{"created":"2023-06-19T07:25:17.442106+00:00","id":12966,"links":{},"metadata":{"_buckets":{"deposit":"86ac5342-99df-4793-acf6-9af597540071"},"_deposit":{"created_by":4,"id":"12966","owners":[4],"pid":{"revision_id":0,"type":"depid","value":"12966"},"status":"published"},"_oai":{"id":"oai:gifu-pu.repo.nii.ac.jp:00012966","sets":["147:219"]},"author_link":["18077","18075","18076"],"item_1_biblio_info_14":{"attribute_name":"書誌情報","attribute_value_mlt":[{"bibliographicIssueDates":{"bibliographicIssueDate":"2013-06-30","bibliographicIssueDateType":"Issued"},"bibliographicPageEnd":"56","bibliographicPageStart":"48","bibliographicVolumeNumber":"62","bibliographic_titles":[{"bibliographic_title":"岐阜薬科大学紀要　"},{"bibliographic_title":"The annual proceedings of Gifu Pharmaceutical University","bibliographic_titleLang":"en"}]}]},"item_1_creator_6":{"attribute_name":"著者名(日)","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"宮腰, 均"}],"nameIdentifiers":[{"nameIdentifier":"18075","nameIdentifierScheme":"WEKO"}]}]},"item_1_creator_7":{"attribute_name":"著者名よみ","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"ミヤコシ, ヒトシ"}],"nameIdentifiers":[{"nameIdentifier":"18076","nameIdentifierScheme":"WEKO"}]}]},"item_1_creator_8":{"attribute_name":"著者名(英)","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"MIYAKOSHI, Hitoshi","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"18077","nameIdentifierScheme":"WEKO"}]}]},"item_1_description_1":{"attribute_name":"ページ属性","attribute_value_mlt":[{"subitem_description":"P(論文)","subitem_description_type":"Other"}]},"item_1_description_11":{"attribute_name":"抄録(日)","attribute_value_mlt":[{"subitem_description":"ヒトデオキシウリジントリホスファターゼ（dUTPase）阻害剤は5-フルオロウラシルをベースとした化学療法との\n併用剤として現在の化学療法の治療効果を改善できる可能性がある。著者はdUTPase 阻害剤の開発を目的にウラシル誘\n導体のSAR 研究を行った。dUTPase を強く阻害できる骨格としてN-カルボニルピロリジンまたはN-スルホニルピロリジ\nン構造を有するウラシル誘導体及び1,2,3-トリアゾール構造を有するウラシル誘導体を見出した。その中で、化合物14c\nは非常に強いヒトdUTPase 阻害活性（IC50 = 0.067 M）且つ良好な薬物動態プロファイルを有しており、in vitro において\nはHeLa S3 細胞に対し、5-フルオロ-2’-デオキシウリジンの細胞増殖抑制効果（EC50 = 0.07 M）を、またin vivo におい\nてはMX-1 細胞に対し、5-フルオロウラシルの抗腫瘍効果を劇的に増強した。また著者は化合物8a とヒトdUTPase との\n共結晶構造解析を行い、新規dUTPase 阻害剤のウラシル環と末端ベンゼンがそれぞれウラシルポケットと疎水性ポケッ\nトと相互作用し、且つスタッキングし安定化することでdUTPase を阻害していることを明らかにした。これらのデータ\nから、見出した化合物14c は臨床においても5-フルオロウラシルのようなチミジレートシンターゼ阻害剤の治療効果を劇\n的に改善することが期待される。","subitem_description_type":"Other"}]},"item_1_description_12":{"attribute_name":"抄録(英)","attribute_value_mlt":[{"subitem_description":"Deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy\nof 5-fluorouracil-based combination chemotherapy. We have initiated a project to develop potent drug-like dUTPase inhibitors based\non structure-activity relationship (SAR) studies of uracil derivatives. N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing\nuracils and 1,2,3-triazole-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (14c)\nhaving excellent potencies (IC50 = 0.067 M) and an improved pharmacokinetic profile. The X-ray structure of a complex of 8a and\nhuman dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a\nhydrophobic region, respectively, and are stacked on each other. Compound 14c dramatically enhanced the growth inhibition activity\nof 5-fluoro-2’-deoxyuridine against HeLa S3 cells in vitro (EC50 = 0.07 M) and the antitumor activity of 5-fluorouracil against\nhuman breast cancer MX-1 xenograft model in mice significantly. These data indicate that 14c is a promising candidate for\ncombination cancer chemotherapies with TS inhibitors.","subitem_description_type":"Other"}]},"item_1_source_id_13":{"attribute_name":"雑誌書誌ID","attribute_value_mlt":[{"subitem_source_identifier":"AA1258935X","subitem_source_identifier_type":"NCID"}]},"item_1_text_10":{"attribute_name":"著者所属(英)","attribute_value_mlt":[{"subitem_text_language":"en","subitem_text_value":"Laboratory of Medicinal & Pharmaceutical Chemistry, Gifu Pharmaceutical University"},{"subitem_text_language":"en","subitem_text_value":"Medicinal Chemistry, Chemistry Research Laboratory, Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd."}]},"item_1_text_2":{"attribute_name":"記事種別(日)","attribute_value_mlt":[{"subitem_text_value":"総説"}]},"item_1_text_3":{"attribute_name":"記事種別(英)","attribute_value_mlt":[{"subitem_text_language":"en","subitem_text_value":"Review"}]},"item_1_text_9":{"attribute_name":"著者所属(日)","attribute_value_mlt":[{"subitem_text_value":"岐阜薬科大学薬化学研究室"},{"subitem_text_value":"大鵬薬品工業株式会社つくば研究センター化学研究所創薬化学研究室"}]},"item_files":{"attribute_name":"ファイル情報","attribute_type":"file","attribute_value_mlt":[{"accessrole":"open_date","date":[{"dateType":"Available","dateValue":"2014-08-01"}],"displaytype":"detail","filename":"５－FU との併用療法を目指すヒトデオキシウリジントリホスファターゼ阻害剤の開発.pdf","filesize":[{"value":"641.4 kB"}],"format":"application/pdf","licensetype":"license_11","mimetype":"application/pdf","url":{"label":"５－FU との併用療法を目指すヒトデオキシウリジントリホスファターゼ阻害剤の開発","url":"https://gifu-pu.repo.nii.ac.jp/record/12966/files/５－FU との併用療法を目指すヒトデオキシウリジントリホスファターゼ阻害剤の開発.pdf"},"version_id":"c4ed1b1d-b772-4a88-b16a-1d66d9f7f6a0"}]},"item_keyword":{"attribute_name":"キーワード","attribute_value_mlt":[{"subitem_subject":"デオキシウリジントリホスファターゼ","subitem_subject_scheme":"Other"},{"subitem_subject":"5-フルオロウラシル","subitem_subject_scheme":"Other"},{"subitem_subject":"チミジレートシンターゼ阻害剤","subitem_subject_scheme":"Other"},{"subitem_subject":"dUTPase","subitem_subject_language":"en","subitem_subject_scheme":"Other"},{"subitem_subject":"5-fluorouracil","subitem_subject_language":"en","subitem_subject_scheme":"Other"},{"subitem_subject":"TS inhibitor","subitem_subject_language":"en","subitem_subject_scheme":"Other"}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"departmental bulletin paper","resourceuri":"http://purl.org/coar/resource_type/c_6501"}]},"item_title":"５－FU との併用療法を目指すヒトデオキシウリジントリホスファターゼ阻害剤の開発","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"５－FU との併用療法を目指すヒトデオキシウリジントリホスファターゼ阻害剤の開発"},{"subitem_title":"Development of Human Deoxyuridine Triphosphatase Inhibitors for Combination Cancer Therapies with 5-FU","subitem_title_language":"en"}]},"item_type_id":"1","owner":"4","path":["219"],"pubdate":{"attribute_name":"公開日","attribute_value":"2014-08-01"},"publish_date":"2014-08-01","publish_status":"0","recid":"12966","relation_version_is_last":true,"title":["５－FU との併用療法を目指すヒトデオキシウリジントリホスファターゼ阻害剤の開発"],"weko_creator_id":"4","weko_shared_id":-1},"updated":"2023-06-19T09:01:34.543178+00:00"}