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NMR and CD studies show that anti-cancer drug mitoxantrone (MTX) binds to parallel G-quadruplex DNA [d-(TTGGGGT)4] as stacked dimer at grooves leading to increase in thermal stabilization of DNA by ~25 °C and inhibits telomerase with IC50 = 2 μM.

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The interaction of the anthraquinone derivative mitoxantrone, a semisynthetic anti-cancer drug with two non-planar side chains, with heptamer G-quadruplex d(TTAGGGT)4 , which contains the human telomere DNA sequence, was evaluated by differential scanning calorimetry, fluorescence Job plotting, absorption, and NMR and CD spectroscopy. Binding led to thermal stabilization of DNA (ΔTm =13-20 °C). The spectra revealed that two mitoxantrone molecules bind externally at two sites of the DNA quadruplex as monomers, by partial insertion of the chromophore and side-chain interaction at the grooves. The inhibition of telomerase (IC50 =2 μM), as determined by a TRAP assay, can be attributed to thermal stabilization of the DNA quadruplex because of the interactions with mitoxantrone. The studies revealed highly specific molecular recognition between a ligand and a parallel-stranded G-quadruplex; this might serve as a platform for the rational design of new drugs.

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The inside back cover picture shows the structure of two molecules of mitoxantrone (an anthraquinone‐based semisynthetic compound used as chemotherapeutic agent) bound externally at two different sites of the DNA G‐quadruplex d(TTAGGGT)4 containing the human telomere repeat sequence TTAGGG. The binding by partial insertion of the mitoxantrone chromophore between base pairs and interaction of its side chains at the grooves of DNA thermally stabilize the G‐quadruplex by 13–20 K, thus resulting in subsequent telomerase inhibition (IC50=2 µm). This specific molecular recognition between a ligand and DNA serves as a platform for rational drug design. More information can be found in the communication by R. Barthwal et al. on page 554 in Issue 7, 2016 (DOI: 10.1002/cbic.201500588).