Abstract
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 ΔTm values of 2.8 and 8.3 °C with their cognate sequence, respectively. The alkyldiamino compounds (7 and 8) were more impressive producing a ΔTm 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 × 106, 3.3 × 105, and 1 × 105 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.
Original language | English (US) |
---|---|
Pages (from-to) | 474-483 |
Number of pages | 10 |
Journal | Bioorganic and Medicinal Chemistry |
Volume | 15 |
Issue number | 1 |
DOIs | |
State | Published - Jan 1 2007 |
Externally published | Yes |
Keywords
- Amine
- Biophysical
- C-terminus
- DNA
- Distamycin
- Polyamides
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry