Synthesis and DNA binding properties of 1-(3-aminopropyl)-imidazole-containing triamide f-Im∗PyIm: 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, David Wilson, W., Lin, Shicai, Kiakos, Kostantinos, Hartley, John A., Lee, Moses
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 15.09.2012
• Subjects: ACGCGT; Diamino; Dicationic; MCB; MluI cell cycle; Polyamide; Polyamide; MluI cell cycle; Dicationic; MCB; Diamino; ACGCGT
• 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, ΔTM, 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 (Keq=2.3×107M−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.