Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

ACS Med Chem Lett. 2010 Jul 1;1(7):306-10. doi: 10.1021/ml100062z.

Mallesham Bejugam ¹, Mekala Gunaratnam ², Sebastian Müller ¹, Deborah A Sanders ¹, Sven Sewitz ¹, Jonathan A Fletcher ³, Stephen Neidle ², Shankar Balasubramanian ⁴

Affiliations

1 The University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom.
2 Cancer Research UK Biomolecular Structure Group, School of Pharmacy, University of London, 29-39 Brunswick Square, London WC19 1AX, United Kingdom.
3 Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115.
4 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.

PMID: 24900212 DOI: 10.1021/ml100062z

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.

Keywords

DNA; c-kit regulation; inhibition; ligand; quadruplex.

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