The influence of positional isomerism on G-quadruplex binding and anti-proliferative activity of tetra-substituted naphthalene diimide compounds

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• 作者：Sheila Mpima ; Stephan A. Ohnmacht ; Maria Barletta ; Jarmila Husby ; Luke C. Pett ; Mekala Gunaratnam ; Stephen T. Hilton ; Stephen Neidle
• 关键词：G-quadruplex ; Naphthalene diimide ; Pancreatic cancer ; Molecular dynamics
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 October, 2013
• 年：2013
• 卷：21
• 期：20
• 页码：6162-6170
• 全文大小：1118 K

文摘

The synthesis together with biophysical and biological evaluation of a series of tetra-substituted naphthalene diimide (ND) compounds, are presented. These compounds are positional isomers of a recently-described series of quadruplex-binding ND derivatives, in which the two N-methyl-piperidine-alkyl side-chains have now been interchanged with the positions of side-chains bearing a range of end-groups. Molecular dynamics simulations of a pair of positional isomers are in accord with the quadruplex stabilization and biological data for these compounds. Analysis of structure-activity data indicates that for compounds where the side-chains are not of equivalent length then the positional isomers described here tend to have improved cell proliferation potency and in some instances, superior quadruplex stabilization ability.