کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1357912 | 981304 | 2014 | 12 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Sequence-specific DNA alkylation and transcriptional inhibition by long-chain hairpin pyrrole–imidazole polyamide–chlorambucil conjugates targeting CAG/CTG trinucleotide repeats Sequence-specific DNA alkylation and transcriptional inhibition by long-chain hairpin pyrrole–imidazole polyamide–chlorambucil conjugates targeting CAG/CTG trinucleotide repeats](/preview/png/1357912.png)
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 (γ-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 γ-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.
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Journal: Bioorganic & Medicinal Chemistry - Volume 22, Issue 17, 1 September 2014, Pages 4646–4657