Specific alkylation of human telomere repeat sequences by a tandem-hairpin motif of pyrrole-imidazole polyamides with indole-seco-CBI

Bioconjug Chem. 2014 Mar 19;25(3):552-9. doi: 10.1021/bc400567m. Epub 2014 Feb 14.

Abstract

We designed and synthesized a tandem-hairpin motif of pyrrole (P)-imidazole (I) polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates (1) that targets the human telomere repeat sequence 5'-d(CCCTAA)n-3'. As a control, conjugate 2 (hairpin PI polyamide with seco-CBI), which also targets the human telomere repeat sequence, was synthesized. High-resolution denaturing polyacrylamide gel electrophoresis (PAGE) using 5' Texas Red-labeled 219-bp DNA fragments revealed the outstandingly high sequence selectivity of 1, with no mismatch alkylation. Furthermore, an evaluation performed in human cancer cell lines demonstrated that conjugate 1 has low cytotoxicity compared with conjugate 2. In addition, a cell-staining analysis indicated that conjugate 1 induced apoptosis moderately by DNA damage. This study demonstrated that conjugate 1 can be used as an effective alkylator for telomere repeat sequences or as an apoptotic inducer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / chemical synthesis
  • Alkylating Agents / chemistry
  • Alkylating Agents / pharmacology*
  • Alkylation
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Electrophoresis, Polyacrylamide Gel
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Molecular Conformation
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Telomere / drug effects*
  • Terminal Repeat Sequences / drug effects*
  • Tumor Cells, Cultured

Substances

  • Alkylating Agents
  • Antineoplastic Agents
  • Imidazoles
  • Indoles
  • Pyrroles
  • polyamide 1-(chloromethyl)-5-hydroxyl-1,2-dihydro--3H-benz(e)indole conjugate