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

Toni Brown, Zarmeen Taherbhai, Jim Sexton, Arden Sutterfield, Mark Turlington, Justin Jones, Lindsay Stallings, Michelle Stewart, Karen Buchmueller, Hilary Mackay, Caroline O'Hare, Jerome Kluza, Binh Nguyen, David Wilson, Moses Lee, John A. Hartley

Research output: Contribution to journalArticle

15 Scopus citations

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 languageEnglish (US)
Pages (from-to)474-483
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Keywords

  • Amine
  • Biophysical
  • C-terminus
  • Distamycin
  • DNA
  • Polyamides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Brown, T., Taherbhai, Z., Sexton, J., Sutterfield, A., Turlington, M., Jones, J., Stallings, L., Stewart, M., Buchmueller, K., Mackay, H., O'Hare, C., Kluza, J., Nguyen, B., Wilson, D., Lee, M., & Hartley, J. A. (2007). Synthesis and biophysical evaluation of minor-groove binding C-terminus modified pyrrole and imidazole triamide analogs of distamycin. Bioorganic and Medicinal Chemistry, 15(1), 474-483. https://doi.org/10.1016/j.bmc.2006.09.037