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Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells
Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked str...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142175/ https://www.ncbi.nlm.nih.gov/pubmed/37110684 http://dx.doi.org/10.3390/molecules28083450 |
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author | Kim, Na Young Vishwanath, Divakar Xi, Zhang Nagaraja, Omantheswara Swamynayaka, Ananda Kumar Harish, Keshav Basappa, Shreeja Madegowda, Mahendra Pandey, Vijay Sethi, Gautam Lobie, Peter E. Ahn, Kwang Seok Basappa, Basappa |
author_facet | Kim, Na Young Vishwanath, Divakar Xi, Zhang Nagaraja, Omantheswara Swamynayaka, Ananda Kumar Harish, Keshav Basappa, Shreeja Madegowda, Mahendra Pandey, Vijay Sethi, Gautam Lobie, Peter E. Ahn, Kwang Seok Basappa, Basappa |
author_sort | Kim, Na Young |
collection | PubMed |
description | Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells. |
format | Online Article Text |
id | pubmed-10142175 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-101421752023-04-29 Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells Kim, Na Young Vishwanath, Divakar Xi, Zhang Nagaraja, Omantheswara Swamynayaka, Ananda Kumar Harish, Keshav Basappa, Shreeja Madegowda, Mahendra Pandey, Vijay Sethi, Gautam Lobie, Peter E. Ahn, Kwang Seok Basappa, Basappa Molecules Article Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2H-chromen-2-one (5d)] was observed to selectively inhibit the proliferation of HER2-positive BC cells. The compound PC-12 exerted DNA damage and induced apoptosis in HER-2 positive BC cells more significantly compared to HER-2 negative BC cells. PC-12 induced PARP cleavage and down-regulated the expression of IAP-1, BCL-2, SURVIVIN, and CYCLIN D1 in BC cells. In silico and theoretical calculations showed that PC-12 could interact with JNK, and in vitro studies demonstrated that it enhanced JNK phosphorylation through ROS generation. Overall, these findings will assist the discovery of new compounds targeting JNK for use in HER2-positive BC cells. MDPI 2023-04-13 /pmc/articles/PMC10142175/ /pubmed/37110684 http://dx.doi.org/10.3390/molecules28083450 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kim, Na Young Vishwanath, Divakar Xi, Zhang Nagaraja, Omantheswara Swamynayaka, Ananda Kumar Harish, Keshav Basappa, Shreeja Madegowda, Mahendra Pandey, Vijay Sethi, Gautam Lobie, Peter E. Ahn, Kwang Seok Basappa, Basappa Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells |
title | Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells |
title_full | Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells |
title_fullStr | Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells |
title_full_unstemmed | Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells |
title_short | Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells |
title_sort | discovery of pyrimidine- and coumarin-linked hybrid molecules as inducers of jnk phosphorylation through ros generation in breast cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10142175/ https://www.ncbi.nlm.nih.gov/pubmed/37110684 http://dx.doi.org/10.3390/molecules28083450 |
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