γ-(S)-Guanidinylmethyl-Modified Triplex-Forming Peptide Nucleic Acids Increase Hoogsteen-Face Affinity for a MicroRNA and Enhance Cellular Uptake.

γ-Modified (i.e., (S)-aminomethyl, (S)-acetamidomethyl, (R)-4-(hydroxymethyl)triazol-1-ylmethyl, and (S)-guanidinylmethyl) triplex-forming peptide nucleic acids (TFPNAs) were synthesized and the effect of the backbone modifications on the binding to a miR-215 model was studied. Among the modifications, an appropriate pattern of three γ-(S)-guanidinylmethyl modifications increased the affinity and Hoogsteen-face selectivity for the miR-215 model without ternary (PNA)2 /RNA complex formation. Moreover, the γ-(S)-guanidinylmethyl groups were observed to facilitate internalization of the TFPNAs into living PC-3 prostate cancer cells.