title: Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: quinone oxidoreductase 1 for internal radiation therapy.
abstract: quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1-targeted radiolabeled agent to establish a novel internal radiation therapy that amplifies the therapeutic effects when combined with external radiation therapy. We designed three NQO1-targeted radioiodinated compounds including two ether linkage compounds ([(125)I]1 and [(125)I]2) and a sulfide linkage compound ([(125)I]3) based on the selective binding of indolequinone analogs to the active site of NQO1 by the stacking effect. These compounds were successfully prepared using an oxidative iododestannylation reaction with high radiochemical yields and purity. In NQO1-expressing tumor cells, [(125)I]1 and [(125)I]2 were readily metabolized to p-[(125)I]iodophenol or m-[(125)I]iodophenol and [(125)I]I(-), whereas over 85% of the initial radioactivity of [(125)I]3 was observed as an intact form at 1h after incubation. The cellular uptake of [(125)I]3 was significantly higher than those of [(125)I]1 and [(125)I]2. The uptake of [(125)I]3 was specific and was dependent on the expression of NQO1. These data suggest that the novel NQO1-targeted radioiodinated compound [(125)I]3 could be used as a novel internal radiation agent for the treatment of cancer.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sasaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.affiliation: Kobe Pharmaceutical University, 4-19-1 Motoyamakita Machi, Higashinada-ku, Kobe 658-8558, Japan.
authors.forename: Masayori
authors.initials: M
authors.lastname: Hagimori
authors.affiliation: Kobe Pharmaceutical University, 4-19-1 Motoyamakita Machi, Higashinada-ku, Kobe 658-8558, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Kobe Pharmaceutical University, 4-19-1 Motoyamakita Machi, Higashinada-ku, Kobe 658-8558, Japan. Electronic address: tmukai@kobepharma-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
mesh_terms: D045744:Cell Line, Tumor; D054879:Halogenation; D006801:Humans; D045563:Indolequinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011878:Radiotherapy / Q000379:methods
chemical_list: D045563:Indolequinones; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: Internal radiation therapy; NQO1; Radioiodine; Stability; Sulfide linkage