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

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-diamidoa...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-07, Vol.16 (14), p.6976-6986
Main Authors: Huang, Hsu-Shan, Huang, Kuo-Feng, Li, Cho-Lu, Huang, Yi-Yuan, Chiang, Yi-Hsuan, Huang, Fong-Chun, Lin, Jing-Jer
Format: Article
Language:English
Subjects:
Anthraquinones
Anthraquinones - chemical synthesis
Anthraquinones - chemistry
Anthraquinones - pharmacology
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
Cells, Cultured
Cytotoxicity
Drug Screening Assays, Antitumor
Fibroblasts - drug effects
G-quadruplex
General aspects
hTERT
Humans
Medical sciences
Pharmacology. Drug treatments
SEAP assay
Structure-Activity Relationship
Telomerase - antagonists & inhibitors
Telomerase - drug effects
Telomerase assay
Telomerase inhibition
TRAP assay
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.05.072