title: Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives.
abstract: Herein we report the design, synthesis, biophysical and biological evaluation of triazole containing prolinamide derivatives as selective c-MYC G-quadruplex binding ligands. A modular synthetic route has been devised for prolinamide derivatives using a copper(i) catalyzed azide-alkyne cycloaddition (CuAAC). The Förster resonance energy transfer (FRET) melting assay indicates that prolinamide trimers can significantly stabilize G-quadruplex structures over duplex DNA compared to prolinamide dimers. The fluorescent intercalator displacement (FID) assay shows that a trimer with prolinamide side chains at the para-position of the benzene ring can discriminate between different quadruplex structures and exhibits the highest binding affinity towards the c-MYC G-quadruplex structure. Molecular modeling studies reveal that the prolinamide trimer stacks upon the terminal G-quartet of the c-MYC G-quadruplex. Atomic force microscopy (AFM) analysis reveals that the tris-prolinamide ligand can be used to regulate the assembly of novel supramolecular nanoarchitectures. Further, in vitro cellular studies with human hepatocellular carcinoma (HepG2) cells indicate that the tris-prolinamide derivatives can inhibit cell proliferation and reduce c-MYC expression in cancer cells.
authors.affiliation: Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, 741 252, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Chauhan
authors.forename: Sushovan
authors.initials: S
authors.lastname: Paladhi
authors.forename: Manish
authors.initials: M
authors.lastname: Debnath
authors.forename: Jyotirmayee
authors.initials: J
authors.lastname: Dash
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D054856:G-Quadruplexes; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry
chemical_list: D008024:Ligands; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D004247:DNA; D011392:Proline; C056291:prolinamide