Cyclic pyrrole-imidazole polyamides targeted to the androgen response element.
Hairpin pyrrole-imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor-DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an gamma-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cyclic polyamide, a lesser-studied architecture mainly attributable to synthetic inaccessibility. We have applied our methodology for solution-phase polyamide synthesis to cyclic polyamides with an improved high-yield cyclization step. Cyclic 8-ring Py-Im polyamides 1-3 target the DNA sequence 5'-WGWWCW-3', which corresponds to the androgen response element (ARE) bound by the androgen receptor transcription factor to modulate gene expression. We find that cyclic Py-Im polyamides 1-3 bind DNA with exceptionally high affinities and regulate the expression of AR target genes in cell culture studies, from which we infer that the cycle is cell permeable.
Chenoweth
David M
DM
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Harki
Daniel A
DA
Phillips
John W
JW
Dose
Christian
C
Dervan
Peter B
PB
D001483:Base Sequence; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D016503:Drug Delivery Systems; D004355:Drug Stability; D006358:Hot Temperature; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D008297:Male; D008958:Models, Molecular; D009757:Nylons / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics*; D020218:Response Elements; D012996:Solutions / Q000737:chemistry
D007093:Imidazoles; D047028:Macrocyclic Compounds; D009757:Nylons; D011758:Pyrroles; D011944:Receptors, Androgen; D012996:Solutions; D004247:DNA