Selective recognition of c-MYC G-quadruplex DNA using prolinamide derivatives
| Autor: | Ajay Chauhan, Jyotirmayee Dash, Manish Debnath, Sushovan Paladhi |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Proline Molecular model Stereochemistry Supramolecular chemistry Triazole Trimer Ligands 010402 general chemistry G-quadruplex 01 natural sciences Biochemistry Substrate Specificity Proto-Oncogene Proteins c-myc chemistry.chemical_compound Humans Physical and Theoretical Chemistry 010405 organic chemistry Chemistry Organic Chemistry DNA Hep G2 Cells Triazoles Ligand (biochemistry) 0104 chemical sciences G-Quadruplexes Förster resonance energy transfer Drug Design |
| Zdroj: | Organic & Biomolecular Chemistry. 14:5761-5767 |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/c6ob00177g |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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