Solution-phase synthesis of pyrrole-imidazole polyamides.
Pyrrole-imidazole polyamides are DNA-binding molecules that are programmable for a large repertoire of DNA sequences. Typical syntheses of this class of heterocyclic oligomers rely on solid-phase methods. Solid-phase methodologies offer rapid assembly on a micromole scale sufficient for biophysical characterizations and cell culture studies. In order to produce gram-scale quantities necessary for efficacy studies in animals, polyamides must be readily synthesized in solution. An 8-ring hairpin polyamide 1, which targets the DNA sequence 5'-WGWWCW-3', was chosen for our synthesis studies as this oligomer exhibits androgen receptor antagonism in cell culture models of prostate cancer. A convergent solution-phase synthesis of 1 from a small set of commercially available building blocks is presented which highlights principles for preparing gram quantities of pyrrole-imidazole oligomers with minimal chromatography.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
David M
DM
Chenoweth
Daniel A
DA
Harki
Peter B
PB
Dervan
D002851:Chromatography, High Pressure Liquid; D007093:Imidazoles / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D009757:Nylons / Q000138:chemical synthesis*; D011758:Pyrroles / Q000138:chemical synthesis*; D012996:Solutions / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet
D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D012996:Solutions