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三取代咪唑通过靶向致癌性PI3K/Akt/mTOR信号通路诱导人乳腺癌细胞凋亡。

Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway.

作者信息

Mohan Chakrabhavi Dhananjaya, Srinivasa V, Rangappa Shobith, Mervin Lewis, Mohan Surender, Paricharak Shardul, Baday Sefer, Li Feng, Shanmugam Muthu K, Chinnathambi Arunachalam, Zayed M E, Alharbi Sulaiman Ali, Bender Andreas, Sethi Gautam, Rangappa Kanchugarakoppal S

机构信息

Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysore 570006, India.

Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Central College Campus, Palace Road, Bangalore 560001, India.

出版信息

PLoS One. 2016 Apr 20;11(4):e0153155. doi: 10.1371/journal.pone.0153155. eCollection 2016.

DOI:10.1371/journal.pone.0153155
PMID:27097161
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4838272/
Abstract

Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of in silico target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.

摘要

PI3K/Akt/mTOR的过度激活与癌症发生相关，是治疗多种癌症的潜在分子治疗靶点。在此，我们报告了三取代咪唑的合成，并鉴定出2-氯-3-(4,5-二苯基-1H-咪唑-2-基)吡啶（CIP）为主要细胞毒性剂。计算机模拟靶点预测的朴素贝叶斯分类器模型显示，CIP靶向包含Akt的RAC-β丝氨酸/苏氨酸蛋白激酶。此外，CIP下调了Akt、PDK和mTOR蛋白的磷酸化，并降低了细胞周期蛋白D1、Bcl-2、生存素、VEGF、procaspase-3的表达，增加了PARP的裂解。此外，CIP显著下调了CXCL12诱导的乳腺癌细胞运动性，分子对接计算表明，与先前报道的Akt2抑制剂文库相比，所有化合物均以高对接分数与Akt2激酶结合。总之，我们报告了通过负调节PI3K/Akt/mTOR信号通路诱导乳腺癌细胞凋亡的咪唑的合成及生物学评价。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/f1065fb03c48/pone.0153155.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/c48c6d126791/pone.0153155.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/1b53c3cc99f2/pone.0153155.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/d7f40b0f7a65/pone.0153155.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/b81ea2bdf32c/pone.0153155.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/d0aebc6d57c5/pone.0153155.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/f1065fb03c48/pone.0153155.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/c48c6d126791/pone.0153155.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/1b53c3cc99f2/pone.0153155.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/d7f40b0f7a65/pone.0153155.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/b81ea2bdf32c/pone.0153155.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/d0aebc6d57c5/pone.0153155.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/74ec/4838272/f1065fb03c48/pone.0153155.g006.jpg

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