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J Inorg Biochem. 2018 Aug;185:1-9. doi: 10.1016/j.jinorgbio.2018.04.019. Epub 2018 May 2.

Novel polypyridyl ruthenium complexes acting as high affinity DNA intercalators, potent transcription inhibitors and antitumor reagents.

Author information

1
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Functional Molecules Analysis and Biotransformation Key Laboratory of Universities in Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, PR China.
2
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Functional Molecules Analysis and Biotransformation Key Laboratory of Universities in Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, PR China. Electronic address: gaofeng@ynu.edu.cn.
3
School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, PR China. Electronic address: 709249906@qq.com.
4
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Functional Molecules Analysis and Biotransformation Key Laboratory of Universities in Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, Yunnan 650091, PR China. Electronic address: zhanghb@ynu.edu.cn.

Abstract

Six novel polypyridyl ruthenium complexes with (E)-2-styryl-1H- imidazo[4,5-f][1,10]phenanthroline ligand and its analogues have been designed to enhance the DNA intercalation ability of their model compound [Ru(bpy)2(pip)]2+ (bpy = 2,2'-bipyridine, pip = 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline). As shown in the optimized geometry of the complexes, the introduction of styryl group not only extended the conjugated area of the intercalative ligand, but also retained the excellent planarity. These two merits have been proven to be beneficial for their DNA intercalation, thus greatly improved their inhibition activity towards DNA transcription by RNA polymerase and DNA topoisomerase, two enzymes closely related to both DNA and tumor cell growth. The relationships between the substituent group structures and the biological activities have also been investigated from energetic and electronic aspects by quantum chemistry calculations. Results from cell cytotoxicity and apoptosis assay testified that the styryl substituted ruthenium complexes possessed higher antitumor activity than [Ru(bpy)2(pip)]2+, as expected. As quantified in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, the tumor cell death is caused mostly through apoptosis for Ru2 and Ru3, while non-apoptotic processes for Ru1, Ru4 and Ru5. In vitro fluorescence evaluation revealed that all complexes located mainly in cytoplasm, but the three complexes with high antiproliferative activity could enter nucleus. All complexes have shown apparent lower cytotoxicity towards normal human colon epithelial cell CCD-841-CON than the examined tumor cell lines.

KEYWORDS:

Antitumor; DNA binding; Ruthenium complex; Transcription inhibition

PMID:
29730231
DOI:
10.1016/j.jinorgbio.2018.04.019
[Indexed for MEDLINE]

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