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

• Published in: Bioorganic & medicinal chemistry 2014-11, Vol.22 (22), p.6503-6508
• Main Authors: Liao, Siyan, Zhang, Zhao, Wu, Qiong, Wang, Xicheng, Mei, Wenjie
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - toxicity; Binding Sites; c-myc G-quadruplex DNA; Cell Line, Tumor; Cell Proliferation - drug effects; Circular Dichroism; G-Quadruplexes; HeLa Cells; Humans; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - toxicity; MCF-7 Cells; Microwaves; Molecular docking; Molecular Docking Simulation; Nucleic Acid Conformation; Nucleic Acid Denaturation; Phenanthrenes - chemistry; Phenanthroimidazole derives; Proto-Oncogene Proteins c-myc - genetics; π–π stacking
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.09.003

[Display omitted] 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 3.6μM. The further studies show that 5 can bind and stabilize c-myc G4 DNA in π–π 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 5′ 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 π–π stacking.