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

• Published in: ACS medicinal chemistry letters Vol. 1; no. 7; pp. 306 - 310
• Main Authors: Bejugam, Mallesham, Gunaratnam, Mekala, Müller, Sebastian, Sanders, Deborah A, Sewitz, Sven, Fletcher, Jonathan A, Neidle, Stephen, Balasubramanian, Shankar
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.10.2010
• Subjects: Letter; c-kit regulation; quadruplex; inhibition; DNA; ligand
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml100062z

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.