1,8-Naphthyridin-2(1H)-ones - Novel bicyclic and tricyclic analogues of thymine in peptide nucleic acids (PNAs)

The synthesis of two novel PNA nucleobases derived from 1,8-naphthyridin-2( 1H)-one (bT) and benzo[b]-1,8-naphthyridin-2(1H)-one (tT) are reported, tog ether with their incorporation into oligomers of PNA and evaluation as subs titutes for thymine. Compound bT is shown to be an effective mimic of the n atural thymine nucleobase in PNA-DNA, PNA-RNA, and PNA-PNA duplex structure s. A study using singly mismatched target sequences showed bT to be selecti ve for the recognition of adenine. The X-ray structure of a PNA hexa mer co ntaining a single bT base (H-GbTATAC-L-lys-NH2) was determined to 1.8 Angst rom resolution and confirmed the base-pairing capability with adenine. The introduction of a bT base does not alter the P-form double helix structure of PNA, as compared to other PNA structures containing natural nucleobases. With the tricyclic derivative, incorporation of several units of tT result ed in decreased specificity in some systems, while maintaining specificity in others. In PNA-DNA-PNA tripler structures, incorporation of bT into the Hoogsteen strand resulted in enhanced stability relative to control triplex es containing only T-A-T and pseudoisocytosine (J)-G-C triplets (DeltaT(m) = +1.5 degreesC/modification). The evaluation of another nucleobase, 3,5-di aza-4-oxophenothiazine (tC), expected to mimic the function of cytosine is similarly reported. Incorporation of tC in place of cytosine in PNA oligome rs increased the thermal stability of the corresponding PNA-DNA, PNA-RNA, a nd PNA-PNA duplexes. However, the sequence specificity was diminished in so me PNA-DNA duplex systems containing several tC units. The thermal stabilit y of triplex structures containing tC in the Hoogsteen strand was reduced r elative to the cytosine-containing control.