title: Sequence-specific alkylation of double-strand human telomere repeat sequence by pyrrole-imidazole polyamides with indole linkers.
abstract: 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 IC(50) 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.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo, Kyoto, 606-8502, Japan.
authors.forename: Shunta
authors.initials: S
authors.lastname: Sasaki
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Masafumi
authors.initials: M
authors.lastname: Minoshima
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Shinohara
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Takaoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000478:Alkylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012091:Repetitive Sequences, Nucleic Acid; D013379:Substrate Specificity; D016615:Telomere / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C470729:polyamide 1-(chloromethyl)-5-hydroxyl-1,2-dihydro--3H-benz(e)indole conjugate