Synthesis of β-Enaminonitrile-Linked 8-Methoxy-1H-Benzo[f]Chromene Moieties and Analysis of Their Antitumor Mechanisms

Abstract

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.

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

“…Previous studies have demonstrated that expression level of caspase-3 is downregulated in cancer; therefore, enhancing its activity with natural and synthetic compounds was suggested as a possible strategy for cancer therapy [ 76 , 77 ]. In fact, pyran-containing, 4 H -chromene derivatives, such as 3-amino-1-(4-fluorophenyl)-1 H -benzo[ f ]chromene-2-carbonitrile [ 78 ] and 3-amino-1-(4-iodophenyl)-8-methoxy-1 H -benzo[ f ]chromene-2-carbonitrile [ 79 ], were found to be effective against HT-29 cells of CRC and -MDA-MB-231 cells of breast cancer, respectively, via a 3-caspase-dependent apoptosis mechanism; therefore, we anticipated that our closely related pyran analogues 4d and 4k might be capase-3 inducers as well. Thus, the real-time quantitative PCR analyses of caspase-3-gene levels following treatment with compounds 4d and 4K at a concentration of 10 mg/mL for 24 h, were performed to investigate their potential as proapoptotic agents.…”

“…Previous studies have demonstrated that expression level of caspase-3 is downregulated in cancer; therefore, enhancing its activity with natural and synthetic compounds was suggested as a possible strategy for cancer therapy [76,77]. In fact, pyran-containing, 4H-chromene derivatives, such as 3-amino-1-(4-fluorophenyl)-1H-benzo[f]chromene-2-carbonitrile [78] and 3amino-1-(4-iodophenyl)-8-methoxy-1H-benzo[f]chromene-2-carbonitrile [79], were found to be effective in a HT-29 cell line of CRC and -MDA-MB-231 cells of breast cancer, respectively, via a 3-caspase-dependent apoptosis mechanism; therefore, we anticipated that our Normally, apoptosis, or programmed cell death, is considered as a safeguard mechanism for managing stress and maintaining tissue homeostasis. It proceeds through a series of well-ordered biochemical cascades of events, which are regulated by a network of proteins.…”

The Crystal Structure of 3-Amino-1-(4-Chlorophenyl)-9-Methoxy-1H-Benzo[f]Chromene-2-Carbonitrile: Antimicrobial Activity and Docking Studies

“…Compound 4 has a chiral feature; consequently, this specific rotation was gauged, utilizing a Carl Zeiss polarimeter to attribute the stereochemistry of the 1-position to the 1H-benzo[f ]-chromene moiety. Results revealed that compound 4 has zero rotation (meaning the molecule is optically inactive) and is obtained in the form of a racemic (±) mixture [26][27][28], as illustrated in Scheme 1.…”

“…The comprehensive biomedical features of chromene molecules have motivated scientific figures within the drug discovery biosphere to cultivate new derivatives of this class of materials and explore their novel biological characteristics. Chromenes have been renowned for their incredible biological functions, which assisted their assimilation into various applications such as antimicrobial activities [10][11][12][13][14], hypolipidemic [15], antileishmanial, antiviral, anti-HIV, antianaphylactic activities [16][17][18], insecticidal [19], targeting of c-Src kinase enzyme [20,21], anticancer and cytotoxic activities [22][23][24][25], cell cycle analysis, apoptotic effects, caspase 3/7, and inhibition of the topoisomerase enzyme [26][27][28][29][30][31][32][33]. Among the synthetic strategies to acquire chromene molecules, microwave irradiation is one of the most efficacious and eco-friendly procedures, which facilitates the isolation of the desired compounds in a short period of time and results in good yields [34][35][36][37].…”

Discovery of benzochromene derivatives first example with dual cytotoxic activity against the resistant cancer cell MCF-7/ADR and inhibitory effect of the P -glycoprotein expression levels

“…For example, some benzochromene derivatives displayed inhibitory behaviour of the c -Src kinase with their antitumor ability and apoptotic effects 28–31 . Other benzochromene templates exhibited antitumor activities, trigger cell cycle arrest at M, S, and G2 stages, enhance the formation of caspases 3/7, and initiate apoptosis with diminished toxicity in tumour cells through the dual inhibition of topoisomerase I/II and in breast cancer xenografts 27 , 31–35 . Alongside its anti-proliferative features, chromene derivatives exhibited a DNA binding ability, the inhibition of the Bcl-2 protein 26 and a high potency for the hAChE 36 .…”