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Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition

Novel semisynthetic coumarin derivatives were synthesized to be developed as chemotherapeutic anticancer agents through topoisomerase II, VEGFR2 inhibition that leads to apoptotic cancer cell death. The coumarin amino acids and dipeptides derivatives were prepared by the reaction of coumarin-3-carbo...

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Autores principales: Gomaa, Mohamed S., Ali, Ibrahim A. I., El Enany, Gaber, El Ashry, El Sayed H., El Rayes, Samir M., Fathalla, Walid, Ahmed, Abdulghany H. A., Abubshait, Samar A., Abubshait, Haya A., Nafie, Mohamed S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737644/
https://www.ncbi.nlm.nih.gov/pubmed/36500372
http://dx.doi.org/10.3390/molecules27238279
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author Gomaa, Mohamed S.
Ali, Ibrahim A. I.
El Enany, Gaber
El Ashry, El Sayed H.
El Rayes, Samir M.
Fathalla, Walid
Ahmed, Abdulghany H. A.
Abubshait, Samar A.
Abubshait, Haya A.
Nafie, Mohamed S.
author_facet Gomaa, Mohamed S.
Ali, Ibrahim A. I.
El Enany, Gaber
El Ashry, El Sayed H.
El Rayes, Samir M.
Fathalla, Walid
Ahmed, Abdulghany H. A.
Abubshait, Samar A.
Abubshait, Haya A.
Nafie, Mohamed S.
author_sort Gomaa, Mohamed S.
collection PubMed
description Novel semisynthetic coumarin derivatives were synthesized to be developed as chemotherapeutic anticancer agents through topoisomerase II, VEGFR2 inhibition that leads to apoptotic cancer cell death. The coumarin amino acids and dipeptides derivatives were prepared by the reaction of coumarin-3-carboxylic acid with amino acid methyl esters following the N,N-dicyclohexylcarbodiimide (DCC) method and 1-hydroxy-benzotriazole (HOBt), as coupling reagents. The synthesized compounds were screened towards VEGFR2, and topoisomerase IIα proteins to highlight their binding affinities and virtual mechanism of binding. Interestingly, compounds 4k (Tyr) and 6c (β-Ala-L-Met) shared the activity towards the three proteins by forming the same interactions with the key amino acids, such as the co-crystallized ligands. Both compounds 4k and 6c exhibited potent cytotoxic activities against MCF-7 cells with IC(50) values of 4.98 and 5.85 µM, respectively causing cell death by 97.82 and 97.35%, respectively. Validating the molecular docking studies, both compounds demonstrated promising VEGFR-2 inhibition with IC(50) values of 23.6 and 34.2 µM, compared to Sorafenib (30 µM) and topoisomerase-II inhibition with IC(50) values of 4.1 and 8.6 µM compared to Doxorubicin (9.65 µM). Hence, these two promising compounds could be further tested as effective and selective target-oriented active agents against cancer.
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spelling pubmed-97376442022-12-11 Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition Gomaa, Mohamed S. Ali, Ibrahim A. I. El Enany, Gaber El Ashry, El Sayed H. El Rayes, Samir M. Fathalla, Walid Ahmed, Abdulghany H. A. Abubshait, Samar A. Abubshait, Haya A. Nafie, Mohamed S. Molecules Article Novel semisynthetic coumarin derivatives were synthesized to be developed as chemotherapeutic anticancer agents through topoisomerase II, VEGFR2 inhibition that leads to apoptotic cancer cell death. The coumarin amino acids and dipeptides derivatives were prepared by the reaction of coumarin-3-carboxylic acid with amino acid methyl esters following the N,N-dicyclohexylcarbodiimide (DCC) method and 1-hydroxy-benzotriazole (HOBt), as coupling reagents. The synthesized compounds were screened towards VEGFR2, and topoisomerase IIα proteins to highlight their binding affinities and virtual mechanism of binding. Interestingly, compounds 4k (Tyr) and 6c (β-Ala-L-Met) shared the activity towards the three proteins by forming the same interactions with the key amino acids, such as the co-crystallized ligands. Both compounds 4k and 6c exhibited potent cytotoxic activities against MCF-7 cells with IC(50) values of 4.98 and 5.85 µM, respectively causing cell death by 97.82 and 97.35%, respectively. Validating the molecular docking studies, both compounds demonstrated promising VEGFR-2 inhibition with IC(50) values of 23.6 and 34.2 µM, compared to Sorafenib (30 µM) and topoisomerase-II inhibition with IC(50) values of 4.1 and 8.6 µM compared to Doxorubicin (9.65 µM). Hence, these two promising compounds could be further tested as effective and selective target-oriented active agents against cancer. MDPI 2022-11-28 /pmc/articles/PMC9737644/ /pubmed/36500372 http://dx.doi.org/10.3390/molecules27238279 Text en © 2022 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
Gomaa, Mohamed S.
Ali, Ibrahim A. I.
El Enany, Gaber
El Ashry, El Sayed H.
El Rayes, Samir M.
Fathalla, Walid
Ahmed, Abdulghany H. A.
Abubshait, Samar A.
Abubshait, Haya A.
Nafie, Mohamed S.
Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
title Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
title_full Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
title_fullStr Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
title_full_unstemmed Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
title_short Facile Synthesis of Some Coumarin Derivatives and Their Cytotoxicity through VEGFR2 and Topoisomerase II Inhibition
title_sort facile synthesis of some coumarin derivatives and their cytotoxicity through vegfr2 and topoisomerase ii inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737644/
https://www.ncbi.nlm.nih.gov/pubmed/36500372
http://dx.doi.org/10.3390/molecules27238279
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