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Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors
The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inh...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715404/ https://www.ncbi.nlm.nih.gov/pubmed/29250520 http://dx.doi.org/10.3389/fchem.2017.00101 |
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author | Hu, Xiuqin Wang, Disha Tong, Yi Tong, Linjiang Wang, Xia Zhu, Lili Xie, Hua Li, Shiliang Yang, You Xu, Yufang |
author_facet | Hu, Xiuqin Wang, Disha Tong, Yi Tong, Linjiang Wang, Xia Zhu, Lili Xie, Hua Li, Shiliang Yang, You Xu, Yufang |
author_sort | Hu, Xiuqin |
collection | PubMed |
description | The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O-anilinopyrimidine ribose derivative 1a possessed potent and specific inhibitory activity against EGFR L858R/T790M over WT EGFR. Based upon molecular docking studies of the binding mode between compound 1a and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants. |
format | Online Article Text |
id | pubmed-5715404 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57154042017-12-15 Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors Hu, Xiuqin Wang, Disha Tong, Yi Tong, Linjiang Wang, Xia Zhu, Lili Xie, Hua Li, Shiliang Yang, You Xu, Yufang Front Chem Chemistry The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O-anilinopyrimidine ribose derivative 1a possessed potent and specific inhibitory activity against EGFR L858R/T790M over WT EGFR. Based upon molecular docking studies of the binding mode between compound 1a and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants. Frontiers Media S.A. 2017-11-15 /pmc/articles/PMC5715404/ /pubmed/29250520 http://dx.doi.org/10.3389/fchem.2017.00101 Text en Copyright © 2017 Hu, Wang, Tong, Tong, Wang, Zhu, Xie, Li, Yang and Xu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Hu, Xiuqin Wang, Disha Tong, Yi Tong, Linjiang Wang, Xia Zhu, Lili Xie, Hua Li, Shiliang Yang, You Xu, Yufang Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors |
title | Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors |
title_full | Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors |
title_fullStr | Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors |
title_full_unstemmed | Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors |
title_short | Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors |
title_sort | design, synthesis, and evaluation of ribose-modified anilinopyrimidine derivatives as egfr tyrosine kinase inhibitors |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715404/ https://www.ncbi.nlm.nih.gov/pubmed/29250520 http://dx.doi.org/10.3389/fchem.2017.00101 |
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