Microwave-assisted synthesis of phenanthroimidazole derivatives as stabilizer of c-myc G-quadruplex DNA

作者：Liao Siyan; Zhang Zhao; Wu Qiong; Wang Xicheng^*; Mei Wenjie

来源：Bioorganic and Medicinal Chemistry, 2014, 22(22): 6503-6508.

DOI：10.1016/j.bmc.2014.09.003

• Phenanthroimidazole derives
• c-myc G-quadruplex DNA
• pi-pi stacking
• Molecular docking

c-myc G-quadruplex DNA, which plays a central role in tumor progression and resistance, has been extensively investigated as potential target of antitumor drugs. In this paper, a series of phenanthroimidazole derives have been synthesized under irradiation of microwave in yields of 51-80%. The antitumor activity of these compounds against various tumor cells has been evaluated, and the results show that these compounds exhibit great inhibition to MDA-MB-231, MCF-7 and Hela cells, especially 5 inhibit the growth of MDA-MB-231 cells with IC50 about 3.6 mu M. The further studies show that 5 can bind and stabilize c-myc G4 DNA in pi-pi stacking mode, which confirmed by the hypochromise in the electronic spectra of 5 with the increasing of c-myc G4 DNA. When dealt with 5, the strength of CD signal attributed to c-myc G4 DNA is decreased and the FRET melting point of c-myc G4 DNA is increased. Moreover, the molecule docking calculation was conducted to show that 5 suitably stack onto the 50 G-quartet surface, and parallels to the surfaces of the G5 and G-quartet consisting of G7, G11, G16, and G20. As a result, the replication of c-myc oligomers is blocked by 5. In a word, this type of phenanthroimidazole derives can act as potential inhibitor against breast cancer cells by binding and stabilizing c-myc G4 DNA through p-p stacking.

• 单位
  1; 广东药学院; 广州医学院