Sequence-Specific Alkylation of Double-Strand Human Telomere Repeat Sequence by Pyrrole-Imidazole Polyamides with Indole Linkers

• Published in: Journal of the American Chemical Society 2006-09, Vol.128 (37), p.12162-12168
• Main Authors: Sasaki, Shunta, Bando, Toshikazu, Minoshima, Masafumi, Shimizu, Tatsuhiko, Shinohara, Ken-ichi, Takaoka, Toshiyasu, Sugiyama, Hiroshi
• Format: Article
• Language: English
• Subjects: Alkylation; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Base Sequence; Cell Line, Tumor; Electrophoresis, Polyacrylamide Gel; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Molecular Sequence Data; Neoplasms - genetics; Neoplasms - metabolism; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Repetitive Sequences, Nucleic Acid; Substrate Specificity; Telomere - chemistry; Telomere - genetics; Telomere - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0626584

We designed and synthesized pyrrole (Py)−imidazole (Im) hairpin polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates 1 and 2, which target both strands of the double-stranded region of the human telomere repeat sequences, 5‘-d(TTAGGG) n -3‘/5‘-d(CCCTAA) n -3‘. High-resolution denaturing polyacrylamide gel electrophoresis demonstrated that conjugates 1 and 2 alkylated DNA at the 3‘ A of 5‘-ACCCTA-3‘ and 5‘-AGGGTTA-3‘, respectively. Cytotoxicities of conjugates 1 and 2 were evaluated using 39 human cancer cell lines; averages of log IC50 values for conjugates 1 and 2 were −6.96 (110 nM) and −7.24 (57.5 nM), respectively. Conjugates 1 and 2 have potential as antitumor drugs capable of targeting telomere repeat sequence.