期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 158, 期 -, 页码 106-122出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.09.008
关键词
Platinum(II) complex; Tacrine; p53; Telomerase; Anticancer activity; Apoptosis
资金
- National Natural Science Foundation of China [21867017, 21761033]
- Natural Science Foundation of Guangxi [2018GXNSFBA138021]
- Key Foundation Project of Colleges and Universities in Guangxi [ZD2014108]
- Innovative Team & Outstanding Talent Program of Colleges and Universities in Guangxi [2014-49, 2017-38]
- PhD Research Startup Program of Yulin Normal University [G2017009]
- project of Guibei characteristic medicine resources research center of Guangxi Province [KYA201703]
- China University Students Innovative Project [201810606008]
- Guilin Normal College [KYA201804]
In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]center dot CH3OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4'-dimethyl-2,2'-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1Pt7 exhibited cytotoxic activity against the tested NCI-H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC50 value of 0.13 +/- 0.16 mu M against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1-Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug. (C) 2018 Elsevier Masson SAS. All rights reserved.
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