title: Design and synthesis of 8-hydroxyquinoline-based radioprotective agents.
abstract: In radiation therapy, adverse side effects are often induced due to the excessive cell death that occurs in radiosensitive normal cells. The radiation-induced cell death of normal cells is caused, at least in part, by apoptosis, which undergoes via activation of p53 and increase in the p53 protein, a zinc-containing transcriptional factor, in response to cellular damage. Therefore, radioprotective drugs that can protect normal cells from radiation and thus suppress adverse side effects would be highly desirable. We report herein on the radioprotective activity of 8-hydroxyquinoline (8HQ) derivatives that were initially designed so as to interact with the Zn(2+) in p53. Indeed, the 5,7-bis(methylaminosulfonyl)-8HQ and 8-methoxyquinoline derivatives considerably protected MOLT-4 cells against γ-ray radiation (10 Gy), accompanied by a low cytotoxicity. However, mechanistic studies revealed that the interaction of these drugs with p53 is weak and the mechanism for inhibiting apoptosis appears to be different from that of previously reported radioprotectors such as bispicen, which inhibits apoptosis via the denaturation of p53 as well as by blocking both transcription-dependent and -independent apoptotic pathways.
authors.affiliation: Center for Technologies Against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ariyasu
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Morita
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hanaya
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Hoshi
authors.affiliation: Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Takahashi
authors.affiliation: Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Center for Technologies Against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan. Electronic address: shinaoki@rs.noda.tus.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Aoki
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D015195:Drug Design; D024202:Electrophoretic Mobility Shift Assay; D005720:Gamma Rays; D006801:Humans; D015125:Oxyquinoline / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011837:Radiation-Protective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015032:Zinc / Q000737:chemistry*
chemical_list: D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D015125:Oxyquinoline; D015032:Zinc
keywords: 8-Hydroxyquinoline; Mechanistic study; Radioprotector