8-羟基喹啉修饰的铂(II)多吡啶配合物的合成及体内外抗癌活性评价

doi:10.6023/A25090300

摘要/Abstract

为了克服顺铂类药物的毒性大和选择性差问题, 本研究以5,7-二碘-8-羟基喹啉(IQ-OH)铂(II)配合物[Pt(IQ- O)(DMSO)Cl] (PtIQ)为中间体, 以2-(1H-咪唑并[4,5-f][1,10]菲咯啉-2-基)喹啉-8-醇(Py)为辅助配体, 合成新型的8-羟基喹啉修饰的铂(II)多吡啶配合物[Pt(IQ-O)(Py)]Cl (PyPt). 通过核磁共振(NMR)、紫外-可见分光光度法(UV-vis)、红外光谱(IR)和元素分析手段对配合物PyPt和PtIQ进行了结构表征. 密度泛函理论计算显示, PyPt和PtIQ的最高占据分子轨道(HOMO)与最低未占据分子轨道(LUMO)之间的能隙分别为2.3和3.2 eV, 说明PyPt与PtIQ的抗癌活性存在差异. 相对于人肺癌细胞(A549)和人肺癌顺铂耐药细胞(A549/DDP), PyPt对人乳腺癌细胞(MDA-MB-231)表现出更好的抑制作用, 其IC₅₀值为(0.05±0.04) μmol/L, 优于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)和临床药物顺铂[(11.1±0.3) μmol/L]; 此外, PyPt对正常肝细胞(HL-7702)的毒性很小, 说明PyPt对MDA-MB-231癌细胞具有更好的选择性. 流式细胞术和显微镜成像显示, PyPt能明显诱导细胞凋亡[ca. (48.0±0.9)%]和衰老[积分光密度(IOD)值=(1.9±0.1)×10⁶], 优于PtIQ [凋亡率=(44.2±0.6)%, 衰老IOD值= (1.8±0.1)×10⁶]和空白对照组[凋亡率=(6.1±0.6)%, 衰老IOD值=(2.1±0.1)×10⁵]. 分子对接结果表明, PyPt与端粒酶逆转录酶(hTERT)中DNA链间的结合能为–53.0 kJ/mol, 明显强于PtIQ (–30.2 kJ/mol). 彗星电泳实验、免疫荧光实验、实时荧光定量PCR(RT-qPCR)和蛋白质印迹(western blotting)实验结果显示, PyPt通过抑制hTERT表达、激活caspase3/7蛋白和引起DNA损伤来诱导MDA-MB-231癌细胞凋亡和衰老, 其诱导能力强于PtIQ. 体内实验显示, PyPt对MDA-MB-231实体瘤有很好的抑制效果, 抑制率为44.4%, 且未对小鼠的存活率(n=6)和体重造成影响. 总之, 本工作开发了一种以DNA和hTERT为靶点的新型8-羟基喹啉修饰铂(II)多吡啶抗癌金属药物.

关键词: 铂(II)配合物, 8-羟基喹啉衍生物, 抗癌活性, DNA损伤, 人端粒酶逆转录酶(hTERT)抑制

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

引用此文

覃其品, 李秋明, 张菊梅, 谭明雄, 梁宏. 8-羟基喹啉修饰的铂(II)多吡啶配合物的合成及体内外抗癌活性评价[J]. 化学学报, 2026, 84(1): 109-118.

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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图/表 11

图1. 配合物PyPt和PtIQ的合成

Figure 1. Synthesis of PyPt and PtIQ

图2. 通过DFT计算PyPt和PtIQ的HOMO-LUMO之间的能隙

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

表1. 顺铂、PyPt和PtIQ对MDA-MB-231和HL-7702细胞的IC50值(μmol/L)

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

图3. PyPt(0.05 μmol/L)和PtIQ (9.0 μmol/L)诱导MDA-MB-231细胞凋亡

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

图4. PyPt(0.05 μmol/L)和PtIQ (9.0 μmol/L)诱导MDA-MB-231细胞衰老

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

图5. 采用彗星试验检测PyPt (0.05 μmol/L)和PtIQ (9.0 μmol/L)作用MDA-MB-231细胞48 h后DNA损伤的情况

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.

图6. 免疫荧光法检测PyPt (0.05 μmol/L)和PtIQ (9.0 μmol/L)作用MDA-MB-231细胞48 h后TRF2和γ-H2AX的含量(n=3)

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.

图7. 分子对接研究PyPt和PtIQ与目标蛋白hTERT中DNA

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

图8. RT-qPCR实验测定PyPt (0.05 μmol/L)和PtIQ (9.0 μmol/L)作用MDA-MB-231癌细胞48 h后hTERT RNA的表达情况

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

图9. 孵育48 h后, 配合物PyPt (0.05 μmol/L)和PtIQ (9.0 μmol/L)对MDA-MB-231细胞中DNA损伤和细胞凋亡通路的影响

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

图10. 在MDA-MB-231荷瘤异种移植小鼠模型中, PyPt (5.0 mg/kg every 2.0 days)的体内抗肿瘤活性

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

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