Targeting Parallel Topology of G-Quadruplex Structures by Indole- Fused Quindoline Scaffolds

Preferential stabilization of G-quadruplex (G4) structures using small-molecule ligands has emerged as an effective approach to develop anticancer drugs. Herein, we report the synthesis of three indole-fused quindoline derivatives with varying lengths of side chains (InqEt1, InqEt2, and InqPr2) as selective ligands for promoter G4 structures. The ligands stabilize the parallel topology of c-MYC and c-KIT1 promoter G4 DNAs over telomeric and duplex DNAs, as evident from the circular dichroism melting and polymerase stop-assay experiments. The lead ligand, InqPr2, downregulates the gene expression of c-MYC and c-KIT in HeLa and HepG2 cells, respectively, leading to apoptotic cell death. Molecular modeling and dynamics studies support the 2:1 binding stoichiometry revealed from the Job plot analysis and show the ligand's structural features that enable the preferential binding to the parallel G4 structures over other topologies. Our studies show that indole-fused quindoline derivatives can be harnessed as new molecular scaffolds for selective targeting of parallel G4 topologies.