title: A small molecule peptidomimetic that binds to c-KIT1 G-quadruplex and exhibits antiproliferative properties in cancer cells.
abstract: A modular synthesis of l-proline derived peptidomimetics has been developed using the Cu(I) 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.
authors: Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur 741 252, India.
authors: Ajay
authors: A
authors: Chauhan
authors: Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur 741 252, India; Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India.
authors: Sushovan
authors: S
authors: Paladhi
authors: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India.
authors: Manish
authors: M
authors: Debnath
authors: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India.
authors: Samir
authors: S
authors: Mandal
authors: Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur 741 252, India.
authors: Rabindra Nath
authors: RN
authors: Das
authors: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India.
authors: Sudipta
authors: S
authors: Bhowmik
authors: Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur 741 252, India; Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India. Electronic address: ocjd@iacs.res.in.
authors: Jyotirmayee
authors: J
authors: Dash
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D008113:Liver Neoplasms / Q000473:pathology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D057786:Peptidomimetics / Q000737:chemistry*; D011392:Proline / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D057786:Peptidomimetics; D054852:Small Molecule Libraries; D011392:Proline
keywords: Click chemistry; FID assay; FRET melting assay; G-quadruplex DNA; Necrosis; Peptidomimetic