In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers

A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synt...

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Main Authors: Fahad Alminderej, Siwar Ghannay, Mohamed O. Elsamani, Fahad Alhawday, Abuzar E. A. E. Albadri, Serag Eldin I. Elbehairi, Mohammad Y. Alfaifi, Adel Kadri, Kaïss Aouadi
Format: Article
Language:English
Published: MDPI AG 2023-07-01
Series:Pharmaceuticals
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Online Access:https://www.mdpi.com/1424-8247/16/7/1025
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author Fahad Alminderej
Siwar Ghannay
Mohamed O. Elsamani
Fahad Alhawday
Abuzar E. A. E. Albadri
Serag Eldin I. Elbehairi
Mohammad Y. Alfaifi
Adel Kadri
Kaïss Aouadi
author_facet Fahad Alminderej
Siwar Ghannay
Mohamed O. Elsamani
Fahad Alhawday
Abuzar E. A. E. Albadri
Serag Eldin I. Elbehairi
Mohammad Y. Alfaifi
Adel Kadri
Kaïss Aouadi
author_sort Fahad Alminderej
collection DOAJ
description A series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, <b>2g</b> and <b>2f</b>, which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (<b>2g</b>), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC<sub>50</sub> for <b>2g</b> were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for <b>2f</b> were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of <b>2f</b> and <b>2g</b> against EGFR afforded good inhibitory activity with IC<sub>50</sub> of 0.298 ± 0.007 μM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound <b>2f</b> arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, <b>2g</b> induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds <b>2f</b> and <b>2g</b> into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity.
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spelling doaj.art-26c4d8ed62d1491e8943f67d07c8c4412023-11-18T20:53:19ZengMDPI AGPharmaceuticals1424-82472023-07-01167102510.3390/ph16071025In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic InducersFahad Alminderej0Siwar Ghannay1Mohamed O. Elsamani2Fahad Alhawday3Abuzar E. A. E. Albadri4Serag Eldin I. Elbehairi5Mohammad Y. Alfaifi6Adel Kadri7Kaïss Aouadi8Department of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi ArabiaDepartment of Chemistry, Faculty of Science and Arts of Baljurashi, Al-Baha University, P.O. Box 1988, Albaha 65527, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi ArabiaDepartment of Biology, Faculty of Science, King Khalid University, Abha 9004, Saudi ArabiaDepartment of Biology, Faculty of Science, King Khalid University, Abha 9004, Saudi ArabiaDepartment of Chemistry, Faculty of Science and Arts of Baljurashi, Al-Baha University, P.O. Box 1988, Albaha 65527, Saudi ArabiaDepartment of Chemistry, College of Science, Qassim University, Buraidah 51452, Saudi ArabiaA series of novel enantiopure isoxazolidine derivatives were synthesized and evaluated for their anticancer activities against three human cancer cell lines such as human breast carcinoma (MCF-7), human lung adenocarcinoma (A-549), and human ovarian carcinoma (SKOV3) by employing MTT assay. The synthesized compounds were characterized by NMR and elemental analysis. Results revealed that all the synthesized compounds displayed significant inhibition towards the tested cell lines. Among them, <b>2g</b> and <b>2f</b>, which differ only by the presence of an ester group at the C-3 position and small EDG (methyl) at the C-5 position of the phenyl ring (<b>2g</b>), were the most active derivatives in attenuating the growth of the three cells in a dose-dependent manner. The IC<sub>50</sub> for <b>2g</b> were 17.7 ± 1 µM (MCF-7), 12.1 ± 1.1 µM (A-549), and 13.9 ± 0.7 µM (SKOV3), and for <b>2f</b> were 9.7 ± 1.3µM (MCF-7), 9.7 ± 0.7µM (A-549), and 6.5 ± 0.9µM (SKOV3), respectively, which were comparable to the standard drug, doxorubicin. The enzymatic inhibition of <b>2f</b> and <b>2g</b> against EGFR afforded good inhibitory activity with IC<sub>50</sub> of 0.298 ± 0.007 μM and 0.484 ± 0.01 µM, respectively, close to the positive control, Afatinib. Compound <b>2f</b> arrested the cell cycle in the S phase in MCF-7 and SKOV3 cells, and in the G2/M phase in the A549 cell; however, <b>2g</b> induced G0/G1 phase cell cycle arrest, and inhibited the progression of the three cancer cells, together with significant apoptotic effects. The docking study of compounds <b>2f</b> and <b>2g</b> into EGFR ATP-active site revealed that it fits nicely with good binding affinity. The pharmacokinetic and drug-likeness scores revealed notable lead-like properties. At 100 ns, the dynamic simulation investigation revealed high conformational stability in the EGFR binding cavity.https://www.mdpi.com/1424-8247/16/7/1025molecular dynamicsmolecular docking simulationisoxazolidineanticancerEGFRapoptosis
spellingShingle Fahad Alminderej
Siwar Ghannay
Mohamed O. Elsamani
Fahad Alhawday
Abuzar E. A. E. Albadri
Serag Eldin I. Elbehairi
Mohammad Y. Alfaifi
Adel Kadri
Kaïss Aouadi
In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
Pharmaceuticals
molecular dynamics
molecular docking simulation
isoxazolidine
anticancer
EGFR
apoptosis
title In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
title_full In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
title_fullStr In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
title_full_unstemmed In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
title_short In Vitro and In Silico Evaluation of Antiproliferative Activity of New Isoxazolidine Derivatives Targeting EGFR: Design, Synthesis, Cell Cycle Analysis, and Apoptotic Inducers
title_sort in vitro and in silico evaluation of antiproliferative activity of new isoxazolidine derivatives targeting egfr design synthesis cell cycle analysis and apoptotic inducers
topic molecular dynamics
molecular docking simulation
isoxazolidine
anticancer
EGFR
apoptosis
url https://www.mdpi.com/1424-8247/16/7/1025
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