Simple Synthesis of a Heterocyclophane Exhibiting Anti-c-Met Activity by Acting as a Hatch Blocking Access to the Active Site*.
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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DOI：
10.1002/chem.202001382
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发表时间：
2021-01-21
期刊：
影响因子：
--
通讯作者：
Jo S
中科院分区：
文献类型：
--
作者：
Takimoto T;Sasaki H;Tsue H;Takahashi H;MacKerell AD Jr;Nakamura A;Nakano K;Okazaki E;Betsuyaku T;Tachibana R;Hioki K;Yoluk O;Jo S
研究了在温和条件下由两个4,4 ' -双噻唑合成杂环烷的简单方法。采用Hantzsch噻唑合成法，以3-叔丁基羰基-3-氮杂戊烷乙硫甲酰胺与1,4-二溴丁烷-2,3-二酮为原料，在甲醇回流条件下仅反应15分钟，制备了两短链杂环烷。这种杂环烷连接体上的氨基可以官能化，得到酰基化和氨基甲酸酯衍生物。研究了它们作为蛋白激酶抑制剂的特性，其中一种杂环醚在7种蛋白激酶中表现出对c-间充质上皮过渡因子的特异性抗活性（IC50 = 603 nM）。利用配体竞争饱和方法进行计算位点鉴定，以确定为什么杂环烷对c-间充质上皮过渡因子具有较强的抗活性。环烷骨架抗c-Met活性：用Hantzsch噻唑类合成法回流制备的Bithiazolophane 1具有抗c-Met活性（IC50 = 603 nM）。通过配体竞争饱和（SILCS-MC）的计算位点鉴定表明，1阻断了c-Met活性位点的通路。
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 minutes. 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 7 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. Anti c-Met activity using cyclophane framework: Bithiazolophane 1 which was conveniently prepared under reflux for only 15 minutes 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.
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影响因子：
6.1
作者：
Altomare, A;Burla, MC;Spagna, R
通讯作者：
Spagna, R
影响因子：
64.8
作者：
NAKAMURA, T;NISHIZAWA, T;SHIMIZU, S
通讯作者：
SHIMIZU, S
影响因子：
2.4
作者：
BABADJAMIAN, A;GALLO, R;METZGER, J
通讯作者：
METZGER, J
DOI：
10.1246/nikkashi1948.82.87
发表时间：
1961-01-01
期刊：
NIPPON KAGAKU ZASSHI
影响因子：
--
作者：
OKAMIYA, J
通讯作者：
OKAMIYA, J
影响因子：
11.2
作者：
Ma, PC;Jagadeeswaran, R;Salgia, R
通讯作者：
Salgia, R