Design, synthesis and biological evaluation of 4-anilinoquinazoline derivatives as new c-myc G-quadruplex ligands

•31 new 4-anilinoquinazoline derivatives were synthesized as G-quadruplex binding ligands.•Some of compounds showed a improved interacting ability to c-myc G-quadruplex DNA.•7a was the best compound as out of the synthesized compounds.•7a significantly down-regulated c-myc gene transcription and expression in Hela cells.

A series of 4-anilinoquinazoline derivatives were designed and synthesized as novel c-myc promoter G-quadruplex binding ligands. Subsequent biophysical and biochemical evaluation demonstrated that the introduction of aniline group at 4-position of quinazoline ring and two side chains with terminal amino group improved their binding affinity and stabilizing ability to G-quadruplex DNA. RT-PCR assay and Western blot showed that compound 7a could down-regulate transcription and expression of c-myc gene in Hela cells, which was consistent with the behavior of an effective G-quadruplex ligand targeting c-myc oncogene. More importantly, RTCA and colony formation assays indicated that 7a obviously inhibited Hela cells proliferation, without influence on normal primary cultured mouse mesangial cells. Flow cytometric assays suggested that 7a induced Hela cells to arrest in G0/G1 phase both in a time-dependent and dose-dependent manner.

Graphical abstractA series of compounds with an introduction of aniline group into 4-position to previous reported quinazoline derivatives were synthesized and evaluated. These compounds showed good c-myc promoter G-quadruplex binding activity and selectivity.Figure optionsDownload full-size imageDownload as PowerPoint slide