Abstract
G-quadruplexes are higher-order DNA structures formed from guanine-rich sequences, and have been identified as attractive anticancer drug targets. Elucidating the three-dimensional structure of G-quadruplex with 9-amino acridines and the specific interactions involved in binding selectivity are the key to understanding their mechanism of action. Fluorescence titration assays, competitive dialysis and NMR studies have been used to study the binding specificity of 9-amino acridines to DNA. Structural models of the complexes with the telomeric DNA G-quadruplex based on NMR measurements were developed and further examined by molecular dynamics simulations and free energy calculations. Selective binding of 9-amino acridines for G-quadruplex sequences were observed. These compounds bind between A and G-tetrads, involving significant π-π interactions and several strong hydrogen bonds. The specific interactions between different moieties of the 9-amino acridines to the DNA were examined and shown to play a significant role in governing the overall stabilities of DNA G-quadruplex complexes. Both 9-amino acridines, with similar binding affinities to the G-quadruplex, were shown to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the two 9-amino acridines.
Highlights
In the last years, tricyclic acridine-containing compounds have been investigated as small molecule chemotherapeutic anticancer agents [1,2]
In summary we have used fluorescence titration assays, competitive dialysis, NMR studies and molecular dynamics simulations in order to determine the binding properties of preclinical 9-amino acridines to DNA
Detailed structural studies by NMR and molecular dynamic simulation on G-quadruplex telomeric complex showed the core of both 9-amino acridines intercalates directly between the virtual planes made by the four A and G
Summary
Tricyclic acridine-containing compounds have been investigated as small molecule chemotherapeutic anticancer agents [1,2]. Studies on the mechanism of action of acridine drugs have shown these compounds are potent inhibitors of topoisomerase and telomerase function in replicating cells [3], which leads to apoptosis and cell death. DNA topoisomerases exist in various eukaryotic and prokaryotic forms [5] and are classified in two large groups, namely type I and type II. Anti-cancer drugs targeting topoisomerase can be classified as either catalytic inhibitors or ‘‘topoisomerase poisons’’ depending on their mechanism of action [6]. The latter can be further sub-classified into two groups: non-intercalating compounds such as etoposide, and intercalators such amsacrine and doxorubicin [7]
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