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.
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
David M
DM
Chenoweth
Daniel A
DA
Harki
John W
JW
Phillips
Christian
C
Dose
Peter B
PB
Dervan
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