Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library

LaTeca S. Glass, Aditi Bapat, Mark Kelley, Millie Georgiadis, Eric C. Long

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

High-throughput fluorescent intercalator displacement (HT-FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT-FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity.

Original languageEnglish
Pages (from-to)1685-1688
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number5
DOIs
StatePublished - Mar 1 2010

Fingerprint

Intercalating Agents
Libraries
Throughput
DNA
Screening
DNA sequences
Cell proliferation
Cell death
Drug Discovery
Glioblastoma
Bioactivity
Freezing
Melting
Cell Death
Demonstrations
Hot Temperature
Cell Proliferation
Molecules
Neoplasms

Keywords

  • Cytotoxicity
  • DNA binding
  • Fluorescent intercalator displacement (FID)
  • High-throughput screening

ASJC Scopus subject areas

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

Cite this

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AU - Bapat, Aditi

AU - Kelley, Mark

AU - Georgiadis, Millie

AU - Long, Eric C.

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AB - High-throughput fluorescent intercalator displacement (HT-FID) was adapted to the semi-automated screening of a commercial compound library containing 60,000 molecules resulting in the discovery of cytotoxic DNA-targeted agents. Although commercial libraries are routinely screened in drug discovery efforts, the DNA binding potential of the compounds they contain has largely been overlooked. HT-FID led to the rapid identification of a number of compounds for which DNA binding properties were validated through demonstration of concentration-dependent DNA binding and increased thermal melting of A/T- or G/C-rich DNA sequences. Selected compounds were assayed further for cell proliferation inhibition in glioblastoma cells. Seven distinct compounds emerged from this screening procedure that represent structures unknown previously to be capable of targeting DNA leading to cell death. These agents may represent structures worthy of further modification to optimally explore their potential as cytotoxic anti-cancer agents. In addition, the general screening strategy described may find broader impact toward the rapid discovery of DNA targeted agents with biological activity.

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