Methionine Sustituted Polyamides are RNAse Mimics that Inhibit Translation

Abstract

RNAse mimics are small molecules that can cleave RNA in a fashion similar to ribonucleases. These compounds would be very useful as gene specific reagents if their activities could be regulated and targeted. We demonstrate here that polyamides with methionine substituents show enhanced RNA cleavage activity relative to other polyamides. Conjugation of these compounds to aminoglycosides produced RNAse mimics that are capable of inhibiting eukaryotic protein synthesis. As a new class of compounds capable of interacting with nucleic acids, these novel aminoglycoside-polyamides constitute promising scaffolds for the construction of nuclease mimics with biological activity.

Aminoglycoside Conjugation for RNA Targeting: Antimicrobials and Beyond

“…Pelletier et al. also developed a methodology for the preparation of several conjugates of 5 and kanamycin with imidazole polyamides functionalized with l ‐methionine, l ‐lysine, l ‐tryptophan, and l ‐asparagine . The aim of this kind of modification was to add RNase activity to the aminoglycosides thanks to the presence of the polyamide core.…”

“…[28] Pelletier et al also developedamethodology for the preparation of several conjugates of 5 and kanamycin with imidazole polyamides functionalized with l-methionine, l-lysine, l-tryptophan, and l-asparagine. [29] The aim of this kind of modification was to add RNase activity to the aminoglycosides thanks to the presence of the polyamide core. As illustrated in Scheme2, the amino groupso f5 and kanamycinA (10)w ere protected with Boc 2 O, then the primary 6''-b-OH group was selectively activatedw ith TIPBSCl to afford compounds 11 and 12.A fter that, the side chain was formed by the reaction with 2-aminoethanethiol, resulting in aminoethyl derivatives 13 and 14.T he coupling reaction of these substrates was realized with Na-Boc-l-Met, Na,Nw-di-Boc-l-Lys, Na,N(In)-di-Boc-l-Trp, and Na-Boc-Asp di-or triimidazole polyamide acids 15.D eprotection in the presence of TFAg ave the final products 16 and 17.…”