title: Targeting specific gene by alkylating pyrrole-imidazole polyamides.
abstract: Targeting specific genes or gene products by small molecules is novel approach of cancer chemotherapy. We have developed sequence-specific DNA alkylating agents, conjugates between pyrrole (Py)-imidazole (Im) polyamides and 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H benz[e]indole (seco-CBI) with an indole linker. These compounds efficiently alkylate DNA at a targeted sequence and inhibit gene expression caused by alkylation at template strand of coding region. Recently, histone H4c gene could be targeted by polyamide-chlorambucil (Chl) conjugates. Thus, we designed and synthesized polyamide seco-CBI conjugates 1-5 targeting histone H4c coding sequence. High resolution denaturing polyacrylamide gel electrophoresis (PAGE) showed polyamide seco-CBI conjugates alkylated at the histone H4c coding sequence.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, 606-8502, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Minoshima
authors.forename: James
authors.initials: J
authors.lastname: Chou
authors.forename: Sophie
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Shinohara
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry*; D020868:Gene Silencing; D006657:Histones / Q000235:genetics*; D007093:Imidazoles / Q000737:chemistry*; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006657:Histones; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles