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A small molecule peptidomimetic that binds to c-KIT1 G-quadruplex and exhibits antiproliferative properties in cancer cells |
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| Affiliation: | 1. University of Naples Federico II, Department of Chemical Sciences, Via Cintia 21, I-80126 Naples, Italy;2. Analytical Chemistry for the Environment and CeSMA (Advanced Metrologic Service Center), University of Naples Federico II, Corso N. Protopisani, 80146 Naples, Italy;3. CNR, Institute of Biostructure and Bioimaging – (Via Mezzocannone Site and Headquarters), 80134 Naples, Italy;4. University of Naples Federico II, Department of Pharmacy, Via Mezzocannone 16, 80134 Naples, Italy |
| Abstract: | A modular synthesis of l-proline derived peptidomimetics has been developed using the CuI catalyzed Huisgen cycloaddition between an azido prolinamide with pyridine and benzene dicarboxamide containing dialkynes. Förster Resonance Energy Transfer (FRET) melting assay provided an initial indication that the pyridyl analogue can stabilize the c-KIT1 quadruplex DNA. A competitive FRET-melting assay and Fluorescent Intercalator Displacement (FID) assay suggest that the pyridyl ligand shows excellent selectivity for c-KIT1 quadruplex over duplex DNA and other investigated G-quadruplexes. Molecular docking studies indicate that the pyridyl ligand can adopt unique conformations upon binding to c-KIT1 quadruplex due to the presence of intramolecular hydrogen bonds. The pyridyl ligand can perturb cell cycle progression and induce necrotic cell death of human hepatocellular liver carcinoma HepG2 cells. |
| Keywords: | Click chemistry FID assay FRET melting assay G-quadruplex DNA Necrosis Peptidomimetic |
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