12-N-Methylated 5,6-dihydrobenzo[c]acridine derivatives: A new class of highly selective ligands for c-myc G-quadruplex DNA

12-N-Methylated and non-methylated 5,6-dihydrobenzo[c]acridine derivatives were designed and synthesized as new series of c-myc G-quadruplex binding ligands. Their interactions with c-myc G-quadruplex were evaluated using fluorescence resonance energy transfer (FRET) melting assay, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR), polymerase chain reaction (PCR) stop assay, and molecular modeling. Compared with the non-methylated derivatives, 12-N-methylated derivatives had stronger binding affinity and stabilizing ability to c-myc G-quadruplex structure, and could more effectively stack on the G-quartet surface. All these derivatives had high selectivity for c-myc G-quadruplex DNA over duplex DNA. The reverse transcription (RT) PCR assay showed that compound 21c could down-regulate transcription of c-myc gene in Ramos cell line containing NHE III1 element, but had no effect in CA46 cell line with NHE III1 element removed.

A series of 5,6-dihydrobenzo[c]acridine derivatives was developed as a new class of c-myc G-quadruplex DNA ligands. 12-N-Methylated compounds (B) were found to be an effective class of ligands.Figure optionsDownload as PowerPoint slideHighlights
► New acridine derivatives were synthesized as selective c-myc G-quadruplex ligands.
► Introduction of positive charge obviously improved binding and stabilizing abilities.
► 21c could down-regulate c-myc gene transcription in Ramos cell, but not in CA46 cell.