title: Naphthyridine-Benzoazaquinolone: Evaluation of a Tricyclic System for the Binding to (CAG)n Repeat DNA and RNA.
abstract: The expansion of CAG repeats in the human genome causes the neurological disorder Huntington's disease. The small-molecule naphthyridine-azaquinolone NA we reported earlier bound to the CAG/CAG motif in the hairpin structure of the CAG repeat DNA. In order to investigate and improve NA-binding to the CAG repeat DNA and RNA, we conducted systematic structure-binding studies of NA to CAG repeats. Among the five new NA derivatives we synthesized, surface plasmon resonance (SPR) assay showed that all of the derivatives modified from amide linkages in NA to a carbamate linkage failed to bind to CAG repeat DNA and RNA. One derivative, NBzA, modified by incorporating an additional ring to the azaquinolone was found to bind to both d(CAG)9 and r(CAG)9 . NBzA binding to d(CAG)9 was similar to NA binding in terms of large changes in the SPR assay and circular dichroism (CD) as well as pairwise binding, as assessed by electron spray ionization time-of-flight (ESI-TOF) mass spectrometry. For the binding to r(CAG)9 , both NA and NBzA showed stepwise binding in ESI-TOF MS, and NBzA-binding to r(CAG)9 induced more extensive conformational change than NA-binding. The tricyclic system in NBzA did not show significant effects on the binding, selectivity, and translation, but provides a large chemical space for further modification to gain higher affinity and selectivity. These studies revealed that the linker structure in NA and NBzA was suitable for the binding to CAG DNA and RNA, and that the tricyclic benzoazaquinolone did not interfere with the binding.
authors.affiliation: Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan.
authors.forename: Jinxing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sakata
authors.affiliation: Chemistry and Chemical Engineering College, Hubei University, Road Youyi 368, Wuchang, Wuhan, Hubei, 430062, China.
authors.forename: Hanping
authors.initials: H
authors.lastname: He
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, and Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Bai
authors.affiliation: Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Murata
authors.affiliation: Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Dohno
authors.affiliation: Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan. nakatani@sanken.osaka-u.ac.jp.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakatani
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012313:RNA / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009287:Naphthyridines; D015363:Quinolones; D012313:RNA; D004247:DNA
keywords: CAG repeats; RNA; recognition; small molecules; surface plasmon resonance; trinucleotide repeats