title: DNA Interstrand Crosslinks by H-pin Polyamide (S)-seco-CBI Conjugates.
abstract: Although DNA interstrand crosslinking (ICL) agents are widely used as antitumor drugs, DNA sequence-specific ICL agents are quite rare. In this study, H-pin imidazole-pyrrole polyamide 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indol-5-ol (seco-CBI) conjugates that produce sequence-specific DNA ICLs were designed and synthesized. Conjugates with H-pin polyamide and seco-CBI moieties were constructed to recognize a 7 bp DNA sequence, and their reactivity and selectivity in DNA alkylation were evaluated by using high-resolution denaturing gel electrophoresis and sequence-specific plasmid cleavage. One conjugate (6), which contained a chiral (S)-seco-CBI, exhibited greater sequence-specific ICL activity toward the target DNA sequence and was cytotoxic to a cancer cell line. Molecular modeling studies indicated that the greater activity of 6 resulted from the relative orientation of the cyclopropane group in the (S)-CBI unit.
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, Japan.
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, Japan.
authors.forename: Sefan
authors.initials: S
authors.lastname: Asamitsu
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, Japan.
authors.forename: Gengo
authors.initials: G
authors.lastname: Kashiwazaki
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Ushinomiyacho, Sakyo-ku, Kyoto, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Bando
authors.affiliation: Department of Chemistry, Graduate School of Science, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, Japan.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida-Ushinomiyacho, Sakyo-ku, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007211:Indoles / Q000737:chemistry* / Q000633:toxicity; D007364:Intercalating Agents / Q000737:chemistry* / Q000633:toxicity; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D007211:Indoles; D007364:Intercalating Agents; D011758:Pyrroles; C029899:imidazole; D004247:DNA
keywords: DNA alkylation; interstrand crosslinks; polyamide; seco-CBI