Telomerase inhibition by new di- and trisubstituted acridine derivatives

Abstract

To study a series of new acridine derivatives containing two basic fragments able to bind to quadruplex DNA at C-4 and C-9 positions as potential telomerase inhibitors. Methods. TRAP assay was used to determine the activity of compounds in vitro. Results. A number of acridines inhibiting the enzyme at micromolar concentrations were found, with IC 50 = 2.6 µM for the most active compound. Conclusions. The introduction of a highly basic N,N-dimethylaminoalkyl group at the C-9 position of the acridine core results in a strong increase of biological activity of compounds, and a 5-methyl substituent further enhances it.

Сationic carboxamide derivatives of tricyclic heteroaromatic compounds: synthesis and preliminary evaluation of antiproliferative activity

“…N-arylamides of acridone-4-carboxylic acid are active against hepatitis C virus infection inhibiting the transcription and RNA replication [36]. N-pyridyl derivatives of acridone carboxamides were found to inhibit NS3 helicase [36,37], telomerase [24], and topoisomerase I [38]. N-aryl(hetaryl)-substituted amides of phenazine-1carboxylic acid appeared to be efficient antimicrobial agents, including the compounds active against drugresistant Mуcobacterium tuberculosis strains [39,40].…”

“…Phenazine and acridone derivatives containing aromatic pyridyl fragments were found to inhibit the topoisomerase I at 100 μM concentration, whereas their analogues with aliphatic basic substituents at carboxamide fragment were less efficient [38]. At the same time, the free core heterocycles and their non-substituted carboxamides are inactive against topoisomerase [38] and telomerase [24].…”