Synthesis and DNA binding properties of 1-(3-aminopropyl)-imidazole-containing triamide f-ImPyIm: A novel diamino polyamide designed to target 5 '-ACGCGT-3 '

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 18; pp. 5898 - 5902
• Main Authors: Satam, Vijay, Babu, Balaji, Porte, Alexander, Savagian, Mia, Lee, Megan, Smeltzer, Thomas, Liu, Yang, Ramos, Joseph, Wilson, W. David, Lin, Shicai, Kiakos, Kostantinos, Hartley, John A., Lee, Moses
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 15.09.2012
• Subjects: Amino groups; Base Sequence; Binding Sites - drug effects; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Deoxyribonuclease; DNA; DNA - chemistry; DNA - drug effects; DNA biosynthesis; Footprinting; imidazole; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Isomers; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; polyamides; Propanols - chemistry; pyrroles; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Science & Technology; Structure-Activity Relationship; CELL-CYCLE BOX; Dicationic; Diamino; TRANSCRIPTION; MluI cell cycle; PYRROLE-IMIDAZOLE POLYAMIDES; MCB; NUCLEAR-LOCALIZATION; MOLECULAR RECOGNITION; ACGCGT; Polyamide; GENE-EXPRESSION; SEQUENCE RECOGNITION; DISTAMYCIN-A; MODULATION; MINOR-GROOVE; Nylon; Targeting; DNA synthesis; Target; Biological fixation; Mlul cell cycle; DNA; Imidazole; Cell cycle
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.071

A novel diamino/dicationic polyamide f-Im*PyIm (5) that contains an orthogonally positioned aminopropyl chain on an imidazole (Im*) moiety was designed to target 5'-ACGCGT-3'. The DNA binding properties of the diamino polyamide 5, determined by CD, Delta T-M, DNase I footprinting, SPR, and ITC studies, were compared with those of its monoamino/monocationic counterpart f-ImPyIm (1) and its diamino/dicationic isomer f-ImPy*Im (2), which has the aminopropyl group attached to the central pyrrole unit (Py*). The results gave evidence for the minor groove binding and selectivity of polyamide 5 for the cognate sequence 5'-ACGCGT-3', and with strong affinity (K-eq = 2.3 x 10(7) M-1). However, the binding affinities varied according to the order: f-ImPy*Im (2) > f-ImPyIm (1) >= f-Im*PyIm (5) confirming that the second amino group can improve affinity, but its position within the polyamide can affect affinity. (C) 2012 Elsevier Ltd. All rights reserved.