title: Comparative analysis of DNA alkylation by conjugates between pyrrole-imidazole hairpin polyamides and chlorambucil or seco-CBI.
abstract: We investigated sequence-specific DNA alkylation using conjugates between the N-methylpyrrole (Py)-N-methylimidazole (Im) polyamide and the DNA alkylating agent, chlorambucil, or 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI). Polyamide-chlorambucil conjugates 1-4 differed in the position at which the DNA alkylating chlorambucil moiety was bound to the Py-Im polyamide. High-resolution denaturing polyacrylamide gel electrophoresis (PAGE) revealed that chlorambucil conjugates 1-4 alkylated DNA at the sequences recognized by the Py-Im polyamide core moiety. Reactivity and sequence specificity were greatly affected by the conjugation position, which reflects the geometry of the alkylating agent in the DNA minor groove. Polyamide-seco-CBI conjugate 5 was synthesized to compare the efficacy of chlorambucil with that of seco-CBI as an alkylating moiety for Py-Im polyamides. Denaturing PAGE analysis revealed that DNA alkylation activity of polyamide-seco-CBI conjugate 5 was similar to that of polyamide-chlorambucil conjugates 1 and 2. In contrast, the cytotoxicity of conjugate 5 was superior to that of conjugates 1-4. These results suggest that the seco-CBI conjugate was distinctly active in cells compared to the chlorambucil conjugates. These results may contribute to the development of more specific and active DNA alkylating agents.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-Ku, Kyoto 606-8502, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Minoshima
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Shinohara
authors.forename: Gengo
authors.initials: G
authors.lastname: Kashiwazaki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nishijima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D009757:Nylons / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D002699:Chlorambucil; C029899:imidazole; D004247:DNA