Document Detail

Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives.
MedLine Citation:
PMID:  18571928     Owner:  NLM     Status:  MEDLINE    
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.
Hsu-Shan Huang; Kuo-Feng Huang; Cho-Lu Li; Yi-Yuan Huang; Yi-Hsuan Chiang; Fong-Chun Huang; Jing-Jer Lin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-06-02
Journal Detail:
Title:  Bioorganic & medicinal chemistry     Volume:  16     ISSN:  1464-3391     ISO Abbreviation:  Bioorg. Med. Chem.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-25     Completed Date:  2008-09-11     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9413298     Medline TA:  Bioorg Med Chem     Country:  England    
Other Details:
Languages:  eng     Pagination:  6976-86     Citation Subset:  IM    
School of Pharmacy, National Defense Medical Center, Neihu, Taipei 114, Taiwan, ROC.
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MeSH Terms
Anthraquinones / chemical synthesis*,  chemistry,  pharmacology*
Antineoplastic Agents / chemical synthesis*
Cell Line, Tumor
Cell Proliferation / drug effects
Cells, Cultured
Drug Screening Assays, Antitumor
Fibroblasts / drug effects
Structure-Activity Relationship
Telomerase / antagonists & inhibitors*,  drug effects
Reg. No./Substance:
0/Anthraquinones; 0/Antineoplastic Agents; EC protein, human; EC

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