Human telomerase inhibition and cytotoxicity of regioisomeric disubstituted amidoanthraquinones and aminoanthraquinones

Hsu Shan Huang, Chung Long Chou, Ching Long Guo, Chun Lung Yuan, Yu Cheng Lu, Fu Ying Shieh, Jing Jer Lin

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Telomerase is an attractive target for the rational design of new anticancer drugs due to its central role in the control of cellular proliferation. A number of 1,4-disubstituted amidoanthraquinones and 1,5-disubstituted aminoanthraquinones that are related to mitoxantrone and ametantrone have previously been prepared. The present study details the effects on human telomerase of these new classes of 1,4- and 1,5-difunctionalized tricyclic anthraquinone compounds. We have used cytotoxicity assay, reporter SEAP assay to monitor the hTERT expression, and TRAP-G4 assay to measure the relative activity of these compounds, and have examined how the attached substituents affect their ability to influence telomerase. Cytotoxicity levels in human tumor cell lines were at comparable levels for several compounds. Structural and activity relationships indicated that the position of disubstituent side chains is important for its inhibitory effect. Moreover, a primary amine or tertiary amine on the substitution group appears to be required for the telomerase inhibitory effect. There is no significant correlation between telomerase activity and cytotoxicity. These symmetrical disubstituted anthraquinones may represent useful leads for the development of human telomerase inhibitors as potential anticancer agents, and the exact mode of intercalative binding is dictated by the positional placement of substituent side chains for effective telomerase inhibition.

Original languageEnglish
Pages (from-to)1435-1444
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number5
DOIs
Publication statusPublished - Mar 1 2005
Externally publishedYes

Keywords

  • Amidoanthraquinones
  • Aminoanthraquinones
  • Cytotoxicity
  • hTERT
  • Telomerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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