Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library.
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.
Department of Chemistry and Chemical Biology, Purdue School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Lateca S
LS
Glass
Aditi
A
Bapat
Mark R
MR
Kelley
Millie M
MM
Georgiadis
Eric C
EC
Long
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D001331:Automation; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D055808:Drug Discovery; D005456:Fluorescent Dyes / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry* / Q000633:toxicity; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D007364:Intercalating Agents; D054852:Small Molecule Libraries; D004247:DNA