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Backbone N-methylated peptide nucleic acids (PNAs) containing the four nucleobases adenine, cytosine, guanine and thymine were synthesized via solid phase peptide oligomerization. The oligomers bind to their complementary target with a thermal stability that is 1.5È4.5 ¡C lower per "" N-methyl nucleobase unit ÏÏ [dependent on the number and position(s) of the N-methyl] than that of unmodiÐed PNA. However, even fully N-methyl modiÐed PNAs bind as efficiently to DNA or RNA targets as DNA itself. Furthermore, the hybridization efficiency per N-methyl unit in a PNA decreased with increasing N-methyl content, and the e †ect was more pronounced when the N-methyl backbone units are present in the Hoogsteen versus the WatsonÈCrick strand in triplexes. (PNA) 2 -DNA Interestingly, CD spectral analyses indicate that 30% (3 out of ten) substitution with N-methyl nucleobases did not alter the structure of PNA-DNA (or RNA) duplexes or triplexes, and likewise CD spectroscopy and (PNA) 2 -DNA X-ray crystallography showed no major structural di †erences between N-methylated (30%) and unmodiÐed PNA-PNA duplexes. However, PNA-DNA duplexes as well as triplexes adopted a di †erent conformation when formed with all-N-methyl PNAs.

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