Synthesis and evaluation of a conformationally constrained pyridazinone PNA-monomer for recognition of thymine in triple-helix structures

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 6; pp. 1551 - 1554
• Main Authors: Olsen, Anne Goldbech, Dahl, Otto, Nielsen, Peter E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 22.03.2004; Elsevier
• Subjects: Biological and medical sciences; DNA recognitition; Drug Evaluation, Preclinical - methods; Medical sciences; Miscellaneous; Molecular Structure; Nucleic Acid Conformation; Nucleobase; Peptide nucleic acid (PNA); Peptide Nucleic Acids - chemistry; Peptide Nucleic Acids - genetics; Pharmacology. Drug treatments; Pyridazines - chemistry; Thermodynamics; Thymine - chemistry; Triplex; Peptide nucleic acid (PNA); Triplex; DNA recognitition; Nucleobase; Molecular rigidity; Molecular hybridization; DNA; Triplet; Pyridazine derivatives; Peptide nucleic acid; Thermodynamic properties; Chemical synthesis; Base pairing; Thermal stability
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.12.093

A novel conformationally constrained pyridazinone E ag-base PNA-monomer 2 capable of binding thymine in a triplex motif was designed and synthesised. A bis-PNA with the E ag-base incorporated in the Hoogsteen strand was hybridised with a complementary DNA. Thermal stability studies revealed an increase in T m (4.3 °C per mod.) compared to a no-base unit, but showed no improvement over a previously described unconstrained analogue (E, 1). Surprisingly, no significant difference was found in the thermodynamic parameters (ΔH°, ΔS° and ΔG°) for PNA–DNA triplex formation involving 2 or the unconstrained analogue 1. A novel conformationally constrained pyridazinone E ag-base PNA-monomer capable of binding thymine in a triplex motif was designed, synthesised and evaluated in terms of thermal stability and thermodynamic parameters (ΔH°, ΔS° and ΔG°).