ml100062z_si_001.pdf (223.45 kB)
Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines
journal contributionposted on 2010-10-14, 00:00 authored by Mallesham Bejugam, Mekala Gunaratnam, Sebastian Müller, Deborah A. Sanders, Sven Sewitz, Jonathan A. Fletcher, Stephen Neidle, Shankar Balasubramanian
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.