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ファイル | 記述 | サイズ | フォーマット | |
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j.bmc.2012.07.047.pdf | 1.8 MB | Adobe PDF | 見る/開く |
タイトル: | A sulfoximine-based inhibitor of human asparagine synthetase kills l-asparaginase-resistant leukemia cells. |
著者: | Ikeuchi, Hideyuki Ahn, Yong-Mo Otokawa, Takuya Watanabe, Bunta https://orcid.org/0000-0003-3645-5712 (unconfirmed) Hegazy, Lamees Hiratake, Jun Richards, Nigel G J |
著者名の別形: | 平竹, 潤 |
キーワード: | Acute lymphoblastic leukemia Asparagine synthetase Transition-state analogue inhibitor Sulfoximine Structure–activity relationship MOLT-4 leukemia cell line l-Asparagine amidohydrolase Cell death |
発行日: | Oct-2012 |
出版者: | Elsevier Ltd. |
誌名: | Bioorganic & medicinal chemistry |
巻: | 20 |
号: | 19 |
開始ページ: | 5915 |
終了ページ: | 5927 |
抄録: | An adenylated sulfoximine transition-state analogue 1, which inhibits human asparagine synthetase (hASNS) with nanomolar potency, has been reported to suppress the proliferation of an l-asparagine amidohydrolase (ASNase)-resistant MOLT-4 leukemia cell line (MOLT-4R) when l-asparagine is depleted in the medium. We now report the synthesis and biological activity of two new sulfoximine analogues of 1 that have been studied as part of systematic efforts to identify compounds with improved cell permeability and/or metabolic stability. One of these new analogues, an amino sulfoximine 5 having no net charge at cellular pH, is a better hASNS inhibitor (K(I)(∗)=8nM) than 1 and suppresses proliferation of MOLT-4R cells at 10-fold lower concentration (IC(50)=0.1mM). More importantly, and in contrast to the lead compound 1, the presence of sulfoximine 5 at concentrations above 0.25mM causes the death of MOLT-4R cells even when ASNase is absent in the culture medium. The amino sulfoximine 5 exhibits different dose-response behavior when incubated with an ASNase-sensitive MOLT-4 cell line (MOLT-4S), supporting the hypothesis that sulfoximine 5 exerts its effect by inhibiting hASNS in the cell. Our work provides further evidence for the idea that hASNS represents a chemotherapeutic target for the treatment of leukemia, and perhaps other cancers, including those of the prostate. |
著作権等: | © 2012 Elsevier Ltd. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 This is not the published version. Please cite only the published version. |
URI: | http://hdl.handle.net/2433/160385 |
DOI(出版社版): | 10.1016/j.bmc.2012.07.047 |
PubMed ID: | 22951255 |
出現コレクション: | 学術雑誌掲載論文等 |
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