med. Chem. Res. 2021, 30, 1419. doi: 10.1007/s00044-021-02739-0
	(b) Wang, F.-Y.; Yang, L.-M.; Wang, S.-S.; Lu, H.; Wang, X.-S.; Lu, Y.; Ni, W.-X.; Liang, H.; Huang, K.-B. J. Med. Chem. 2024, 67, 6738. doi: 10.1021/acs.jmedchem.4c00285
[16]	Qin, Q.-P.; Wang, S.-L.; Tan, M.-X.; Wang, Z.-F.; Luo, D.-M.; Zou, B.-Q.; Liu, Y.-C.; Yao, P.-F.; Liang, H. Eur. J. Med. Chem. 2018, 158, 106. doi: S0223-5234(18)30780-3 pmid: 30205260
[17]	Lunagariya, M. V.; Thakor, K. P.; Varma, R. R.; Waghela, B. N.; Pathak, C.; Patel, M. N. Med. Chem. Commun. 2018, 9, 282. doi: 10.1039/C7MD00472A
[18]	Li, L.; Chen, Y.; Zhang, M.; Li, S.; Feng, S.; He, Y.-Q.; Zhang, N.; Liu, Z.; Liu, M.; Wang, Q. Dalton Trans. 2024, 53, 13890. doi: 10.1039/D4DT01794C
[19]	(a) Ma, X.; Lu, J.; Yang, P.; Zhang, Z.; Huang, B.; Li, R.; Ye, R. Dalton Trans. 2022, 51, 13902. doi: 10.1039/D2DT01765B
	(b) Xu, X.; Wang, S.; Mi, Y.; Zhao, H.; Zheng, Z.; Zhao, X. J. Coord. Chem. 2019, 72, 201. doi: 10.1080/00958972.2018.1548703
[20]	Liao, L.-S.; Chen, Y.; Hou, C.; Liu, Y.-H.; Su, G.-F.; Liang, H.; Chen, Z.-F. J. Med. Chem. 2023, 66, 10497. doi: 10.1021/acs.jmedchem.3c00603
[21]	(a) Feng, T.; Tang, Z.; Shu, J.; Wu, X.; Jiang, H.; Chen, Z.; Chen, Y.; Ji, L.; Chao, H. Angew. Chem., Int. Ed. 2024, 63, e202405679. doi: 10.1002/anie.v63.31
	(b) Liang, C.-J.; Wu, R.-C.; Huang, X.-Q.; Qin, Q.-P.; Liang, H.; Tan, M.-X. Dalton Trans. 2024, 53, 2143. doi: 10.1039/D3DT03197G
	(c) Zhao, T.; Wang, P.; Ji, M.; Li, S.; Yang, M.; Pu, X. Acta Chim. Sinica 2021, 79, 1385. (in Chinese) doi: 10.6023/A21060282
	(赵添堃, 王鹏, 姬明宇, 李善家, 杨明俊, 蒲秀瑛, 化学学报, 2021, 79, 1385.) doi: 10.6023/A21060282
	(d) Zhang, L.; Li, W.; Liu, L.; Zheng, C.; Wang, Y.; Xu, Y.; Shi, D.; Nie, X.; Guo, J.; Zhu, C.; Wang, J. Chin. J. Org. Chem. 2017, 37, 1721. (in Chinese) doi: 10.6023/cjoc201704006
	(张磊, 李文赟, 刘来, 郑诚月, 王杨, 徐应淑, 史大斌, 聂绪强, 国佳莹, 朱春媛, 王京, 有机化学, 2017, 37, 1721.) doi: 10.6023/cjoc201704006
	(e) Hu, J.; Zhang, C.; Zhu, W.; He, Y.; Peng, S.; Chen, Z.; Li, M.; Liu, Z.; Chen, H. Chin. J. Org. Chem. 2024, 44, 1870. (in Chinese) doi: 10.6023/cjoc202401013
	(胡健灵, 张超, 朱文达, 何业谱, 彭姝羚, 陈振强, 李明月, 刘志军, 陈河如, 有机化学, 2024, 44, 1870.) doi: 10.6023/cjoc202401013
[22]	(a) Wang, M.-M.; Deng, D.-P.; Zhou, A.-M.; Su, Y.; Yu, Z.-H.; Liu, H. K.; Su, Z. Inorg. Chem. 2024, 63, 4758. doi: 10.1021/acs.inorgchem.4c00060 pmid: 28657713
	(b) Charif, R.; Granotier-Beckers, C.; Charlotte Bertrand, H.; Poupon, J.; Segal-Bendirdjian, E.; Teulade-Fichou, M.-P.; Boussin, F. D.; Bombard, S. Chem. Res. Toxicol. 2017, 30, 1629. doi: 10.1021/acs.chemrestox.7b00131 pmid: 28657713
	(c) Tabrizi, L.; Thompson, K.; Mnich, K.; Chintha, C.; Gorman, A. M.; Morrison, L.; Luessing, J.; Lowndes, N. F.; Dockery, P.; Samali, A.; Erxleben, A. Mol. Pharmaceutics 2020, 17, 3009. doi: 10.1021/acs.molpharmaceut.0c00417 pmid: 28657713
[23]	(a) Liu, Q.; Cai, D.; Qi, Y.; Le, X. Acta Chim. Sinica 2020, 78, 263. (in Chinese) doi: 10.6023/A19110403
	(刘启雁, 蔡戴宏, 戚永育, 乐学义, 化学学报, 2020, 78, 263.) doi: 10.6023/A19110403
	(b) Wang, X.; Gu, Y.; Chen, D.; Fang, Y.; Huang, Y. Acta Chim. Sinica 2010, 68, 2463. (in Chinese)
	(王晓星, 顾彦, 陈登霞, 方艳芬, 黄应平, 化学学报, 2010, 68, 2463.)
[24]	Xiong, K.; Ouyang, C.; Liu, J.; Karges, J.; Lin, X.; Chen, X.; Chen, Y.; Wan, J.; Ji, L.; Chao, H. Angew. Chem., Int. Ed. 2022, 61, e202204866. doi: 10.1002/anie.v61.33
[25]	Afzaal, H.; Altaf, R.; Ilyas, U.; Zaman, S. U.; Hamdani, S. D. A.; Khan, S.; Zafar, H.; Babar, M. M.; Duan, Y. Front. Pharmacol. 2022, 13, 1048691. doi: 10.3389/fphar.2022.1048691
[26]	Sanner, M. F. J. Mol. Graph. Model. 1999, 17, 57. pmid: 10660911
[27]	(a) Wang, C.-X.; Zhang, Z.-L.; Yin, Q.-K.; Tu, J.-L.; Wang, J.-E.; Xu, Y.-H.; Rao, Y.; Ou, T.-M.; Huang, S.-L.; Li, D.; Wang, H.-G.; Li, Q.-J.; Tan, J.-H.; Chen, S.-B.; Huang, Z.-S. J. Med. Chem. 2020, 17, 9752.
	(b) Gu, Y.-Q.; Yang, K.; Yang, Q.-Y.; Li, H.-Q.; Hu, M.-Q.; Ma, M.-X.; Chen, N.-F.; Liu, Y.-H.; Liang, H.; Chen, Z.-F. J. Med. Chem. 2023, 66, 9592. doi: 10.1021/acs.jmedchem.3c00318
[28]	(a) Chai, J.; Du, C.; Wu, J.W.; Kyin, S.; Wang, X.; Shi, Y. Nature 2000, 406, 855. doi: 10.1038/35022514
	(b) Zhou, Q.; Zhang, X.-B.; Liu, A.-L.; Niu, Z.-G.; Li, G.-N.; Yu, F.-B. Bioorg. Chem. 2025, 161, 108507. doi: 10.1016/j.bioorg.2025.108507
	(c) Qin, P.; Ma, H.; Zhang, F.-G.; Ma, J.-A. Acta Chim. Sinica 2023, 81, 697. (in Chinese) doi: 10.6023/A23040154
	(秦沛, 马海, 张发光, 马军安, 化学学报, 2023, 81, 697.) doi: 10.6023/A23040154

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