Synthesis and screening of small molecule libraries active in binding to DNA.
Five synthetic combinatorial libraries of 2,080 components each were screened as mixtures for inhibition of DNA binding to two transcription factors. Rapid, solution-phase synthesis coupled to a gel-shift assay led to the identification of two compounds active at a 5- to 10-microM concentration level. The likely mode of inhibition is intercalation between DNA base pairs. The efficient deconvolution through sublibrary synthesis augurs well for the use of large mixtures of small, nonpeptide molecules in biological screens.
Shipps
G W
GW
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Pryor
K E
KE
Xian
J
J
Skyler
D A
DA
Davidson
E H
EH
Rebek
J
J
D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D007364:Intercalating Agents / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014508:Urea / Q000031:analogs & derivatives*; D014966:Xanthenes / Q000737:chemistry*
D004268:DNA-Binding Proteins; D007364:Intercalating Agents; D014157:Transcription Factors; D014966:Xanthenes; D014508:Urea; D004247:DNA