Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 22, Issue 17, Pages 4646-4657Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.07.019
Keywords
Pyrrole-imidazole polyamide; CAG/CTG repeat sequence; Sequence-specific DNA; Transcriptional inhibition
Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Core Research for Evolutional Science and Technology (CREST) from Japan Science and Technology (JST)
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Introducing novel building blocks to solid-phase peptide synthesis, we readily synthesized long-chain hairpin pyrrole-imidazole (PI) polyamide-chlorambucil conjugates 3 and 4 via the introduction of an amino group into a GABA (gamma-turn) contained in 3, to target CAG/CTG repeat sequences, which are associated with various hereditary disorders. A high-resolution denaturing polyacrylamide sequencing gel revealed sequence-specific alkylation both strands at the N3 of adenines or guanines in CAG/CTG repeats by conjugates 3 and 4, with 11 bp recognition. In vitro transcription assays using conjugate 4 revealed that specific alkylation inhibited the progression of RNA polymerase at the alkylating sites. Chiral substitution of the gamma-turn with an amino group resulted in higher binding affinity observed in SPR assays. These assays suggest that conjugates 4 with 11 bp recognition has the potential to cause specific DNA damage and transcriptional inhibition at the alkylating sites. (C) 2014 Elsevier Ltd. All rights reserved.
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