Specific Alkylation of Human Telomere Repeat Sequences by a Tandem-Hairpin Motif of Pyrrole鈥揑midazole Polyamides with Indole-seco-CBI
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- 作者：Makoto Yamamoto ; Toshikazu Bando ; Yusuke Kawamoto ; Rhys Dylan Taylor ; Kaori Hashiya ; Hiroshi Sugiyama
- 刊名：Bioconjugate Chemistry
- 出版年：2014
- 出版时间：March 19, 2014
- 年：2014
- 卷：25
- 期：3
- 页码：552-559
- 全文大小：477K
- 年卷期：v.25,no.3(March 19, 2014)
- ISSN：1520-4812
文摘
We designed and synthesized a tandem-hairpin motif of pyrrole (P)鈥攊midazole (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鈥?d(CCCTAA)n-3鈥? 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鈥?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.