Cyclic Pyrrole-lmidazole Polyamides Targeted to the Androgen Response Element

摘要

Hairpin pyrrole-imidazole (Py-lm) 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-lm ring pairs with an γ-amino acid turn unit affords the classical hairpin Py-lm 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-lm 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-lm 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.