Issue 75, 2016

Molecular recognition of parallel quadruplex [d-(TTGGGGT)]4 by mitoxantrone: binding with 1 : 4 stoichiometry leads to telomerase inhibition

Abstract

The interaction of mitoxantrone (MTX), an anticancer drug, with parallel stranded tetra-molecular G-quadruplex DNA [d-(TTGGGGT)]4 has been studied using Surface Plasmon Resonance (SPR), thermal melting profiles, absorption, nuclear magnetic resonance and Circular Dichroism (CD) spectroscopy. Mitoxantrone binds to G-quadruplex DNA with the affinity constant KA ∼ 3 × 104 M−1 and the binding stoichiometry of the mitoxantrone : DNA quadruplex complex is found to be 4 : 1. The DNA melting (Tm) experiments show that binding leads to an increase in Tm indicating the thermal stabilization of DNA. Tm increases with D/N, that is, the ratio of added mole equivalents of mitoxantrone (D) to DNA (N) and saturates at D/N = 4.0 yielding total ΔTm = 26 °C. Proton and phosphorus-31 chemical shifts show that the base pairs of DNA do not open to allow intercalation of a mitoxantrone chromophore. The 2D NOESY spectra reveal that mitoxantrone binds as a stacked dimer having head to tail (anti-parallel) orientation at two opposite ends externally to the DNA quadruplex. CD spectra show the induced CD band of mitoxantrone having exciton splitting at 630–690 nm. The TRAP assay gives IC50 ∼ 2 μM for inhibition of telomerase by mitoxantrone, which may be attributed to thermal stabilization of the DNA quadruplex. The present study suggests that a dimer formed by stacking of two mitoxantrone molecules might provide highly specific molecular recognition between ligands and a parallel stranded G-quadruplex and hence serve as a platform for rational design of new G-quadruplex groove binders.

Graphical abstract: Molecular recognition of parallel quadruplex [d-(TTGGGGT)]4 by mitoxantrone: binding with 1 : 4 stoichiometry leads to telomerase inhibition

Supplementary files

Article information

Article type
Paper
Submitted
28 Ақп. 2016
Accepted
18 Шіл. 2016
First published
18 Шіл. 2016

RSC Adv., 2016,6, 71652-71661

Molecular recognition of parallel quadruplex [d-(TTGGGGT)]4 by mitoxantrone: binding with 1 : 4 stoichiometry leads to telomerase inhibition

T. P. Pradeep, S. Tripathi and R. Barthwal, RSC Adv., 2016, 6, 71652 DOI: 10.1039/C6RA05266E

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements