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Rational design of acridine-based ligands with selectivity for human telomeric quadruplexes.

Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two p... Full description

Journal Title: Journal of the American Chemical Society September 8, 2010, Vol.132(35), pp.12263-12272
Main Author: Sparapani, Silvia
Other Authors: Haider, Shozeb M , Doria, Filippo , Gunaratnam, Mekala , Neidle, Stephen
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
ID: E-ISSN: 1520-5126 ; DOI: 10.1021/ja1003944
Link: http://search.proquest.com/docview/753998012/?pq-origsite=primo
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recordid: proquest753998012
title: Rational design of acridine-based ligands with selectivity for human telomeric quadruplexes.
format: Article
creator:
  • Sparapani, Silvia
  • Haider, Shozeb M
  • Doria, Filippo
  • Gunaratnam, Mekala
  • Neidle, Stephen
subjects:
  • Acridines–Chemical Synthesis
  • Antineoplastic Agents–Chemistry
  • Cell Line, Tumor–Pharmacology
  • Cell Proliferation–Chemical Synthesis
  • DNA–Chemistry
  • Drug Screening Assays, Antitumor–Pharmacology
  • Enzyme Inhibitors–Drug Effects
  • Fibroblasts–Drug Effects
  • G-Quadruplexes–Chemical Synthesis
  • Humans–Chemistry
  • Ligands–Pharmacology
  • Models, Molecular–Drug Effects
  • Molecular Structure–Drug Effects
  • Proto-Oncogene Proteins C-Kit–Chemistry
  • Stereoisomerism–Genetics
  • Structure-Activity Relationship–Antagonists & Inhibitors
  • Telomerase–Chemistry
  • Telomere–Drug Effects
  • Triazoles–Chemistry
  • Acridines
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Ligands
  • Triazoles
  • DNA
  • Calf Thymus DNA
  • Proto-Oncogene Proteins C-Kit
  • Tert Protein, Human
  • Telomerase
ispartof: Journal of the American Chemical Society, September 8, 2010, Vol.132(35), pp.12263-12272
description: Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.
language: eng
source:
identifier: E-ISSN: 1520-5126 ; DOI: 10.1021/ja1003944
fulltext: fulltext
issn:
  • 15205126
  • 1520-5126
url: Link


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titleRational design of acridine-based ligands with selectivity for human telomeric quadruplexes.
creatorSparapani, Silvia ; Haider, Shozeb M ; Doria, Filippo ; Gunaratnam, Mekala ; Neidle, Stephen
contributorSparapani, Silvia (correspondence author) ; Sparapani, Silvia (record owner)
ispartofJournal of the American Chemical Society, September 8, 2010, Vol.132(35), pp.12263-12272
identifierE-ISSN: 1520-5126 ; DOI: 10.1021/ja1003944
subjectAcridines–Chemical Synthesis ; Antineoplastic Agents–Chemistry ; Cell Line, Tumor–Pharmacology ; Cell Proliferation–Chemical Synthesis ; DNA–Chemistry ; Drug Screening Assays, Antitumor–Pharmacology ; Enzyme Inhibitors–Drug Effects ; Fibroblasts–Drug Effects ; G-Quadruplexes–Chemical Synthesis ; Humans–Chemistry ; Ligands–Pharmacology ; Models, Molecular–Drug Effects ; Molecular Structure–Drug Effects ; Proto-Oncogene Proteins C-Kit–Chemistry ; Stereoisomerism–Genetics ; Structure-Activity Relationship–Antagonists & Inhibitors ; Telomerase–Chemistry ; Telomere–Drug Effects ; Triazoles–Chemistry ; Acridines ; Antineoplastic Agents ; Enzyme Inhibitors ; Ligands ; Triazoles ; DNA ; Calf Thymus DNA ; Proto-Oncogene Proteins C-Kit ; Tert Protein, Human ; Telomerase
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descriptionStructure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs. A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method. Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures. These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios. Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA. Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular the separation of the two alkyl-amino terminal groups. Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.
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authorSparapani, Silvia ; Haider, Shozeb M ; Doria, Filippo ; Gunaratnam, Mekala ; Neidle, Stephen
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