Specific alkylation of human telomere repeat sequences by a tandem-hairpin motif of pyrrole-imidazole polyamides with indole-seco-CBI.
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.
Department of Chemistry, Graduate School of Science, and ‡Institute for Integrated Cell-Materials Science (iCeMS), Kyoto University , Sakyo, Kyoto 606-8502, Japan.
Makoto
M
Yamamoto
Toshikazu
T
Bando
Yusuke
Y
Kawamoto
Rhys Dylan
RD
Taylor
Kaori
K
Hashiya
Hiroshi
H
Sugiyama
D000477:Alkylating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects*; D020079:Terminal Repeat Sequences / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D011758:Pyrroles; C470729:polyamide 1-(chloromethyl)-5-hydroxyl-1,2-dihydro--3H-benz(e)indole conjugate