Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives

Hsu Shan Huang, Kuo Feng Huang, Cho L. Li, Yi Yuan Huang, Yi Hsuan Chiang, Fong Chun Huang, Jing J. Lin

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. A series of 2,7-diamidoanthraquinone were designed and synthesized. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and cytotoxicity. In the series, compounds (6, 10, 13, 16, 18, 19, 20-22, and 24) showed potent telomerase inhibitory activity, while compounds 19, 21, and 22 activated hTERT expression in normal human fibroblasts. The results indicated that 2,7-diamidoanthraquinones represent an important class of compounds for telomerase-related drug developments. Compounds 8, 16, 18, 26, and 32 were also selected by the NCI for Screening Program and demonstrated high anti-proliferative activity against 60 human cancer cell lines. Structure-activity relationships (SAR) study revealed that the test compounds with side chains two carbon spacer between amido and amine are important structural moiety for telomerase inhibition. Although the exact mechanism of how this amine group contributes to its activity is still unclear, however, the amine group in the extended arm of the bis-substituted anthraquinone might contribute to proper binding to the residues within the grove of G-quadruplex structure. Our results indicated that the 2,7-disubstituted amido-anthraquinones are potent telomerase inhibitors that have the potential to be further developed into novel anticancer chemotherapeutic agents.

Original languageEnglish
Pages (from-to)6976-6986
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume16
Issue number14
DOIs
Publication statusPublished - Jul 15 2008
Externally publishedYes

Fingerprint

Anthraquinones
Telomerase
Amines
Tumors
Neoplasms
Cells
G-Quadruplexes
Cell proliferation
Fibroblasts
Structure-Activity Relationship
Cytotoxicity
Antineoplastic Agents
Screening
Carbon
Cell Proliferation
Cell Line

Keywords

  • Anthraquinones
  • Cytotoxicity
  • G-quadruplex
  • hTERT
  • SEAP assay
  • Telomerase assay
  • Telomerase inhibition
  • TRAP assay

ASJC Scopus subject areas

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

Cite this

Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives. / Huang, Hsu Shan; Huang, Kuo Feng; Li, Cho L.; Huang, Yi Yuan; Chiang, Yi Hsuan; Huang, Fong Chun; Lin, Jing J.

In: Bioorganic and Medicinal Chemistry, Vol. 16, No. 14, 15.07.2008, p. 6976-6986.

Research output: Contribution to journalArticle

Huang, Hsu Shan ; Huang, Kuo Feng ; Li, Cho L. ; Huang, Yi Yuan ; Chiang, Yi Hsuan ; Huang, Fong Chun ; Lin, Jing J. / Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives. In: Bioorganic and Medicinal Chemistry. 2008 ; Vol. 16, No. 14. pp. 6976-6986.
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AU - Chiang, Yi Hsuan

AU - Huang, Fong Chun

AU - Lin, Jing J.

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