title: Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates.
abstract: We designed and synthesized human telomere alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1-6). The C-type conjugates 1-3 possessed a chlorambucil moiety at the C terminus, whereas the N-type conjugates 4-6 had one of these moieties at the N terminus. The DNA alkylating activity of these conjugates was evaluated by high-resolution denaturing polyacrylamide gel electrophoresis using a 220bp DNA fragment containing the human telomere repeat sequence 5'-(GGGTTA)(4)-3'/5'-(TAACCC)(4)-3'. C-type conjugates are designed to alkylate the G-rich-strand-containing 5'-GGGTTA-3' and N-type conjugates were designed to alkylate the complementary C-rich strand-containing 5'-TAACCC-3' sequence. The difference between conjugates 1-3 and 4-6 lies in the linker region between the polyamide moiety and chlorambucil. Conjugates 1 and 4 efficiently alkylated the 5'-GGTTAGGGTTA-3' and 5'-CCCTAACCCTAA-3' sequences, respectively, by recognizing 11bp in the presence of distamycin A (Dist), in a heterotrimeric manner: one long alkylating polyamide conjugate (1-6) and two short partners (Dist).
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo, Kyoto 606-8502, Japan.
authors.forename: Gengo
authors.initials: G
authors.lastname: Kashiwazaki
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Shinohara
authors.forename: Masafumi
authors.initials: M
authors.lastname: Minoshima
authors.forename: Hana
authors.initials: H
authors.lastname: Kumamoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishijima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D002699:Chlorambucil / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009757:Nylons / Q000737:chemistry*; D016615:Telomere / Q000378:metabolism*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D009757:Nylons; D002699:Chlorambucil