Issue 23, 2010

DNA binding by pixantrone

Abstract

The binding of the anticancer drug pixantrone (6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate) to the octanucleotide duplexes d(ACGATCGT)2 and the corresponding C-5 methylated cytosine (5MeC) analogue d(A5MeCGAT5MeCGT)2 has been studied by NMR spectroscopy and molecular modelling. The large upfield shifts observed for the resonances from the aromatic protons of pixantrone upon addition to either d(ACGATCGT)2 or the corresponding 5MeC analogue is consistent with the drug binding the octanucleotides by intercalation. The selective reduction in the sequential NOEs between the C2-G3 and C6-G7 nucleotides in NOESY spectra of either octanucleotide with added pixantrone confirms the intercalative binding mechanism. Strong NOEs from the side-chain ethylene protons of pixantrone to the H5 protons and the 5-CH3 protons of the C2 and C6 residues of d(ACGATCGT)2 and d(A5MeCGAT5MeCGT)2, respectively, indicate that pixantrone predominantly intercalates from the DNA major groove at the 5′-CG and 5′-5MeCG sites. Simple molecular models based on the conclusions from the NMR experiments indicated that the 5MeC groups do not represent a steric barrier to intercalation from the major groove. However, the observation of weak NOEs from the ethylene protons of pixantrone to a variety of minor groove protons from either octanucleotide suggests that the drug can also associate in the minor groove.

Graphical abstract: DNA binding by pixantrone

Supplementary files

Article information

Article type
Paper
Submitted
21 Jun 2010
Accepted
23 Aug 2010
First published
24 Sep 2010

Org. Biomol. Chem., 2010,8, 5359-5366

DNA binding by pixantrone

N. Adnan, D. P. Buck, B. J. Evison, S. M. Cutts, D. R. Phillips and J. G. Collins, Org. Biomol. Chem., 2010, 8, 5359 DOI: 10.1039/C0OB00295J

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