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±0.04μmol/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, we developed a novel 8-hydroxyquinoline-modified platinum(II) polypyridine anticancer metal drug targeting DNA and hTERT.

Key words: Platinum(II) complexes, 8-hydroxyquinoline derivatives, anticancer activity, DNA damage, hTERT inhibition

Cite this article

Qi-Pin Qin, Qiu-Ming Li, Ju-Mei Zhang, Ming-Xiong 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, doi: 10.6023/A25090300.

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