AI Article Synopsis
- The study focuses on the synthesis and evaluation of macrocyclic naphthalene diimides to enhance their ability to bind G-quadruplexes, which are structures associated with cancer biology.
- These new compounds show improved stability and selectivity for quadruplex DNA over regular duplex DNA, with notable anticancer activity observed in various cancer cell lines.
- Molecular modeling techniques revealed that electrostatic interactions are key to why these compounds preferentially recognize G-quadruplexes.
Article Abstract
The synthesis, biological and molecular modeling evaluation of a series of macrocyclic naphthalene diimides is reported. The present investigation expands on the study of structure-activity relationships of prototype compound 2 by constraining the molecule into a macrocyclic structure with the aim of improving its G-quadruplex binding activity and selectivity. The new derivatives, compounds 4-7 carry spermidine- and spermine-like linkers while in compound 8 the inner basic nitrogen atoms of spermine have been replaced with oxygen atoms. The design strategy has led to potent compounds stabilizing both human telomeric (F21T) and c-KIT2 quadruplex sequences, and high selectivity for quadruplex in comparison to duplex DNA. Antiproliferative effects of the new derivatives 4-8 have been evaluated in a panel of cancer cell lines and all the tested compounds showed activity in the low micromolar or sub-micromolar range of concentrations. In order to rationalize the molecular basis of the DNA G-quadruplex versus duplex recognition preference, docking and molecular dynamics studies have been performed. The computational results support the observation that the main driving force in the recognition is due to electrostatic factors.
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| http://dx.doi.org/10.1016/j.bmc.2015.03.076 | DOI Listing |
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