Structure-based design, synthesis and evaluation of novel anthra[1,2-d]imidazole-6,11-dione derivatives as telomerase inhibitors and potential for cancer polypharmacology.

A series of anthra[1,2-d]imidazole-6,11-dione derivatives were synthesized and evaluated for telomerase inhibition, hTERT expression and suppression of cancer cell growth in vitro. All of the compounds tested, except for compounds 4, 7, 16, 24, 27 and 28 were selected by the NCI screening system. Among them, compounds 16, 39, and 40 repressed hTERT expression without greatly affecting cell growth, suggesting for the selectivity toward hTERT expression. Taken together, our findings indicated that the analysis of cytotoxicity and telomerase inhibition might provide information applicable for further developing potential telomerase and polypharmacological targeting strategy.

[1]  J. Shay,et al.  Telomerase therapeutics for cancer: challenges and new directions , 2006, Nature Reviews Drug Discovery.

[2]  K. Collins.  Mammalian telomeres and telomerase. , 2000, Current opinion in cell biology.

[3]  R. O'Sullivan,et al.  Telomeres: protecting chromosomes against genome instability , 2010, Nature Reviews Molecular Cell Biology.

[4]  R. Janknecht,et al.  Regulation of telomerase reverse transcriptase gene activity by upstream stimulatory factor , 2003, Oncogene.

[5]  M. Dempster,et al.  Human telomeres contain at least three types of G-rich repeat distributed non-randomly. , 1989, Nucleic acids research.

[6]  Takashi Tsuruo,et al.  Involvement of 14‐3‐3 proteins in nuclear localization of telomerase , 2000, The EMBO journal.

[7]  J. Chiou,et al.  Activation of human telomerase reverse transcriptase expression by some new symmetrical bis-substituted derivatives of the anthraquinone. , 2003, Journal of medicinal chemistry.

[8]  Souvik Maiti,et al.  Hoechst 33258 binds to G-quadruplex in the promoter region of human c-myc. , 2003, Biochemical and biophysical research communications.

[9]  J. Guh,et al.  Synthesis, antiproliferative activities and telomerase inhibition evaluation of novel asymmetrical 1,2-disubstituted amidoanthraquinone derivatives. , 2012, European journal of medicinal chemistry.

[10]  Jean-Louis Mergny,et al.  Targeting telomeres and telomerase. , 2008, Biochimie.

[11]  Jean-Louis Mergny,et al.  Detection of telomerase inhibitors based on g-quadruplex ligands by a modified telomeric repeat amplification protocol assay. , 2002, Cancer research.

[12]  Hsu-Shan Huang,et al.  Human telomerase inhibition and cytotoxicity of regioisomeric disubstituted amidoanthraquinones and aminoanthraquinones. , 2005, Bioorganic & medicinal chemistry.

[13]  B. Xue,et al.  Rapid colorimetric assay for cell growth and survival in application of immunotoxicology , 1988 .

[14]  K. Collins,et al.  Telomerase in the human organism , 2002, Oncogene.

[15]  Hsu-Shan Huang,et al.  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. , 2009, Bioorganic & medicinal chemistry.

[16]  C B Harley,et al.  Specific association of human telomerase activity with immortal cells and cancer. , 1994, Science.

[17]  D. Scudiero,et al.  New colorimetric cytotoxicity assay for anticancer-drug screening. , 1990, Journal of the National Cancer Institute.

[18]  S. Bhattacharya,et al.  An experimental and computational analysis on the differential role of the positional isomers of symmetric bis-2-(pyridyl)-1H-benzimidazoles as DNA binding agents. , 2007, The Journal of organic chemistry.

[19]  U. Martens,et al.  Telomeres and telomerase as targets for cancer therapy , 2007, Cellular and Molecular Life Sciences.

[20]  D. Corey,et al.  Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Malim,et al.  Secreted placental alkaline phosphatase as a eukaryotic reporter gene. , 1992, Methods in enzymology.

[22]  C. Monneret.  Recent developments in the field of antitumour anthracyclines. , 2001, European journal of medicinal chemistry.

[23]  Hsu-Shan Huang,et al.  Synthesis and human telomerase inhibition of a series of regioisomeric disubstituted amidoanthraquinones. , 2007, Chemical & pharmaceutical bulletin.

[24]  Hsu-Shan Huang,et al.  NSC746364, NSC746365, and NSC746366: the spectra of cytotoxicity and molecular correlates of response to telomerase activity , 2010, Anti-cancer drugs.

[25]  Kanyawim Kirtikara,et al.  Sulforhodamine B colorimetric assay for cytotoxicity screening , 2006, Nature Protocols.

[26]  Stephen Neidle,et al.  Human telomeric G‐quadruplex: The current status of telomeric G‐quadruplexes as therapeutic targets in human cancer , 2010, The FEBS journal.

[27]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[28]  Hsu-Shan Huang,et al.  Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives. , 2008, Bioorganic & medicinal chemistry.

[29]  Marie C. M. Lin,et al.  Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation , 2012, Oncogene.

[30]  T. Cech.  Beginning to Understand the End of the Chromosome , 2004, Cell.

[31]  F. Denizot,et al.  Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. , 1986, Journal of immunological methods.

[32]  J. Shay,et al.  A survey of telomerase activity in human cancer. , 1997, European journal of cancer.

[33]  P. Wakeley,et al.  Synthesis , 2013, The Role of Animals in Emerging Viral Diseases.

[34]  M. Haughton,et al.  The nature of telomere fusion and a definition of the critical telomere length in human cells. , 2007, Genes & development.