Design, synthesis and evaluation of 4,5-di-substituted acridone ligands with high G-quadruplex affinity and selectivity, together with low toxicity to normal cells

KRAS oncogene repression in colon cancer cell lines by G-quadruplex binding indolo[3,2-c]quinolines

“…Moreover, the FRET competition experiments showed that 3e binds preferentially to KRAS21R compared to the human telomeric 21-mer G4 sequence (Figure 3). Competition binding studies have previously shown that some small molecules can bind preferentially to quadruplex compared to triplex or duplex structures3132, and/or have differing inductive stabilization effects over G4 DNA sequences of different lengths. This is the case for those IQb compounds with 3 basic side chains in positions 7, 10 and 11, which showed higher Δ T m values for 21 mer G4-forming DNA sequences (KRAS21R, HT21, HSP90A) compared to 27 mer G4 DNA (cKit1) or longer G4 DNA structures with more complex topologies (HIF-1α)22.…”

Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives

“…Particularly, a novel series of 4, 5-di-substituted acridone derivatives (18) were found to have high affinity for telomeric Gquadruplex DNA in classical and competition FRET assays, with improved selectivity compared with tri-substituted acridine compounds. Most of the compounds have distinguishing cytotoxicity between cancer cells and normal cell lines [84].…”

Development of highly predictive 3D-QSAR CoMSIA models for anthraquinone and acridone derivatives as telomerase inhibitors targeting G-quadruplex DNA telomere

“…Effects of amide bond direction on modulation of Gquadruplex recognition and telomerase inhibition by substituted anthracenedione derivatives have studied [20]. Recently, Cuenca et al postulated that the incorporation of aromatic side chains to the acridone core in the 4 and 5 position would enhance G-quadruplex affinity, although these derivatives did not show telomerase inhibitory activity [21]. A three-dimensional structure-activity relationship (3D-QSAR) as rational basis for the G-quadruplex ligand optimization for anthraquinones and acridones remains unreported.…”