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.
Highlights
Cancer is still one of the leading cause of death and among the major public health concerns (Sung et al, 2021)
The 1H-NMR (500 MHz) and 13C-NMR (125 MHz) spectra were recorded on BRUKER AV 500 MHz spectrometer (Billerica, MA) in DMSO-d6 as a solvent, using tetramethylsilane (TMS) as an internal standard, and chemical shifts were expressed as δ
We found that the synthesized benzochromene derivatives with monohalogenated phenyl ring (4a, 4c–4f) had the most pronounced cytotoxicity toward all tested cancer cell lines with a GR50 range of 1.0–8.1 μM and GRmax range of −0.76–−1, and compound 4c showed the greatest in vitro antiproliferative/ cytotoxic activities against the six different types of cancer cell lines with a GR50 range of 1.0–4.9 μM and GRmax range of −0.9–−1
Summary
Cancer is still one of the leading cause of death and among the major public health concerns (Sung et al, 2021). The lipophilic properties of the benzopyran structures enable efficient transport of these compounds across biological membranes (Nicolaou et al., 2000) Some of these molecules exhibit potential therapeutic activities, which can be exploited in the treatment of cancer, and infectious and inflammatory diseases. Aryl-4H-benzo[h]chromene-3-carbonitrile (E) exhibited cytotoxic and proapoptotic effects on a variety of human cancer cell lines (Kheirollahi et al, 2014). Aryl-substituted derivatives of 3amino-8/9-bromo-1-aryl-1H-benzo[f]-chromene-2-carbonitrile (L) have been shown to induce cell cycle arrest and apoptosis in human cancer cells via dual inhibition of topoisomerases and tubulin (Figure 3) (Fouda et al, 2019; Fouda et al, 2020). Intracellular effects and intracellular targets of benzochromene compounds with mono-meta/parahalogenated-substituted phenyl ring (4a, 4c–4f), which exhibited the most pronounced cytotoxicity against the human cancer cell lines tested, were analyzed in vitro and in vivo
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