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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Autores principales:	Menna Elgaafary, Ahmed M. Fouda, Hany M. Mohamed, Abdelaaty Hamed, Heba K. A. El-Mawgoud, Lu Jin, Judith Ulrich, Thomas Simmet, Tatiana Syrovets, Ahmed M. El-Agrody
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	1H-benzo[f]chromenes cell cycle caspase 3/7 reactive oxygen species (ROS) mitochondrial membrane potential structure–activity relationship Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/70effce2f73b4006a150cfbc62b2ba7b
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spelling	oai:doaj.org-article:70effce2f73b4006a150cfbc62b2ba7b2021-11-22T06:29:24ZSynthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms2296-264610.3389/fchem.2021.759148https://doaj.org/article/70effce2f73b4006a150cfbc62b2ba7b2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fchem.2021.759148/fullhttps://doaj.org/toc/2296-2646A 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.Menna ElgaafaryMenna ElgaafaryAhmed M. FoudaHany M. MohamedHany M. MohamedAbdelaaty HamedHeba K. A. El-MawgoudLu JinJudith UlrichThomas SimmetTatiana SyrovetsAhmed M. El-AgrodyFrontiers Media S.A.article1H-benzo[f]chromenescell cyclecaspase 3/7reactive oxygen species (ROS)mitochondrial membrane potentialstructure–activity relationshipChemistryQD1-999ENFrontiers in Chemistry, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	1H-benzo[f]chromenes cell cycle caspase 3/7 reactive oxygen species (ROS) mitochondrial membrane potential structure–activity relationship Chemistry QD1-999
spellingShingle	1H-benzo[f]chromenes cell cycle caspase 3/7 reactive oxygen species (ROS) mitochondrial membrane potential structure–activity relationship Chemistry QD1-999 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
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.
format	article
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
title	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_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_sort	synthesis of β-enaminonitrile-linked 8-methoxy-1h-benzo[f]chromene moieties and analysis of their antitumor mechanisms
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/70effce2f73b4006a150cfbc62b2ba7b
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Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms

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