{"title":"2,7-萘啶-1(2H)- 1与二芳基碘鎓盐的高效芳基化及一种新的选择性MET/AXL激酶抑制剂的发现","authors":"Ming-Shu Wang, Hong-Chuang Xu, Yi Gong, Ren-Yu Qu, Lin-Sheng Zhuo*, Wei Huang*","doi":"10.1021/acscombsci.0c00074","DOIUrl":null,"url":null,"abstract":"<p >New 8-chloro-2-phenyl-2,7-naphthyridin-1(2<i>H</i>)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based <i>N</i>-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2<i>H</i>)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, <b>17c</b> (IC<sub>50,MET</sub> of 13.8 nM) or <b>17e</b> (IC<sub>50,AXl</sub> of 17.2 nM) and <b>17i</b> (IC<sub>50,AXl</sub> of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2<i>H</i>)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.7840,"publicationDate":"2020-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00074","citationCount":"8","resultStr":"{\"title\":\"Efficient Arylation of 2,7-Naphthyridin-1(2H)-one with Diaryliodonium Salts and Discovery of a New Selective MET/AXL Kinase Inhibitor\",\"authors\":\"Ming-Shu Wang, Hong-Chuang Xu, Yi Gong, Ren-Yu Qu, Lin-Sheng Zhuo*, Wei Huang*\",\"doi\":\"10.1021/acscombsci.0c00074\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >New 8-chloro-2-phenyl-2,7-naphthyridin-1(2<i>H</i>)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based <i>N</i>-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2<i>H</i>)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, <b>17c</b> (IC<sub>50,MET</sub> of 13.8 nM) or <b>17e</b> (IC<sub>50,AXl</sub> of 17.2 nM) and <b>17i</b> (IC<sub>50,AXl</sub> of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2<i>H</i>)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.</p>\",\"PeriodicalId\":14,\"journal\":{\"name\":\"ACS Combinatorial Science\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7840,\"publicationDate\":\"2020-06-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1021/acscombsci.0c00074\",\"citationCount\":\"8\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Combinatorial Science\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acscombsci.0c00074\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Chemistry\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Combinatorial Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscombsci.0c00074","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Chemistry","Score":null,"Total":0}
Efficient Arylation of 2,7-Naphthyridin-1(2H)-one with Diaryliodonium Salts and Discovery of a New Selective MET/AXL Kinase Inhibitor
New 8-chloro-2-phenyl-2,7-naphthyridin-1(2H)-one building blocks bearing diverse substitutes on the 2-phenyl group were synthesized via an efficient diaryliodonium salt-based N-arylation strategy with the advantage of mild conditions, short reaction times, and high yields. A small combinatorial library of 8-amino substituted 2-phenyl-2,7-naphthyridin-1(2H)-one was further conveniently constructed based on the above chlorinated naphthyridinones and substituted aniline. Preliminary biochemical screening resulted in the discovery of the new 2,7-naphthyridone-based MET/AXL kinase inhibitors. More importantly, 17c (IC50,MET of 13.8 nM) or 17e (IC50,AXl of 17.2 nM) and 17i (IC50,AXl of 31.8 nM) can efficient selectively inhibit MET or AXL kinase, respectively, while commercial cabozantinib showed no selectivity. The further exploration of the 8-substituted 2-phenyl-2,7-naphthyridin-1(2H)-one combinatorial library would significantly accelerate the discovery of more potent and selective inhibitors against diverse kinases.
期刊介绍:
The Journal of Combinatorial Chemistry has been relaunched as ACS Combinatorial Science under the leadership of new Editor-in-Chief M.G. Finn of The Scripps Research Institute. The journal features an expanded scope and will build upon the legacy of the Journal of Combinatorial Chemistry, a highly cited leader in the field.