Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 58, Issue 11, Pages 4771-4789Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00444
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Funding
- National Natural Science Foundation of China [21271051, 21431001, 81473102]
- National Basic Research Program of China [2012CB723501]
- Natural Science Foundation of Guangxi Province [2012GXNSFDA385001]
- BAGUI Scholar program of Guangxi Province of China
- [IRT1225]
- [CMEMR2012-A22]
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Three water-soluble ruthenium(II) complexes with chiral 4-(2,3-dihydroxypropyl)-formamide oxoaporphine (FOA) were synthesized and characterized. It was found that these ruthenium(II) complexes exhibited considerable in vitro anticancer activities and that they were the effective stabilizers of telomeric and G-quadruplex-DNA (G4-DNA) in promoter of c-myc, which acted as a telomerase inhibitor targeting G4-DNA and induced cell senescence and apoptosis. Interestingly, the in vitro anticancer activity of 6 (LC-003) was higher than those of 4 (LC-001) and 5 (LC-002), more selective for BEL-7404 cells than for normal HL-7702 cells, and preferred to activate caspases-3/9. The different biological behaviors of the ruthenium complexes could be correlated with the chiral nature of 4-(2,3-dihydroxypropyl)-formamide oxoaporphine. More significantly, 6 exhibited effective inhibitory on tumor growth in BEL-7402 xenograft mouse model and higher in vivo safety than cisplatin. These mechanistic insights indicate that 6 displays low toxicity and can be a novel anticancer drug candidate.
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