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Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2008 Jul 15; Vol. 16 (14), pp. 6976-86. Date of Electronic Publication: 2008 Jun 02. - Publication Year :
- 2008
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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.
- Subjects :
- Anthraquinones chemistry
Cell Line, Tumor
Cell Proliferation drug effects
Cells, Cultured
Drug Screening Assays, Antitumor
Fibroblasts drug effects
Humans
Structure-Activity Relationship
Telomerase drug effects
Anthraquinones chemical synthesis
Anthraquinones pharmacology
Antineoplastic Agents chemical synthesis
Telomerase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 16
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 18571928
- Full Text :
- https://doi.org/10.1016/j.bmc.2008.05.072