Synthesis, biophysical and biological evaluation of 3,6-bis-amidoacridines with extended 9-anilino substituents as potent G-quadruplex-binding telomerase inhibitors

被引：61

作者：

Schultes, CM ^{[1
]}

Guyen, W ^{[1
]}

Cuesta, J ^{[1
]}

Neidle, S ^{[1
]}

机构：

[1] Univ London, Sch Pharm, Canc Res UK Biomol Struct Grp, London WC1N 1AX, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 16期

关键词：

telomerase; telomere; quadruplex DNA; FRET; TRAP; acridines;

D O I：

10.1016/j.bmcl.2004.05.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Telomerase and telomere maintenance are emerging targets for the treatment of human cancers. We report here on the targeting of the telomere-telomerase complex with a series of small molecules based on an acridine platform. A series of 3,6-bis-amidoacridines with extended 9-anilino sidechains were designed and synthesised as potential telomeric G-quadruplex DNA (G4) interacting compounds. G4-stabilisation was assessed using a high-throughput FRET (fluorescence resonance energy transfer) assay and telomerase inhibition quantified by a modified TRAP (telomerase repeat amplification protocol) method. Within the series, the compounds showed significant G4-stabilising ability (DeltaT(m) values of 25-36degreesC at 1 muM concentration) and telomerase inhibition in the nanomolar region ((EC50)-E-tel values of 80-318 nM). Furthermore, a direct correlation between the FRET and TRAP assays was observed, supporting the use of the rapid screening FRET assay for early assessment of potential G4-stabilising telomerase inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.

引用

页码：4347 / 4351

页数：5

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