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Synthesis, cytotoxicity and human telomerase inhibition activities of a series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione homologues.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2009 Nov 01; Vol. 17 (21), pp. 7418-28. Date of Electronic Publication: 2009 Sep 23. - Publication Year :
- 2009
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Abstract
- A series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione tetracyclic analogues with different side chain were prepared using an various synthetic route via acylation, cyclization, condensation, and intramolecular heterocyclization. Tetracyclic system containing alkyl and aryl, aromatic and heterocyclic, linear and cyclic, polar and apolar, and basic and acids residues were incorporated. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and in vitro cytotoxicity against NCI's 60 cell line human tumor screen. Compounds 4, 11, 12, 14, 15, 16, 17, 19, 20, 23, 25, and 26 were selected by the NCI for one dose screening program and further studies on 4, 23 and 25 where the curves cross these lines represent the interpolated values to cause 50% growth inhibition (GI(50)), total growth inhibition (TGI) and 50% cell killing (LC(50)), respectively. Further studies did not reveal any compound that showed potent and significant on telomerase inhibitory activity and hTERT repressing ability. Comparative testing of these compounds in the NCI's screen revealed varying levels of potency and differential cytotoxicity, apparently related to the unsaturation levels in and substitution patterns on the core ring system. It appeared that addition of a fourth planar aromatic system to a tricyclic chromophore might enhances potent cytotoxic agents, at a level equivalent to a second side chain in one of the tricyclic series. Although the exact mechanism of how this pharmacophore contributes to its activity is still unclear, however, the group in the extended arm of the tetracyclic system might contribute to proper binding to the residues within the grove of G-quadruplex structure.
- Subjects :
- Anthraquinones chemistry
Anthraquinones toxicity
Antineoplastic Agents chemistry
Antineoplastic Agents toxicity
Cell Line, Tumor
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Humans
Imidazoles chemistry
Imidazoles toxicity
Reverse Transcriptase Inhibitors chemistry
Reverse Transcriptase Inhibitors toxicity
Structure-Activity Relationship
Telomerase metabolism
Thiadiazoles chemistry
Thiadiazoles toxicity
Anthraquinones chemical synthesis
Antineoplastic Agents chemical synthesis
Imidazoles chemical synthesis
Reverse Transcriptase Inhibitors chemical synthesis
Telomerase antagonists & inhibitors
Thiadiazoles chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 17
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19804981
- Full Text :
- https://doi.org/10.1016/j.bmc.2009.09.033