Inhibition of PNA triplex formation by N4-benzoylated cytosine.
The synthesis of N-((N4-(benzoyl)cytosine-1-yl)acetyl)- N -(2-Boc-aminoethyl)glycine (CBz) and the incorporation of this monomer into PNA oligomers are described. A single CBzresidue within a 10mer homopyrimidine PNA is capable of switching the preferred binding mode from a parallel to an antiparallel orientation when targeting a deoxyribonucleotide sequence at neutral pH. The resulting complex has a thermal stability equal to that of the corresponding PNA-DNA duplex, indicative of a strong destabilization of Hoogsteen strand PNA binding due to steric interference by the benzoyl moieties. Accordingly, incorporation of the CBz residue into linked PNAs (bis-PNAs) results in greatly reduced thermal stability of the formed PNA:DNA complexes. Thus, incorporation of the CBz monomer could eliminate the stability bias of triplex-forming sequences in PNA used in hybridization arrays and combinatorial library formats. Furthermore, it is shown that the benzoyl moiety does not severely interfere with Watson-Crick hydrogen bonding, thereby presenting an interesting route for novel cytosine modifications.
Christensen
L
L
Center for Biomolecular Recognition, IMBG, Department of Biochemistry B, The Panum Institute, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
Hansen
H F
HF
Koch
T
T
Nielsen
P E
PE
D001565:Benzoates; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D009841:Oligonucleotides / Q000138:chemical synthesis*; D010455:Peptides / Q000138:chemical synthesis*
D001565:Benzoates; C113095:N-((N(4)-(benzoyl)cytosine-1-yl)acetyl)-N-(2-(tert-butoxycarbonyl)aminoethyl)glycine; D009841:Oligonucleotides; D010455:Peptides; D003596:Cytosine