Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms
A series of aryl-substituted 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a–4q) were designed and synthesized via reaction of 6-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. The structures of the novel compounds 4b...
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Frontiers Media S.A.
2021-11-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2021.759148/full |
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| author | Menna Elgaafary Menna Elgaafary Ahmed M. Fouda Hany M. Mohamed Hany M. Mohamed Abdelaaty Hamed Heba K. A. El-Mawgoud Lu Jin Judith Ulrich Thomas Simmet Tatiana Syrovets Ahmed M. El-Agrody |
| author_facet | Menna Elgaafary Menna Elgaafary Ahmed M. Fouda Hany M. Mohamed Hany M. Mohamed Abdelaaty Hamed Heba K. A. El-Mawgoud Lu Jin Judith Ulrich Thomas Simmet Tatiana Syrovets Ahmed M. El-Agrody |
| author_sort | Menna Elgaafary |
| collection | DOAJ |
| description | A series of aryl-substituted 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a–4q) were designed and synthesized via reaction of 6-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. The structures of the novel compounds 4b, 4c, 4f, 4g, 4i, 4l, 4m, and 4o–4q were established according to IR, 1H-NMR, 13C-NMR/13C-NMR-DEPT, and MS. The benzochromene derivative 4c with a single chlorine at the meta position of the phenyl ring and, to a lesser extent, other benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) exhibited the highest cytotoxicity against six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, 5,637, and Hep G2. The mechanisms of the cytotoxic activities of benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) were further analyzed using triple-negative breast cancer cell line MDA-MB-231. Cell cycle analysis showed accumulation of the treated cells in S phase for 4a, 4d–4f, and S-G2/M phases for 4c. In vivo, 4a and 4c–4f inhibited growth, proliferation, and triggered apoptosis in preestablished breast cancer xenografts grown on the chick chorioallantoic membranes while exhibiting low systemic toxicity. Compounds 4a and 4c–4f increased levels of mitochondrial superoxide and decreased mitochondrial membrane potential resulting in initiation of apoptosis as demonstrated by caspase 3/7 activation. In addition, 4c induced general oxidative stress in cancer cells. The SAR study confirmed that halogens of moderate size at meta or para positions of the pendant phenyl ring enhance the cytotoxic activity of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles, and these compounds could serve as leads for the development of novel anticancer therapies. |
| first_indexed | 2024-12-21T00:13:41Z |
| format | Article |
| id | doaj.art-70effce2f73b4006a150cfbc62b2ba7b |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-21T00:13:41Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Chemistry |
| spelling | doaj.art-70effce2f73b4006a150cfbc62b2ba7b2022-12-21T19:22:17ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462021-11-01910.3389/fchem.2021.759148759148Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor MechanismsMenna Elgaafary0Menna Elgaafary1Ahmed M. Fouda2Hany M. Mohamed3Hany M. Mohamed4Abdelaaty Hamed5Heba K. A. El-Mawgoud6Lu Jin7Judith Ulrich8Thomas Simmet9Tatiana Syrovets10Ahmed M. El-Agrody11Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyDepartment of Pharmacognosy, College of Pharmacy, Cairo University, Cairo, EgyptChemistry Department, Faculty of Science, King Khalid University, Abha, Saudi ArabiaChemistry Department, Faculty of Science, Jazan University, Jazan, Saudi ArabiaChemistry Department, Faculty of Science, Al-Azhar University, Cairo, EgyptChemistry Department, Faculty of Science, Al-Azhar University, Cairo, EgyptChemistry Department, Faculty of Women for Arts, Science, and Education, Ain Shams University, Cairo, EgyptInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyInstitute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, GermanyChemistry Department, Faculty of Science, Al-Azhar University, Cairo, EgyptA series of aryl-substituted 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles (4a–4q) were designed and synthesized via reaction of 6-methoxy-2-naphthol with a mixture of appropriate aromatic aldehydes and malononitrile under microwave conditions. The structures of the novel compounds 4b, 4c, 4f, 4g, 4i, 4l, 4m, and 4o–4q were established according to IR, 1H-NMR, 13C-NMR/13C-NMR-DEPT, and MS. The benzochromene derivative 4c with a single chlorine at the meta position of the phenyl ring and, to a lesser extent, other benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) exhibited the highest cytotoxicity against six human cancer cell lines MDA-MB-231, A549, HeLa, MIA PaCa-2, 5,637, and Hep G2. The mechanisms of the cytotoxic activities of benzochromenes with monohalogenated phenyl ring (4a, 4c–4f) were further analyzed using triple-negative breast cancer cell line MDA-MB-231. Cell cycle analysis showed accumulation of the treated cells in S phase for 4a, 4d–4f, and S-G2/M phases for 4c. In vivo, 4a and 4c–4f inhibited growth, proliferation, and triggered apoptosis in preestablished breast cancer xenografts grown on the chick chorioallantoic membranes while exhibiting low systemic toxicity. Compounds 4a and 4c–4f increased levels of mitochondrial superoxide and decreased mitochondrial membrane potential resulting in initiation of apoptosis as demonstrated by caspase 3/7 activation. In addition, 4c induced general oxidative stress in cancer cells. The SAR study confirmed that halogens of moderate size at meta or para positions of the pendant phenyl ring enhance the cytotoxic activity of 3-amino-1-aryl-8-methoxy-1H-benzo[f]chromene-2-carbonitriles, and these compounds could serve as leads for the development of novel anticancer therapies.https://www.frontiersin.org/articles/10.3389/fchem.2021.759148/full1H-benzo[f]chromenescell cyclecaspase 3/7reactive oxygen species (ROS)mitochondrial membrane potentialstructure–activity relationship |
| spellingShingle | Menna Elgaafary Menna Elgaafary Ahmed M. Fouda Hany M. Mohamed Hany M. Mohamed Abdelaaty Hamed Heba K. A. El-Mawgoud Lu Jin Judith Ulrich Thomas Simmet Tatiana Syrovets Ahmed M. El-Agrody Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms Frontiers in Chemistry 1H-benzo[f]chromenes cell cycle caspase 3/7 reactive oxygen species (ROS) mitochondrial membrane potential structure–activity relationship |
| title | Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms |
| title_full | Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms |
| title_fullStr | Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms |
| title_full_unstemmed | Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms |
| title_short | Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms |
| title_sort | synthesis of β enaminonitrile linked 8 methoxy 1h benzo f chromene moieties and analysis of their antitumor mechanisms |
| topic | 1H-benzo[f]chromenes cell cycle caspase 3/7 reactive oxygen species (ROS) mitochondrial membrane potential structure–activity relationship |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2021.759148/full |
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