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Rational design, synthesis, biophysical and antiproliferative evaluation of fluorenone derivatives with DNA G-quadruplex binding properties

Alcaro, Stefano; Artese, Anna; Iley, James N.; Missailidis, Sotiris; Ortuso, Francesco; Parrotta, Lucia; Pasceri, Raffaele; Paduano, Francesco; Sissi, Claudia; Trapasso, Francesco and Vigorita, Maria Gabriella (2010). Rational design, synthesis, biophysical and antiproliferative evaluation of fluorenone derivatives with DNA G-quadruplex binding properties. ChemMedChem, 5(4) pp. 575–583.

DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1002/cmdc.200900541
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Abstract

Molecular modeling studies carried out with experimental DNA models with the sequence d[AG3(T2AG3)3] suggest that the introduction of a net positive charge onto the side chain of a series of fluorenone carboxamides can improve G-quadruplex binding. The terminal morpholino moiety was replaced with a novel N-methylmorpholinium cation starting from two 4-carboxamide compounds. A different substitution on the fluorenone ring was also investigated and submitted to the same quaternarization process. All compounds were analyzed for their DNA binding properties by competition dialysis methods. In vitro antiproliferative tests were carried out against two different tumor cell lines. Docking experiments were conducted by including all four known human repeat unit G-quadruplex DNA sequences (27 experimentally determined conformations) against the most active fluorenone derivatives. The results of theoretical, biophysical, and in vitro experiments indicate two novel derivatives as lead compounds for the development of a new generation of G-quadruplex ligands with greater potency and selectivity.

Item Type: Journal Article
Copyright Holders: 2010 WILEY-VCH Verlag GmbH & Co. KGaA
ISSN: 1860-7179
Keywords: docking; fluorenones; G-quadruplex binders; morpholine; telomeres
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 19601
Depositing User: James Iley
Date Deposited: 16 Jul 2010 16:02
Last Modified: 10 Mar 2014 10:31
URI: http://oro.open.ac.uk/id/eprint/19601
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