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Design, synthesis and biological evaluation of selective survivin inhibitors

The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. F...

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Detalles Bibliográficos
Autores principales: Xiao, Min, Xue, Yi, Wu, Zhongzhi, Lei, Zi-Ning, Wang, Jin, Chen, Zhe-Sheng, Li, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Editorial Department of Journal of Biomedical Research 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477172/
https://www.ncbi.nlm.nih.gov/pubmed/30174320
http://dx.doi.org/10.7555/JBR.31.20160173
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author Xiao, Min
Xue, Yi
Wu, Zhongzhi
Lei, Zi-Ning
Wang, Jin
Chen, Zhe-Sheng
Li, Wei
author_facet Xiao, Min
Xue, Yi
Wu, Zhongzhi
Lei, Zi-Ning
Wang, Jin
Chen, Zhe-Sheng
Li, Wei
author_sort Xiao, Min
collection PubMed
description The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the P-glycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.
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spelling pubmed-64771722019-06-05 Design, synthesis and biological evaluation of selective survivin inhibitors Xiao, Min Xue, Yi Wu, Zhongzhi Lei, Zi-Ning Wang, Jin Chen, Zhe-Sheng Li, Wei J Biomed Res Original Article The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the P-glycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells. Editorial Department of Journal of Biomedical Research 2019 /pmc/articles/PMC6477172/ /pubmed/30174320 http://dx.doi.org/10.7555/JBR.31.20160173 Text en /creativecommons.org/licenses/by/4.0/ This is an open access article under the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited
spellingShingle Original Article
Xiao, Min
Xue, Yi
Wu, Zhongzhi
Lei, Zi-Ning
Wang, Jin
Chen, Zhe-Sheng
Li, Wei
Design, synthesis and biological evaluation of selective survivin inhibitors
title Design, synthesis and biological evaluation of selective survivin inhibitors
title_full Design, synthesis and biological evaluation of selective survivin inhibitors
title_fullStr Design, synthesis and biological evaluation of selective survivin inhibitors
title_full_unstemmed Design, synthesis and biological evaluation of selective survivin inhibitors
title_short Design, synthesis and biological evaluation of selective survivin inhibitors
title_sort design, synthesis and biological evaluation of selective survivin inhibitors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477172/
https://www.ncbi.nlm.nih.gov/pubmed/30174320
http://dx.doi.org/10.7555/JBR.31.20160173
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