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De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells
In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dime...
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/PMC9952374/ https://www.ncbi.nlm.nih.gov/pubmed/36829653 http://dx.doi.org/10.3390/bioengineering10020159 |
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author | Ravish, Akshay Shivakumar, Rashmi Xi, Zhang Yang, Min Hee Yang, Ji-Rui Swamynayaka, Ananda Nagaraja, Omantheswara Madegowda, Mahendra Chinnathambi, Arunachalam Alharbi, Sulaiman Ali Pandey, Vijay Sethi, Gautam Ahn, Kwang Seok Lobie, Peter E. Basappa, Basappa |
author_facet | Ravish, Akshay Shivakumar, Rashmi Xi, Zhang Yang, Min Hee Yang, Ji-Rui Swamynayaka, Ananda Nagaraja, Omantheswara Madegowda, Mahendra Chinnathambi, Arunachalam Alharbi, Sulaiman Ali Pandey, Vijay Sethi, Gautam Ahn, Kwang Seok Lobie, Peter E. Basappa, Basappa |
author_sort | Ravish, Akshay |
collection | PubMed |
description | In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC(50) value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC. |
format | Online Article Text |
id | pubmed-9952374 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-99523742023-02-25 De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells Ravish, Akshay Shivakumar, Rashmi Xi, Zhang Yang, Min Hee Yang, Ji-Rui Swamynayaka, Ananda Nagaraja, Omantheswara Madegowda, Mahendra Chinnathambi, Arunachalam Alharbi, Sulaiman Ali Pandey, Vijay Sethi, Gautam Ahn, Kwang Seok Lobie, Peter E. Basappa, Basappa Bioengineering (Basel) Article In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides. Compound 3f with 2,3-dichlorophenyl substitution was recognized among the tested series as a lead structure that inhibited the viability of MCF-7 cells with an IC(50) value of 9.2 μM. A dose- and time-dependent inhibition of STAT3 phosphorylation at Tyr705 and Ser727 was observed in MCF-7 and T47D cells when compound 3f was added in vitro. Calculations using density functional theory showed that the title compounds HOMOs and LUMOs are situated on imidazopyridine-pyrazoline and nitrophenyl rings, respectively. Hence, compound 3f effectively inhibited STAT3 phosphorylation in MCF-7 and T47D cells, indicating that these structures may be an alternative synthon to target STAT3 signaling in BC. MDPI 2023-01-24 /pmc/articles/PMC9952374/ /pubmed/36829653 http://dx.doi.org/10.3390/bioengineering10020159 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 Ravish, Akshay Shivakumar, Rashmi Xi, Zhang Yang, Min Hee Yang, Ji-Rui Swamynayaka, Ananda Nagaraja, Omantheswara Madegowda, Mahendra Chinnathambi, Arunachalam Alharbi, Sulaiman Ali Pandey, Vijay Sethi, Gautam Ahn, Kwang Seok Lobie, Peter E. Basappa, Basappa De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells |
title | De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells |
title_full | De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells |
title_fullStr | De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells |
title_full_unstemmed | De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells |
title_short | De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells |
title_sort | de novo design of imidazopyridine-tethered pyrazolines that target phosphorylation of stat3 in human breast cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9952374/ https://www.ncbi.nlm.nih.gov/pubmed/36829653 http://dx.doi.org/10.3390/bioengineering10020159 |
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