AzaHx, a novel fluorescent, DNA minor groove and G·C recognition element: Synthesis and DNA binding properties of a p-anisyl-4-aza-benzimidazole-pyrrole-imidazole (azaHx-PI) polyamide

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3681-5. doi: 10.1016/j.bmcl.2015.06.055. Epub 2015 Jun 19.

Abstract

The design, synthesis, and DNA binding properties of azaHx-PI or p-anisyl-4-aza-benzimidazole-pyrrole-imidazole (5) are described. AzaHx, 2-(p-anisyl)-4-aza-benzimidazole-5-carboxamide, is a novel, fluorescent DNA recognition element, derived from Hoechst 33258 to recognize G·C base pairs. Supported by theoretical data, the results from DNase I footprinting, CD, ΔT(M), and SPR studies provided evidence that an azaHx/IP pairing, formed from antiparallel stacking of two azaHx-PI molecules in a side-by-side manner in the minor groove, selectively recognized a C-G doublet. AzaHx-PI was found to target 5'-ACGCGT-3', the Mlu1 Cell Cycle Box (MCB) promoter sequence with specificity and significant affinity (K(eq) 4.0±0.2×10(7) M(-1)).

Keywords: AzaHx; DNA; Distamycin; Hoechst 33258; Hx-amides; Minor groove; Polyamides; Sequence recognition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism
  • Base Pairing
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Binding Sites
  • Chemistry Techniques, Synthetic
  • Circular Dichroism
  • DNA / chemistry
  • DNA / metabolism*
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Deoxyribonuclease I / chemistry
  • Drug Design
  • Fluorescent Dyes / chemistry*
  • Fluorescent Dyes / metabolism
  • Nylons / chemical synthesis
  • Nylons / chemistry*
  • Promoter Regions, Genetic
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry*
  • Pyrroles / metabolism

Substances

  • Antigens, Neoplasm
  • Benzimidazoles
  • DNA-Binding Proteins
  • Fluorescent Dyes
  • Nylons
  • Pyrroles
  • p-anisyl-4-aza-benzimidazole-pyrrole-imidazole
  • DNA
  • Deoxyribonuclease I
  • DNA Topoisomerases, Type II