Specific Alkylation of Human Telomere Repeat Sequences by a Tandem-Hairpin Motif of Pyrrole–Imidazole Polyamides with Indole-<i>seco</i>-CBI

We designed and synthesized a tandem-hairpin motif of pyrrole (P)imidazole (I) polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3<i>H</i>-benz­[e]­indole (<i>seco</i>-CBI) conjugates (<b>1</b>) that targets the human telomere repeat sequence 5′-d­(CCCTAA)_<i>n</i>-3′. As a control, conjugate <b>2</b> (hairpin PI polyamide with <i>seco</i>-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 <b>1</b>, with no mismatch alkylation. Furthermore, an evaluation performed in human cancer cell lines demonstrated that conjugate <b>1</b> has low cytotoxicity compared with conjugate <b>2</b>. In addition, a cell-staining analysis indicated that conjugate <b>1</b> induced apoptosis moderately by DNA damage. This study demonstrated that conjugate <b>1</b> can be used as an effective alkylator for telomere repeat sequences or as an apoptotic inducer