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Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines

Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothieno...

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Autores principales: Safwat, Ghada M., Hassanin, Kamel M. A., Mohammed, Eman T., Ahmed, Essam Kh., Abdel Rheim, Mahmoud R., Ameen, Mohamed A., Abdel-Aziz, Mohamed, Gouda, Ahmed M., Peluso, Ilaria, Almeer, Rafa, Abdel-Daim, Mohamed M., Abdel-Wahab, Ahmed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728392/
https://www.ncbi.nlm.nih.gov/pubmed/35003514
http://dx.doi.org/10.1155/2021/4759821
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author Safwat, Ghada M.
Hassanin, Kamel M. A.
Mohammed, Eman T.
Ahmed, Essam Kh.
Abdel Rheim, Mahmoud R.
Ameen, Mohamed A.
Abdel-Aziz, Mohamed
Gouda, Ahmed M.
Peluso, Ilaria
Almeer, Rafa
Abdel-Daim, Mohamed M.
Abdel-Wahab, Ahmed
author_facet Safwat, Ghada M.
Hassanin, Kamel M. A.
Mohammed, Eman T.
Ahmed, Essam Kh.
Abdel Rheim, Mahmoud R.
Ameen, Mohamed A.
Abdel-Aziz, Mohamed
Gouda, Ahmed M.
Peluso, Ilaria
Almeer, Rafa
Abdel-Daim, Mohamed M.
Abdel-Wahab, Ahmed
author_sort Safwat, Ghada M.
collection PubMed
description Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothienopyrimidinones. Our results indicated that the synthesis of chalcone-thienopyrimidine derivatives from the corresponding thienopyrimidine and chalcones proceeded in a relatively short reaction time with good yields and high purity. Most of these novel compounds exhibited moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells similar to that of 5-fluorouracil (5-FU). The results indicated that IC(50) of the two compounds (3b and 3g) showed more potent anticancer activities against HepG2 and MCF-7 than 5-FU. An MTT assay and flow cytometry showed that only 3b and 3g had anticancer activity and antiproliferative activities at the G1 phase against MCF-7 cells, while six compounds (3a-e and 3g) had cytotoxicity and cell cycle arrest at different phases against HepG2 cells. Their cytotoxicity was achieved through downregulation of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9. Although all tested compounds increased oxidative stress via increment of MDA levels and decrement of glutathione reductase (GR) activities compared to control, the 3a, 3b, and 3g in HepG2 and 3b and 3g in MCF-7 achieved the target results. Moreover, there was a positive correlation between cytotoxic efficacy of the compound and apoptosis in both HepG2 (R(2) = 0.531; P = 0.001) and MCF-7 (R(2) = 0.219; P = 0.349) cell lines. The results of molecular docking analysis of 3a-g into the binding groove of Bcl-2 revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Like venetoclax, compounds 3a-g showed 2 violations from Lipinski's rule. However, the results of the ADME study also revealed higher drug-likeness scores for compounds 3a-g than for venetoclax. In conclusion, the tested newly synthesized chalcone-pyridothienopyrimidinone derivatives showed promising antiproliferative and apoptotic effects. Mechanistically, the compounds increased ROS production with concomitant cell cycle arrest and apoptosis. Therefore, regulation of the cell cycle and apoptosis are possible targets for anticancer therapy. The tested compounds could be potent anticancer agents to be tested in future clinical trials after extensive pharmacodynamic, pharmacokinetic, and toxicity profile investigations.
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spelling pubmed-87283922022-01-06 Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines Safwat, Ghada M. Hassanin, Kamel M. A. Mohammed, Eman T. Ahmed, Essam Kh. Abdel Rheim, Mahmoud R. Ameen, Mohamed A. Abdel-Aziz, Mohamed Gouda, Ahmed M. Peluso, Ilaria Almeer, Rafa Abdel-Daim, Mohamed M. Abdel-Wahab, Ahmed Oxid Med Cell Longev Research Article Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothienopyrimidinones. Our results indicated that the synthesis of chalcone-thienopyrimidine derivatives from the corresponding thienopyrimidine and chalcones proceeded in a relatively short reaction time with good yields and high purity. Most of these novel compounds exhibited moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells similar to that of 5-fluorouracil (5-FU). The results indicated that IC(50) of the two compounds (3b and 3g) showed more potent anticancer activities against HepG2 and MCF-7 than 5-FU. An MTT assay and flow cytometry showed that only 3b and 3g had anticancer activity and antiproliferative activities at the G1 phase against MCF-7 cells, while six compounds (3a-e and 3g) had cytotoxicity and cell cycle arrest at different phases against HepG2 cells. Their cytotoxicity was achieved through downregulation of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9. Although all tested compounds increased oxidative stress via increment of MDA levels and decrement of glutathione reductase (GR) activities compared to control, the 3a, 3b, and 3g in HepG2 and 3b and 3g in MCF-7 achieved the target results. Moreover, there was a positive correlation between cytotoxic efficacy of the compound and apoptosis in both HepG2 (R(2) = 0.531; P = 0.001) and MCF-7 (R(2) = 0.219; P = 0.349) cell lines. The results of molecular docking analysis of 3a-g into the binding groove of Bcl-2 revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Like venetoclax, compounds 3a-g showed 2 violations from Lipinski's rule. However, the results of the ADME study also revealed higher drug-likeness scores for compounds 3a-g than for venetoclax. In conclusion, the tested newly synthesized chalcone-pyridothienopyrimidinone derivatives showed promising antiproliferative and apoptotic effects. Mechanistically, the compounds increased ROS production with concomitant cell cycle arrest and apoptosis. Therefore, regulation of the cell cycle and apoptosis are possible targets for anticancer therapy. The tested compounds could be potent anticancer agents to be tested in future clinical trials after extensive pharmacodynamic, pharmacokinetic, and toxicity profile investigations. Hindawi 2021-12-28 /pmc/articles/PMC8728392/ /pubmed/35003514 http://dx.doi.org/10.1155/2021/4759821 Text en Copyright © 2021 Ghada M. Safwat et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Safwat, Ghada M.
Hassanin, Kamel M. A.
Mohammed, Eman T.
Ahmed, Essam Kh.
Abdel Rheim, Mahmoud R.
Ameen, Mohamed A.
Abdel-Aziz, Mohamed
Gouda, Ahmed M.
Peluso, Ilaria
Almeer, Rafa
Abdel-Daim, Mohamed M.
Abdel-Wahab, Ahmed
Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines
title Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines
title_full Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines
title_fullStr Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines
title_full_unstemmed Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines
title_short Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone-Thienopyrimidine Derivatives in HepG2 and MCF-7 Cell Lines
title_sort synthesis, anticancer assessment, and molecular docking of novel chalcone-thienopyrimidine derivatives in hepg2 and mcf-7 cell lines
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728392/
https://www.ncbi.nlm.nih.gov/pubmed/35003514
http://dx.doi.org/10.1155/2021/4759821
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