title: Spectroscopic probing of recognition of the G-quadruplex in c-kit promoter by small-molecule natural products.
abstract: The c-kit oncogene plays important roles in cell growth and proliferation which is associated with many human tumors. In this study, electrospray ionization mass spectrometry (ESI-MS) and circular dichroism (CD) spectroscopy were used to evaluate the formation and recognition of the G-quadruplex by d(AGGGAGGGCGCTGGGAGGAGGG) in the promoter region of the c-kit oncogene. Among the twelve small natural molecules studied, three crescent-shaped small molecules (chelerythrine, jatrorrhizine and berberine, named as P1-P3) and one flexible cyclic small molecule (fangchinoline, named as P4) were found to bind to the G-quadruplex with high affinities. The melting experiments demonstrate that P1-P4 can significantly enhance the stability of the G-quadruplex with the ordering of P1≈P4>P3>P2. Further insight into the binding mode of small molecules with the G-quadruplex by Autodock3 analysis reveals that P1-P3 prefer the end-stacking mode with the G-quadruplex through π-π interaction and P4 prefers to insert into the groove outside the G-tetrads. Thus, our research finds that four ligands (P1-P4) from small natural molecules have high affinity to, and can significantly enhance the stability of the G-quadruplex in the promoter region of the c-kit oncogene.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Cui
authors.forename: Sen
authors.initials: S
authors.lastname: Lin
authors.forename: Gu
authors.initials: G
authors.lastname: Yuan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015195:Drug Design; D054856:G-Quadruplexes / Q000187:drug effects; D008024:Ligands; D008958:Models, Molecular; D011355:Prodrugs / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D013057:Spectrum Analysis
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D008024:Ligands; D011355:Prodrugs; D019009:Proto-Oncogene Proteins c-kit