Hx-amides: DNA sequence recognition by the fluorescent Hx (p-anisylbenzimidazole)•pyrrole and Hx•imidazole pairings

• Published in: Bioorganic & medicinal chemistry letters 2013-03, Vol.23 (6), p.1699-1702
• Main Authors: Satam, Vijay, Patil, Pravin, Babu, Balaji, Gregory, Matthew, Bowerman, Michael, Savagian, Mia, Lee, Megan, Tzou, Samuel, Olson, Kevin, Liu, Yang, Ramos, Joseph, Wilson, W. David, Bingham, John P., Kiakos, Kostantinos, Hartley, John A., Lee, Moses
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Anisoles - chemistry; Base Pairing; Benzimidazoles - chemistry; chemistry; Circular Dichroism; deoxyribonuclease I; Distamycin; DNA; DNA - chemistry; DNA - metabolism; fluorescence; Fluorescent Dyes - chemistry; Hoechst 33258; Hx-amides; Imidazoles - chemistry; Minor groove; Nucleic Acid Conformation; nucleotide sequences; Pyrroles - chemistry; Sequence recognition
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.01.075

Hx-amides are fluorescent hybrids of imidazole (I)- and pyrrole (P)-containing polyamides and Hoechst 33258, and they bind in the minor groove of specific DNA sequences. Synthesis and DNA binding studies of HxII (5) complete our studies on the first set of Hx-amides: Hx–I/P–I/P. HxPP (2), HxIP (3) and HxPI (4) were reported earlier. Results from DNase I footprinting, biosensor-SPR, CD and ΔTM studies showed that Hx-amides interacted with DNA via the anti-parallel and stacked, side-by-side motif. Hx was found to mimic the DNA recognition properties of two consecutive pyrrole units (PP) in polyamides. Accordingly, the stacked Hx/PP pairing binds preferentially to two consecutive AT base pairs, A/T–A/T; Hx/IP prefers C–A/T; Hx/PI prefers A/T–C; and Hx/II prefers C–C. The results also showed that Hx-amides bound their cognate sequence at a higher affinity than their formamido-triamide counterparts.