title: Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines.
abstract: Herein, we demonstrate the design, synthesis, biophysical properties, and preliminary biological evaluation of 6-substituted indenoisoquinolines as a new class of G-quadruplex stabilizing small molecule ligands. We have synthesized 6-substituted indenoisoquinolines 1a-e in two steps from commercially available starting materials with excellent yields. The G-quadruplex stabilization potential of indenoisoquinolines 1a-e was evaluated by fluorescence resonance energy transfer-melting analysis, which showed that indenoisoquinolines show a high level of stabilization of various G-quadruplex DNA structures. Indenoisoquinolines demonstrated potent inhibition of cell growth in the GIST882 patient-derived gastrointestinal stromal tumor cell line, accompanied by inhibition of both c-Kit transcription and KIT oncoprotein levels.
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
authors.forename: Mallesham
authors.initials: M
authors.lastname: Bejugam
authors.affiliation: Cancer Research UK Biomolecular Structure Group, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC19 1AX, United Kingdom.
authors.forename: Mekala
authors.initials: M
authors.lastname: Gunaratnam
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Sanders
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
authors.forename: Sven
authors.initials: S
authors.lastname: Sewitz
authors.affiliation: Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Cancer Research UK Biomolecular Structure Group, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC19 1AX, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.affiliation: The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom ; School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SP, United Kingdom ; Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom.
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
keywords: DNA; c-kit regulation; inhibition; ligand; quadruplex