RRC ID 45330
Author Sasaki J, Sano K, Hagimori M, Yoshikawa M, Maeda M, Mukai T.
Title Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: quinone oxidoreductase 1 for internal radiation therapy.
Journal Bioorg. Med. Chem.
Abstract NAD(P)H: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.
Volume 22(21)
Pages 6039-46
Published 2014-11-1
DOI 10.1016/j.bmc.2014.09.006
PII S0968-0896(14)00642-7
PMID 25281270
MeSH Cell Line, Tumor Halogenation Humans Indolequinones / chemical synthesis Indolequinones / chemistry* Indolequinones / metabolism Indolequinones / pharmacokinetics Iodine Radioisotopes / chemistry Iodine Radioisotopes / metabolism Iodine Radioisotopes / pharmacokinetics NAD(P)H Dehydrogenase (Quinone) / metabolism* Neoplasms / metabolism Neoplasms / radiotherapy* Radiopharmaceuticals / chemical synthesis Radiopharmaceuticals / chemistry* Radiopharmaceuticals / metabolism Radiopharmaceuticals / pharmacokinetics Radiotherapy / methods
IF 2.802
Times Cited 4
WOS Category CHEMISTRY, MEDICINAL CHEMISTRY, ORGANIC BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells