Sequence specific recognition of DNA by tailor-made hairpin conjugates of achiral seco-cyclopropaneindoline-2-benzofurancarboxamide and pyrrole–imidazole polyamides

• Published in: Bioorganic & medicinal chemistry letters 2005-06, Vol.15 (12), p.3151-3156
• Main Authors: Price, Carly A., Lingerfelt, Brian M., Handl, Heather L., Kiakos, Konstantinos, Hartley, John A., Lee, Moses
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amides - metabolism; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Antineoplastic agents; AT Rich Sequence - physiology; Benzofurans - chemistry; Benzofurans - metabolism; Binding Sites; Biological and medical sciences; Conjugates; DNA; DNA - genetics; DNA - metabolism; DNA - radiation effects; DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Duocarmycins; GC Rich Sequence - physiology; General aspects; Hot Temperature; Imidazoles - chemistry; Medical sciences; Miscellaneous; Molecular Conformation; Nucleic Acid Conformation; Pharmacology. Drug treatments; Polyamides; Promoter Regions, Genetic - genetics; Pyrroles - chemistry; Sequence specificity; Substrate Specificity; Thermodynamics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.04.006

[Display omitted] Hairpin conjugates of achiral seco-cyclopropaneindoline-2-benzofurancarboxamide (achiral seco-CI-Bf) and three diamides (ImPy 1, PyIm 2, and PyPy 3, where Py is pyrrole, and Im is imidazole), linked by a γ-aminobutyrate group, were synthesized. The sequence-specific covalent alkylation of the achiral CI moiety with adenine-N3 in the minor groove was ascertained by thermally induced DNA cleavage experiments. The results provide evidence that hairpin conjugates of achiral seco-CI-Bf-γ-polyamides could be tailored to target specific DNA sequences according to a set of general rules: the achiral CI moiety selectively reacts with adenine-N3, a stacked pair of imidazole/benzofuran prefers a G/C base pair, and a pyrrole/benzofuran prefers an A/T or T/A base pair. Models for the binding of hairpin conjugates 1– 3 with sequences 5′-TC A(888)G-3′, 5′-CA A(857)C-3′, and 5′-TT A(843)C-3′ are proposed.