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嘧啶和香豆素连接的杂合分子通过 ROS 生成诱导乳腺癌细胞中 JNK 磷酸化的发现。

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells.

机构信息

Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea.

Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India.

出版信息

Molecules. 2023 Apr 13;28(8):3450. doi: 10.3390/molecules28083450.

DOI:10.3390/molecules28083450
PMID:37110684
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10142175/
Abstract

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-2-chromen-2-one ()] 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.

摘要

人表皮生长因子受体 2（HER2）阳性乳腺癌表现出早期复发、预后不良和高复发率。在此，开发了一种针对 JNK 的靶向化合物，它可能对 HER2 阳性乳腺癌有用。探索了针对 JNK 的嘧啶和香豆素连接结构的设计，并且观察到先导结构 PC-12 [4-(3-((2-((4-氯苄基)硫代)嘧啶-4-基)氧基)丙氧基)-6-氟-2-色满-2-酮()]选择性抑制 HER2 阳性 BC 细胞的增殖。与 HER2 阴性 BC 细胞相比，该化合物 PC-12 在 HER-2 阳性 BC 细胞中更显著地引发 DNA 损伤并诱导细胞凋亡。PC-12 诱导 PARP 切割，并下调 BC 细胞中 IAP-1、BCL-2、SURVIVIN 和 CYCLIN D1 的表达。计算机模拟和理论计算表明，PC-12 可以与 JNK 相互作用，并且体外研究表明它通过 ROS 生成增强 JNK 磷酸化。总的来说，这些发现将有助于发现针对 JNK 的用于治疗 HER2 阳性 BC 细胞的新化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/0e2824b3b16c/molecules-28-03450-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/a895e7a42fc7/molecules-28-03450-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/d9b4283687f9/molecules-28-03450-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/f86f1bcf8420/molecules-28-03450-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/26dd394b7232/molecules-28-03450-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/266ad827ab1d/molecules-28-03450-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/e8ae488ebdef/molecules-28-03450-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/0fbbecdd75f6/molecules-28-03450-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/a2e5cbcd689b/molecules-28-03450-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/0e2824b3b16c/molecules-28-03450-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/a895e7a42fc7/molecules-28-03450-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/d9b4283687f9/molecules-28-03450-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/f86f1bcf8420/molecules-28-03450-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/26dd394b7232/molecules-28-03450-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/266ad827ab1d/molecules-28-03450-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/e8ae488ebdef/molecules-28-03450-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/0fbbecdd75f6/molecules-28-03450-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/a2e5cbcd689b/molecules-28-03450-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9f43/10142175/0e2824b3b16c/molecules-28-03450-g008.jpg

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