Alternative heterocycles for DNA recognition : An N-methylpyrazole/N-methylpyrrole pair specifies for A.T/T.A base pairs

• Published in: Bioorganic & medicinal chemistry Vol. 9; no. 1; pp. 7 - 17
• Main Authors: NGUYEN, Doan H, SZEWCZYK, Jason W, BAIRD, Eldon E, DERVAN, Peter B
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 2001
• Subjects: Analytical, structural and metabolic biochemistry; Base Pairing; Base Sequence; Binding Sites; Biological and medical sciences; DNA - chemistry; Dna, deoxyribonucleoproteins; Fundamental and applied biological sciences. Psychology; Imidazoles - chemistry; Molecular Sequence Data; Nucleic acids; Nylons - chemical synthesis; Pyrazoles - chemistry; Pyrroles - chemistry; Sulfur nitrogen heterocycle; Imidazole derivatives; Sequence specificity; Five membered ring; Hairpin loop; Peptides; Nucleotide sequence; Minor groove; Nitrogen heterocycle; Thiazole derivatives; Molecular interaction; Base pairing; Pyrrole derivatives; DNA; Pyrazole derivatives; Affinity; Solid phase; Chemical synthesis
• ISSN: 0968-0896; 1464-3391

Side-by-side pairs of three five-membered rings, N-methylpyrrole (Py), N-methylimidazole (Im), and N-methylhydroxy-pyrrole (Hp), have been demonstrated to distinguish each of the four Watson Crick base pairs in the minor groove of DNA. However, not all DNA sequences targeted by these pairing rules achieve affinities and specificities comparable to DNA binding proteins. We have initiated a search for new heterocycles which can expand the sequence repetoire currently available. Two heterocyclic aromatic amino acids. N-methylpyrazole (Pz) and 4-methylthiazole (Th), were incorporated into a single position of an eight-ring polyamide of sequence ImImXPy-gamma-lmPyPyPy-beta-Dp to examine the modulation of affinity and specificity for DNA binding by a Pz/Py pair and or a Th/Py pair. The X/Py pairings Pz/Py and Th/Py were evaluated by quantitative DNase I footprint titrations on a DNA fragment with the four sites 5'-TGGNCA-3' (N=T, A, G, C). The Pz/Py pair binds T.A and A.T with similar affinity to a Py/Py pair but with improved specificity. disfavoring both G.C and C.G by about 100-fold. The Th/Py pair binds poorly to all four Watson Crick base pairs. These results demonstrate that in some instances new heterocyclic aromatic amino acid pairs can be incorporated into imidazole-pyrrole polyamides to mimic the DNA specificity of Py/Py pairs which may be relevant as biological criteria in animal studies become important.