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

Hsu Shan Huang, Tsung Chih Chen, Ruei Huei Chen, Kuo Feng Huang, Fong Chun Huang, Jing Ru Jhan, Chun Liang Chen, Chia Chung Lee, Yang Lo, Jing Jer Lin

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)7418-7428
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number21
DOIs
Publication statusPublished - Nov 1 2009
Externally publishedYes

Fingerprint

Anthraquinones
Telomerase
Cytotoxicity
Cells
G-Quadruplexes
Acylation
Cyclization
Cytotoxins
Cell proliferation
Chromophores
Growth
Tumor Cell Line
Tumors
Condensation
Screening
Substitution reactions
Cell Proliferation
Acids
Testing
heparinized hydrophilic polymer

Keywords

  • Anthra[1,2-d]imidazole-6,11-dione
  • Cytotoxicity
  • Heteroannelated anthraquinones
  • NCI's 60 cell line human tumor screen
  • Telomerase

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Medicine(all)
  • Drug Discovery
  • Pharmaceutical Science

Cite this

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. / Huang, Hsu Shan; Chen, Tsung Chih; Chen, Ruei Huei; Huang, Kuo Feng; Huang, Fong Chun; Jhan, Jing Ru; Chen, Chun Liang; Lee, Chia Chung; Lo, Yang; Lin, Jing Jer.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 21, 01.11.2009, p. 7418-7428.

Research output: Contribution to journalArticle

Huang, Hsu Shan ; Chen, Tsung Chih ; Chen, Ruei Huei ; Huang, Kuo Feng ; Huang, Fong Chun ; Jhan, Jing Ru ; Chen, Chun Liang ; Lee, Chia Chung ; Lo, Yang ; Lin, Jing Jer. / 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. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 21. pp. 7418-7428.
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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.",
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