Oligomerization route to Py-Im polyamide macrocycles

Abstract

Cyclic eight-ring pyrrole-imidazole polyamides are sequence-specific DNA-binding small molecules that are cell permeable and can regulate endogenous gene expression. Syntheses of cyclic polyamides have been achieved by solid-phase and solution-phase methods. A rapid solution-phase oligomerization approach to eight-ring symmetrical cyclic polyamides yields 12- and 16-membered macrocycles as well. A preference for DNA binding by the 8- and 16-membered oligomers was observed over the 12-ring macrocycle, which we attributed to a conformational constraint not present in the smaller and larger systems.

Figure 1

Structures of macrocyclic polyamides 1z–3z and 1–3, and their ball-and-stick models. Polyamide shorthand code: closed circles, Im monomer; open circles, Py monomer.

Figure 2

Reverse phase HPLC analysis (20 hr) of the oligomerization reaction revealing products 1z, 2z, and 3z. Peaks were identified by high-resolution mass spectrometry following isolation and Cbz-deprotection.

Scheme 1

Synthesis of macrocyclic polyamides 1–3 and higher order cycles by oligomerization of bifunctional intermediate 5.