Simple Synthesis of a Heterocyclophane Exhibiting Anti-c-Met Activity by Acting as a Hatch Blocking Access to the Active Site** |
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| Authors: | Dr Tatsuya Takimoto Prof Hideaki Sasaki Prof Hirohito Tsue Dr Hiroki Takahashi Prof Alexander D MacKerell Jr Ayumi Nakamura Katsuya Nakano Eori Okazaki Tatsuki Betsuyaku Ryosuke Tachibana Dr Kazuhito Hioki Dr Ozge Yoluk Dr Sunhwan Jo |
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| Institution: | 1. Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, chuo-ku, Kobe, 650-8586 Japan;2. Graduate School of Human and Environmental Studies, Kyoto University, Yoshida Nihonmatsu-cho, Sakyo-ku, Kyoto, 606-8501 Japan;3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, 20 Penn Street, Baltimore, Maryland, 21201 USA;4. SilcsBio LLC, 20 Penn Street, Baltimore, Maryland, 21201 USA |
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| Abstract: | A simple approach to the synthesis of heterocyclophane consisting of two 4,4’-bithiazoles has been developed in mild conditions. The heterocyclophane with two short chains was conveniently prepared by Hantzsch thiazoles synthesis using the reaction of 3-tert-butoxycarbonyl-3-azapentanethiocarboxamide with 1,4-dibromobutane-2,3-dione in methanol under reflux for only 15 min. Amino groups at the linkers of this heterocyclophane can be functionalized to give acylated and carbamate derivatives. Their properties as protein kinase inhibitors were investigated, and one of the heterocyclophanes exhibited specific anti-activity for c-mesenchymal epithelial transition factor (IC50=603 nm ), among seven types of protein kinases investigated. The computational site identification by ligand competitive saturation method was used to determine why the one heterocyclophane exhibited strong anti-activity for c-mesenchymal epithelial transition factor. |
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| Keywords: | computational chemistry cyclophanes drug design inhibitors synthetic design |
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