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Trisubstituted Isoalloxazines as a New Class of G-Quadruplex Binding Ligands:  Small Molecule Regulation of c-kit Oncogene Expression

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journal contribution
posted on 31.10.2007, 00:00 by Mallesham Bejugam, Sven Sewitz, Pravin S. Shirude, Raphaël Rodriguez, Ramla Shahid, Shankar Balasubramanian
Herein, we report the design, synthesis, biophysical evaluation with primary biological data of 3,8,10-trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands. We have developed a short and robust synthesis for trisubstituted isoalloxazines in good yields. The G-quadruplex binding and stabilization potential of isoalloxazines was assessed by surface plasmon resonance and fluorescence resonance energy transfer assay. The data revealed that these isoalloxazines bind and stabilize G-quadruplex DNA, but not duplex DNA, and exhibit potential for discriminating between DNA quadruplexes. Cell-based experiments using cell lines that express the proto-oncogene c-kit (MCF-7 and HGC-27) showed that such isoalloxazines can inhibit the expression of c-kit.