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Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer
Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9056536/ https://www.ncbi.nlm.nih.gov/pubmed/35518146 http://dx.doi.org/10.1039/d0ra06428a |
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author | Mansour, Mai A. Lasheen, Deena S. Gaber, Hatem M. Abouzid, Khaled A. M. |
author_facet | Mansour, Mai A. Lasheen, Deena S. Gaber, Hatem M. Abouzid, Khaled A. M. |
author_sort | Mansour, Mai A. |
collection | PubMed |
description | Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure–activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC(50) values of 4.5 μM and 6 μM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents. |
format | Online Article Text |
id | pubmed-9056536 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-90565362022-05-04 Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer Mansour, Mai A. Lasheen, Deena S. Gaber, Hatem M. Abouzid, Khaled A. M. RSC Adv Chemistry Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo[2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure–activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo[2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC(50) values of 4.5 μM and 6 μM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents. The Royal Society of Chemistry 2020-08-28 /pmc/articles/PMC9056536/ /pubmed/35518146 http://dx.doi.org/10.1039/d0ra06428a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Mansour, Mai A. Lasheen, Deena S. Gaber, Hatem M. Abouzid, Khaled A. M. Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
title | Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
title_full | Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
title_fullStr | Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
title_full_unstemmed | Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
title_short | Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
title_sort | elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (pi3kα) inhibitors to combat pancreatic cancer |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9056536/ https://www.ncbi.nlm.nih.gov/pubmed/35518146 http://dx.doi.org/10.1039/d0ra06428a |
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