Simple Synthesis of a Heterocyclophane Exhibiting Anti‐c‐Met Activity by Acting as a Hatch Blocking Access to the Active Site. Issue 5 (15th December 2020)

• Record Type: Journal Article
• Authors: Takimoto, Tatsuya; Sasaki, Hideaki; Tsue, Hirohito; Takahashi, Hiroki; MacKerell, Alexander D.; Nakamura, Ayumi; Nakano, Katsuya; Okazaki, Eori; Betsuyaku, Tatsuki; Tachibana, Ryosuke; Hioki, Kazuhito; Yoluk, Ozge; Jo, Sunhwan
• Is Part Of: Chemistry. Volume 27:Issue 5(2021)
• Page Start: 1648
• Page End: 1654
• Publication Date: 2020-12-15
• Subjects: computational chemistry -- cyclophanes -- drug design -- inhibitors -- synthetic design; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202001382
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Anti‐c‐Met activity using cyclophane framework: Bithiazolophane 1, which was conveniently prepared under reflux for only 15 min by Hantzsch thiazoles synthesis, exhibited anti‐activity (IC50 =603 nm ) against c‐Met. The computational site identification by ligand competitive saturation (SILCS‐MC) showed 1 blocked access to the active site of c‐Met by acting as a hatch.