DNA threading bis(9-aminoacridine-4-carboxamides): Effects of piperidine sidechains on DNA binding, cytotoxicity and cell cycle arrest

DNA threading bis(9-aminoacridine-4-carboxamides): Effects of piperidine sidechains on DNA binding, cytotoxicity and cell cycle arrest

A series of bis(9-aminoacridine-4-carboxamides) with ethylpiperidino and N-methylpiperidin-4-yl sidechains were synthesized and evaluated for the effects on DNA binding, cytotoxicity and cell cycle arrest. We describe the synthesis of a series of DNA-threading bis(9-aminoacridine-4-carboxamides) com...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry Vol. 16; no. 8; pp. 4390 - 4400
Main Authors: He, Zhicong, Bu, Xianyong, Eleftheriou, Alexandra, Zihlif, Malik, Qing, Zhang, Stewart, Bernard W., Wakelin, Laurence P.G.
Format: Journal Article
Language:English
Published: Oxford Elsevier Ltd 15-04-2008
Elsevier Science
Subjects:
Aminoacridines - chemical synthesis
Aminoacridines - chemistry
Aminoacridines - toxicity
Antineoplastic agents
Biological and medical sciences
Bisintercalator
Cell Cycle - drug effects
Cell Line, Tumor
Diacridine
Dimerization
DNA - genetics
General aspects
Humans
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Piperidines - chemistry
Structure-Activity Relationship
Threading agent
Transcriptional inhibitor
Transcriptional inhibitor
Threading agent
Bisintercalator
Diacridine
Antineoplastic agent
Intercalating agent
Transcription
Acridine derivatives
Cytotoxicity
In vitro
Biological activity
Biological fixation
Side chain
DNA
Piperidine derivatives
Aminoacridine
Carboxamide
Inhibitor
Chemical synthesis
Antimitotic
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Summary:A series of bis(9-aminoacridine-4-carboxamides) with ethylpiperidino and N-methylpiperidin-4-yl sidechains were synthesized and evaluated for the effects on DNA binding, cytotoxicity and cell cycle arrest. We describe the synthesis of a series of DNA-threading bis(9-aminoacridine-4-carboxamides) comprising ethylpiperidino and N-methylpiperidin-4-yl sidechains, joined via neutral flexible alkyl chains, charged flexible polyamine chains and a semi-rigid charged piperazine linker. Their cytotoxicity towards human leukaemic cells gives IC 50 values ranging from 99 to 1100 nM, with the ethylpiperidino series generally being more cytotoxic than the N-methylpiperidin-4-yl series. Measurements with supercoiled DNA indicate that they bisintercalate.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.02.063