Synthesis and biophysical evaluation of minor-groove binding C-terminus modified pyrrole and imidazole triamide analogs of distamycin

• Published in: Bioorganic & medicinal chemistry 2007, Vol.15 (1), p.474-483
• Main Authors: Brown, Toni, Taherbhai, Zarmeen, Sexton, Jim, Sutterfield, Arden, Turlington, Mark, Jones, Justin, Stallings, Lindsay, Stewart, Michelle, Buchmueller, Karen, Mackay, Hilary, O’Hare, Caroline, Kluza, Jerome, Nguyen, Binh, Wilson, David, Lee, Moses, Hartley, John A.
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amine; Base Sequence; Binding Sites; Binding, Competitive; Biophysical; C-terminus; Circular Dichroism - methods; Distamycin; Distamycins - chemical synthesis; Distamycins - chemistry; Distamycins - pharmacology; DNA; DNA - chemistry; DNA - drug effects; DNA Footprinting - methods; Imidazoles - chemistry; Molecular Sequence Data; Molecular Structure; Nylons - chemical synthesis; Nylons - chemistry; Nylons - pharmacology; Polyamides; Pyrroles - chemistry; Sensitivity and Specificity; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Surface Plasmon Resonance - methods; Temperature; Time Factors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.09.037

Five polyamide derivatives with rationally modified C-terminus moieties were synthesized and their DNA binding specificity and affinity determined. A convergent approach was employed to synthesize polyamides containing an alkylaminopiperazine ( 4 and 5), a truncated piperazine ( 6), or an alkyldiamino-C-terminus moiety ( 7 and 8) with two specific objectives: to investigate the effects of number of potential cationic centers and steric bulk at the C-terminus. CD studies confirmed that compounds 4, 5, 7, and 8 bind in the minor groove of DNA. The alkylpiperazine containing compounds ( 4 and 5) showed only moderate binding to DNA with Δ T m values of 2.8 and 8.3 °C with their cognate sequence, respectively. The alkyldiamino compounds ( 7 and 8) were more impressive producing a Δ T m of >17 and >22 °C, respectively. Compound 6 (truncated piperazine) did not stabilize its cognate DNA sequence. Footprints were observed for all compounds (except compound 6) with their cognate DNA sequence using DNase I footprinting, with compound 7 producing a footprint of 0.1 μM at the expected 5′-ACGCGT-3′ site. SPR analysis of compound 7 binding to 5′-ACGCGT-3′, 5′-ACCGGT-3′, and 5′-AAATTT-3′ produced binding affinities of 2.2 × 10 6, 3.3 × 10 5, and 1 × 10 5 M −1, respectively, indicating a preference for its cognate sequence of 5′-ACGCGT-3′. These results are in good agreement with the footprinting data. The results indicate that steric crowding at the C-terminus is important with respect to binding. However, the number of cationic centers within the molecule may also play a role. The alkyldiamino-containing compounds ( 7 and 8) warrant further investigation in the field of polyamide research.