Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones

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概要

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• Telomerase is the enzymatic activity that maintains the ends of eukaryotic chromosomes. Telomerase activity is detected in most tumor cells whereas it is low or undetectable in most normal somatic cells. Expression of the telomerase catalytic component, the human telomerase reverse transcriptase (hTERT), is believed to be controlled primarily at the level of transcription. Because of this selective expression property of telomerase, it has been touted as a specific target for antitumor chemotherapeutics. However, a concern for the applicability of telomerase inhibitors is that they require a long lag time for telomeres to be shortened to critical length before cancer cells stop proliferating. Here we investigate telomerase inhibitory, cytotoxicity and the hTERT repressing effects on a number of synthesized 2,6-diamidoanthraquinones and 1,5-diamidoanthraquinones as compared to their disubstituted homologues. We found that several of the 1,5-diamidoanthraquinones and 2,6-diamidoanthraquinones inhibited telomerase activity effectively with IC_<50> at the sub-micro to micro molar range and caused acute cytotoxicity to cancer cells with EC_<50> similar or better than that of mitoxantrone. Particularly, 2,6-diamidoanthraquinone with 2-ethylaminoacetamido side chains 33, even though not affecting cell proliferation, showed to be endowed with a strong telomerase effect, probably related to a marked stabilization of the G-quadruplex-binding structure. The results suggested that these compounds caused multiple effects to cancer cells. More significantly, they overcome the long lag period problem of classical telomerase inhibitors that they are also potent cytotoxic agents. These results greatly expand the potential of tricyclic anthraquinone pharmacophore in preventive and/or curative therapy.

• 公益社団法人日本薬学会の論文
• 2007-02-01

著者

• Huang Hsu-shan

  School Of Pharmacy National Defense Medical Center

• Shieh Fu-ying

  Institute Of Biopharmaceutical Science National Yang-ming University

• Lu Wei-chih

  Cheng-hsin Medical Center

• CHEN In-Been

  School of Pharmacy, National Defense Medical Center

• Huang Kuo-feng

  Chi-mei Medical Center

• Huang Yi-yuan

  Institute Of Biopharmaceutical Science National Yang-ming University

• Lin Jing-jer

  Institute Of Biopharmaceutical Science National Yang-ming University

• Lin Jing-jer

  Institute Of Bio-pharmaceutical Science National Yang-ming University

• Chen In-been

  School Of Pharmacy National Defense Medical Center

• HUANG Fong-Chun

  Institute of Biopharmaceutical Science, National Yang-Ming University

• Huang Fong-chun

  Institute Of Biopharmaceutical Science National Yang-ming University

関連論文

• Synthesis and Antitumor Activity of 1,8-Diaminoanthraquinone Derivatives
• Synthesis and Antitumor Evaluation of Symmetrical 1,5-Diamidoanthraquinone Derivatives as Compared to Their Disubstituted Homologues
• Synthesis of Symmetrical 1,5-bis-thio-Substituted Anthraquinones for Cytotoxicity in Cultured Tumor Cells and Lipid Peroxidation
• Studies on Anthracenes.2.Synthesis and Cytotoxic Evaluation of 9-Acyloxy 1, 8-Dichloroanthracene Derivatives
• New Constituent from Podocarpus macrophyllus var. macrophyllus Shows Anti-tyrosinase Effect and Regulates Tyrosinase-Related Proteins and mRNA in Human Epidermal Melanocytes
• Small-Molecule Anthracene-Induced Cytotoxicity and Induction of Apoptosis through Generation of Reactive Oxygen Species(Medicinal Chemistry)
• Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones
• Stduies on Anthracenes.3.Synthesis, Lipid Peroxidation and Cytotoxic Evaluation of 10-Substituted 1, 5-Dichloro-9(10H)-anthracenone Derivatives
• Studies on Anthracenes. 1. Human Telomerase Inhibition and Lipid Peroxidation of 9-Acyloxy 1, 5-Dichloroanthracene Derivatives

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