The migrated cells were then imaged with the inverted fluorescence microscope (Leica DMi8, Germany) and counted with ImageJ software for three independent fields randomly. Bioorg. Ferulin C triggers potent PAK1 and p21-mediated anti-tumor effects in breast cancer by inhibiting Tubulin polymerization in vitro and in vivo. Epub 2012 Dec 12. Molecules 24 (22), 4034. doi:10.3390/molecules24224034, Wang, X., Bathina, M., Lynch, J., Koss, B., Calabrese, C., Frase, S., et al. (2022). R. L. Siegel, A. Jemal, R. C. Wender, T. Gansler, J. Ma, O. W. Brawley, CA Cancer J. Clin. Meanwhile, the predicted result from network pharmacology was verified which compound 6e might stimulate the oxidative stress response of KB cells. Both natural and synthetic coumarins are endowed with a great therapeutic potential due to the wide spectrum of biological properties including anticancer, antimicrobial, antiviral, anti-inflammatory, neuroprotective, and antioxidant activities. Curr. Variances between two groups were analyzed by One-Way ANOVA followed by post hoc Tukeys test. All the synthetic characterization data of compounds 4a-g are outlined in Supplementary Material. Anticancer (PC-3 Cell Line) Activity. HJ and JC contributed to manuscript revision. In this study, we designed and synthesized a series of novel 3-(coumarin-3-yl)-acrolein hybrids 5a-g and 6a-g for further development of anti-tumor drugs. Network pharmacology and molecular docking integrated strategy to investigate the pharmacological mechanism of palmatine in Alzheimer's disease. In normal cells, JC-1 can form aggregates in healthy mitochondria, emitting red fluorescence, while in apoptotic cells, JC-1 will stay in monomers that emit green fluorescence, implying a low value of m. 6 Articles, This article is part of the Research Topic, https://doi.org/10.3389/fphar.2023.1141121, http://lilab-ecust.cn/pharmmapper/index.html, http://bioinformatics.psb.ugent.be/Webtools/Venn/, https://www.frontiersin.org/articles/10.3389/fphar.2023.1141121/full#supplementary-material. Cinnamaldehyde in diabetes: A review of pharmacology, pharmacokinetics and safety. All the synthetic characterization data of compounds 2a-g are outlined in Supplementary Material. The mitochondria-dependent apoptotic pathway is regulated by pro- and anti-apoptotic members of the Bcl-2 protein family as well as caspase family (Guerra et al., 2011; Wang et al., 2013). Med. Accessibility M. p. 195C196C. Eur. 1H and 13C NMR spectra were recorded on 400MHz JNM-ECZ400S/L1 spectrometers (Varian INOVA, America) with tetramethylsilane (TMS) as an internal reference. 27 (12), 13511364. M. p. 149C151C. A549 and KB cells were cultured in RMPI-1640 medium (Gibco, America). B., et al. 1H-NMR (400MHz, CDCl3) 10.29 (d, J = 6.8 Hz, 1H), 8.47 (s, 1H), 7.68 (d, J = 6.7 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.92 (dd, J = 8.7, 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.02 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.07 (t, J = 7.4 Hz, 4H). Pharmacol. 39 (1), 6573. INTRODUCTION. On the other hand, the other samples were tested by flow cytometry (Beckman, America). official website and that any information you provide is encrypted The molecular effects of acrolein. A., Kang, S. M., Han, D. C., and Kwon, B. M. (2016). Multicomponent synthesis of chromophores - The one-pot approach to functional -systems. 2016 Aug 25;119:141-68. doi: 10.1016/j.ejmech.2016.03.087. PMC (2021). The results showed that compound 6e upregulated the expression of the cleaved 17-kD caspase-3 in KB cells at the concentration of 1.60M. (B) Quantification of the cell apoptosis results (n = 3). Pharmacol. Clipboard, Search History, and several other advanced features are temporarily unavailable. Synthesis of compounds 5a-g and 6a-g. Reagents and conditions: (i) POCl3, DMF, rt to 60C70C, 5h. All the synthesized compounds were screened for in vitro antiproliferative activity against four human cancer cell lines A549 (human lung cancer cell line), KB (human oral epidermoid carcinoma cell line), Hela (human cervical carcinoma cell line), MCF-7 (human breast cancer cell line) and two human normal cell lines HUVEC (human umbilical vein endothelial cell) and LO2 (human normal hepatocytes) through the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Synthesis and biological evaluation of novel coumarin-pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents. M. p. 250C252C. After 4 h, the culture medium was removed and 100L DMSO was added. eCollection 2023. Coumarin-containing hybrids and their anticancer activities. Study of multicomponent synthesis of 7-alkyl or aryl-6H,7H-benzo[f]chromeno[4,3-b] chromen-6-ones involving N,N-disulfopiperidiniumbisulfate [DSPP][HSO. Biological evaluation of novel amidino substituted coumarin-benzazole hybrids as promising therapeutic agents. After completion of the reaction, the reaction mixture was diluted with deionized water (20mL) and extracted with ethyl acetate (20mL 3). TABLE 1. Coumarins are fused benzene and pyrone ring systems which prompt biological investigation to assess their potential therapeutic significance. 2023 Mar 30;16(4):511. doi: 10.3390/ph16040511. Toxicol. Thus, Compound 6e was chosen for the further study on KB cell lines. 1H-NMR (400MHz, CDCl3) 10.30 (d, J = 6.7 Hz, 1H), 8.49 (s, 1H), 7.68 (d, J = 6.7 Hz, 1H), 7.58 (d, J = 13.4 Hz, 2H), 7.50 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 5.14 (s, 2H). HRMS-ESI: m/z Calcd for C13H10ClO3 [M + H]+: 249.0318; Found: 249.0325. No use, distribution or reproduction is permitted which does not comply with these terms. Epub 2023 Apr 5. To a stirred solution of phosphorus oxychloride (0.1mL, 1.1mmol) in DMF (5mL), the solution of compounds 4a-g (1.0mmol) in DMF (2mL) was added dropwise, and the reaction mixture was stirred at 60C70C for 5h. After completion of the reaction, the reaction mixture was diluted with saturated brine (10mL), and then extracted with ethyl acetate (20mL 3). Chem. (A) Dot plot depicting KB cells treated with compound 6e. It was observed that the majority of the synthesized compounds displayed potent anticancer activity on these cancer cell lines and better inhibition against KB and A549 cell lines. (2007). (2022). 238, 114467. doi:10.1016/j.ejmech.2022.114467, Tang, M. S., Wang, H. T., Hu, Y., Chen, W. S., Akao, M., Feng, Z., et al. All the reactions were monitored by thin-layer chromatography (TLC) on precoated silica gel GF254 plates (Qingdao Haiyang, Qingdao, Shandong Province, China) and visualized with UV light (254nm and 365nm). HHS Vulnerability Disclosure, Help Children's Hospital of Philadelphia, United States. 13C NMR (100MHz, CDCl3) 188.22, 162.97, 156.49, 148.09, 145.32, 142.65, 133.01, 131.05, 130.51, 129.89, 127.93 (2C), 124.24 (2C), 114.37, 112.18, 108.58, 101.95, 69.46. The multiplicities were designated by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, brs = broad singlet. Cancer 74 (5), 18291836. Their mechanisms of antitumor actions such as apoptosis induction, cell cycle arrestment and production of oxidative stress have been revealed (Hong et al., 2016). However, when the hydroxyl group was replaced by an alkoxy group such as methoxy, ethoxy, n-propoxy or isopropoxy group (6a-d), the activity was enhanced, and the carbon number of alkoxyl groups showed no significant effect on the antitumor activity. FIGURE 9. Compound 6e decreased Bcl-2/Bax ratio and increased the level of active-caspase 3, indicating that compound 6e induced caspase-3-dependent apoptosis in KB cells, as evidenced by Western blot (Figure 9B). Each lower chamber was filled with 600L of medium containing 10% FBS. Anticancer; Coumarins; IC(50); SAR; Synthesis; Targets. Cancer Lett. Yield: 51.2%. HRMS-ESI: m/z Calcd for C15H14ClO4 [M + H]+: 293.0581; Found: 293.0586. Hepatology 54 (1), 296306. Compared with the human normal cells, compound 6e displayed outstanding selectivity to KB cells. 1H-NMR (400MHz, DMSO-d6) 10.17 (d, J = 6.8 Hz, 1H), 8.83 (s, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 6.8 Hz, 1H), 7.11 (m, 1H), 7.06 (dd, J = 8.7, 1.8 Hz, 1H), 3.91 (s, 3H). In addition, the expression levels of mitochondria-related apoptosis proteins (Caspase-3, Bcl-2 and Bax) were also changed significantly by the intervention of compound 6e. As shown in Figure 6B, the interaction network contained 67 targets (nodes) and 230 relationships (edges). Sci. 1H-NMR (400MHz, CDCl3) 10.29 (d, J = 6.7 Hz, 1H), 8.47 (s, 1H), 7.66 (d, J = 6.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.42 (m, 4H), 7.38 (m, 1H), 7.00 (dd, J = 8.7, 2.5 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 5.17 (s, 2H). (2019). Meanwhile, acrolein moiety was also extensively used as a highly active linker in the design of antitumor agents. Be A, Racan L, onja L, Persoons L, Daelemans D, Starevi K, Vianello R, Hranjec M. RSC Med Chem. M. p. 223C225C. The detailed procedures and characterizations have been exhibited below. Aiming to develop more potent coumarin derivatives for cancer treatment, a series of coumarin acrolein hybrids were designed and synthesized by using molecular hybridization approach, and investigated for their antiproliferative activity against A549, KB, Hela and MCF-7 cancer cells as well as HUVEC and LO2 human normal cells. doi:10.1002/hep.24367, Gugliucci, A. All rights reserved. Molecules 23 (3), 515. doi:10.3390/molecules23030515, Wu, Y., Xu, J., Liu, Y., Zeng, Y., and Wu, G. (2020). Identification of molecular targets and potential mechanisms of yinchen wuling san against head and neck squamous cell carcinoma by network pharmacology and molecular docking. Then the treated cells were resuspended with 400L of 1X Annexin V binding buffer and mixed with 5L FITC and 5L PI (Annexin V-FITC Apoptosis Analysis Kit, Tianjing), and incubated at room temperature in the dark for 5min. Creative Commons Attribution License (CC BY). All of the solvents and reagents are commercially available and were purchased from Accela ChemBio Co., Ltd. (Shanghai, China) without further purification unless otherwise specified. Epub 2023 Feb 17. FIGURE 1. Careers. Res. (A) Fluorescence images of KB cells treated with compound 6e. doi:10.1016/j.ijbiomac.2013.03.028, Cai, X., Yang, J., Zhou, J., Lu, W., Hu, C., Gu, Z., et al. The influence of the substituents at the C-6 or C-7 position of coumarin nucleus on the activity was then explored. After completion of reaction, the reaction mixture was diluted with deionized water (4mL). HRMS-ESI: m/z Calcd for C16H17ClNO3 [M + H]+: 306.0897; Found: 306.0901. Design, synthesis and preliminary biological evaluation of benzylsulfone coumarin derivatives as anti-cancer agents. Compound 6e reduced MMP in KB cells. KB cells were harvested and resuspended in serum-free medium, treated with different concentrations of compound 6e (0.5 IC50, IC50, 2 IC50), and added into the upper wells of the transwell chamber at density of 1105 cells/200L. Eur. 10, 592853. doi:10.3389/fonc.2020.592853, Wu, Y., Xu, X., Liu, M., Qin, X., Wu, Q., Ding, H., et al. Front Chem. The site is secure. This is the first standalone review that emphasis on the assorted retrosynthetic approaches, important targets for molecularly targeted cancer therapy and structure activity relationship studies that highlight the chemical groups responsible for evoking the anticancer potential of coumarin derivatives reported from 2011 to 2014. Macromol. (2022). FIGURE 7. 1H-NMR (400MHz, DMSO-d6) 10.17 (dd, J = 6.8, 1.7 Hz, 1H), 8.84 (s, 1H), 8.28 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.7 Hz, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 6.8 Hz, 1H), 7.21 (s, 1H), 7.17 (dd, J = 8.7, 1.9 Hz, 1H), 5.46 (s, 2H). (2011). J. Med. Unable to load your collection due to an error, Unable to load your delegates due to an error. Molecules 27 (17), 5464. doi:10.3390/molecules27175464, de la Cruz-Concepcin, B., Gutirrez-Escobar, A., Lorenzo-Moran, H. Y., Navarro-Tito, N., Martnez-Carrillo, D. N., Ortuo-Pineda, C., et al. Phytother. After completion of reaction, the reaction mixture was diluted with deionized water (4mL). doi:10.1016/j.gene.2019.02.076, Pei, H., Zeng, J., Chen, W., He, Z., and Du, R. (2022). The result of transwell migration assay also revealed that the treatment of compound 6e significantly attenuated the migratory ability of KB cells in a concentration-dependent manner (Figure 3). Yield: 34.3%. Cinnamaldehyde: A compound with antimicrobial and synergistic activity against ESBL-producing quinolone-resistant pathogenic enterobacteriaceae. For invasion assay, the transwells (8m pore size, Corning Incorporated) were precoated with 40L Matrigel for 2h at 37C to achieve solidification. It is well-known that mitochondrial damage is a major trigger for the induction of cell apoptosis and necrosis (Kharroubi et al., 2017; Meng et al., 2021). The invasion of KB cells was significantly inhibited by compound 6e in a dose-dependent way. In vitro cell migration and invasion assays. 14:1141121. doi: 10.3389/fphar.2023.1141121. Disclaimer. Before (2021). Anti-breast Cancer Potential of Natural and Synthetic Coumarin Derivatives. M. p. 250C252 C. A review on anti-tumor mechanisms of coumarins. doi:10.1101/gad.215855.113, Wang, X. R., Wang, S., Li, W. B., Xu, K. Y., Qiao, X. P., Jing, X. L., et al. 1H-NMR (400MHz, DMSO-d6) 11.57 (s, 1H), 10.16 (ddd, J = 6.9, 2.0, 1.0 Hz, 1H), 8.78 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 6.9 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 6.88 (s, 1H). In summary, compound 6e suppressed cell proliferation, migration, invasion and induced cell apoptosis through inhibition of PI3K/AKT signaling pathway in KB cells (Figure 10). Eur. Med. After completion of the reaction, the reaction mixture was diluted with deionized water (10mL) and the obtained precipitate was filtered off. (2021). Dandriyal J, Singla R, Kumar M, Jaitak V. Eur J Med Chem. All the mediums were supplemented with 10% fetal bovine serum (FBS) (BI, State of Israel), 100 U/mL penicillin and 100g/mL streptomycin (Gibco, America), and all the cells were incubated in a sterile incubator at 37C in an environment of 5% CO2. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. According to the most recent WHO reports, cancer was found to be the second leading reason for death globally. The site is secure. 9, 815531. doi:10.3389/fchem.2021.815531, Jeong, H. W., Han, D. C., Son, K. H., Han, M. Y., Lim, J. S., Ha, J. H., et al. 8600 Rockville Pike Eur J Med Chem. Coumarin sulfonamides and amides derivatives: Design, synthesis, and antitumor activity in vitro. Baruah K, Kalita S, Kashyap N, Bora DB, Paul S, Borah R. Mol Divers. The potential targets of oral cancer were identified by the Genetic Association Database (https://geneticassociationdb.nih.gov/), which is a database of genetic association data from complex diseases and disorders. At the highest dose tested (2 IC50), compound 6e reduced KB cell invasion by more than 64% (Figure 4). (B) The MMP of KB cells treated with compound 6e was determined by flow cytometry. SRC, MAPK1, PTPN11, GRB2 and EGFR as the targets ranked in the top five were regarded as the potential core targets (Supplementary Table S1). The preliminary action mechanism studies suggested that compound 6e, the representative compound, was capable of dose-dependently suppressing migration, invasion and inducing significant apoptosis. In view of the appealing structural scaffold of coumarin derivatives and the favorable antitumor activity of acrolein moiety, we designed and synthesized a series of 3-(coumarin-3-yl)-acrolein derivatives based on molecular hybridization strategy in continuation of our studies on coumarin derivatives. Accessibility Western blot analysis of related proteins of KB cells treated with compound 6e. Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction. J. Vis. Anticancer Mechanisms Coumarins Act as CA Inhibitors CA is a zinc-containing metal enzyme, catalyzing reversible hydration of carbon dioxide, maintaining pH inside and outside the cell, and transmembrane transport of ions, etc., and affecting a variety of metabolic activities ( 3 ). HRMS-ESI: m/z Calcd for C12H7BrClO3 [M + H]+: 312.9267; Found: 312.9260. FOIA J. Biochem. (A) Microscope images of the KB cells that invaded through the matrigel after treatment of compound 6e. The crude product was dried and purified by silica gel column chromatography (Methylene chloride: methanol = 100:1) to obtain pure yellow powder. Lett. After 24h, the cells were adherent to the wall and treated with different concentrations of compound 6e (0.5 IC50, IC50, 2 IC50) for 48h. Afterwards, cells were collected, washed twice with cold PBS. This site needs JavaScript to work properly. Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies Coumarins are fused benzene and pyrone ring systems which prompt biological investigation to assess their potential therapeutic significance. Compound 5d and 6e were identified as the most potent compounds with the IC50 values of 0.70 0.054.23 0.15 M and 0.39 0.0714.82 0.28M against the tested cancer cell lines, respectively. We reported the derivatives attached a sulfonamide moiety at C-3 position of coumarin nucleus (Figure 1E), and revealed that their mechanism of inducing apoptosis was probably associated with increasing reactive oxygen species (ROS) levels and upregulating caspase-3 expression (Zhang et al., 2021a). Discovery of novel coumarin-indole derivatives as tubulin polymerization inhibitors with potent anti-gastric cancer activities. Non-small-cell lung cancer (A549), oral epidermoid carcinoma (KB), cervical cancer (Hela) and breast cancer (MCF-7) cells were purchased from the American Type Culture Collection (ATCC, America). 22 (9), 31153121. These authors have contributed equally to this work and share first authorship, Novel Small Molecules in Targeted Cancer Therapy, View all doi:10.1002/iub.2104, Kwon, J. Y., Hong, S. H., Park, S. D., Ahn, S. G., Yoon, J. H., Kwon, B. M., et al. Mol. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give an orange solid. Med. Synthesis of compounds 2a-g and 4a-g. Reagents and conditions: (i) Piperidine, C2H5OH, rt, 0.52h (ii) K2CO3, DMF, N2, rt, 1620h. SCHEME 2. Possible mechanism of the antitumor effects of compound 6e. de Oliveira LMG, Carreira RB, de Oliveira JVR, do Nascimento RP, Dos Santos Souza C, Trias E, da Silva VDA, Costa SL. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give orange red solid. HRMS-ESI: m/z Calcd for C14H12ClO4 [M + H]+: 279.0424; Found: 279.0417. Sci. IR (KBr) max (cm-1) 3081, 2923, 1713, 1663, 1617. Curr Top Med Chem. During the early stage of apoptosis, caspase-3 (32 KD) is cleaved to the active 17-kD caspase-3 fragment, which is responsible for morphological and biochemical changes in apoptosis. Coumarin is a naturally occurring material as well as a versatile synthetic scaffold exhibiting a wide spectrum of biological impacts including potential anticancer activities ( Vosooghi et al., 2010) such as seselin (skin cancer) ( Nishino et al., 1990 ), acronycin (lung, colon, and ovarian cancers) ( Thakur et al., 2015 ), calanone (leukemia a. 3-(coumarin-3-yl)-acrolein derivative 5a was initially prepared and screened, which showed significant antiproliferative activity comparable to or even stronger than 5-FU against the four cancer cell lines. The increasing morbidity and high mortality of cancer create a great demand for the development of novel anticancer drugs. Curr Top Med Chem. Bookshelf Would you like email updates of new search results? Network construction and PPI network core screening. Nutr. Gene 698, 120128. 2020 Deutsche Pharmazeutische Gesellschaft. Bcl-2 and Bax are the cell survival proteins located on the mitochondrial membrane and capable of controlling the MMP (m) and the activation of caspase cascade. Biochem. All authors read, and approved the submitted version. Ka et al. Int. Social activity. The increasing morbidity and high mortality of cancer create a great demand for the development of novel anticancer drugs. Eur. doi:10.26355/eurrev_202112_27612, Dhara, L., and Tripathi, A. After the incubation, the samples were immediately analyzed by a Beckman Flow Cytometer. M. p. 150C152 C. Bethesda, MD 20894, Web Policies In May 2023, Frontiers adopted a new reporting platform to be Counter 5 compliant, in line with industry standards. IUBMB Life 71 (10), 15951610. doi:10.1016/j.ejphar.2012.09.027, Lee, C. W., Lee, S. H., Lee, J. W., Ban, J. O., Lee, S. Y., Yoo, H. S., et al. Enrique Ortega-Forte. doi:10.1254/jphs.fp0061204, Lee, S. H., Lee, C. W., Lee, J. W., Choi, M. S., Son, D. J., Chung, Y. (2020). The information of the total 81 predicted targets was imported into the String database to obtain the data of PPI and the visualized PPI network. 2023 Feb 24;12(3):565. doi: 10.3390/antiox12030565. 5-Fluorouracil (5-FU) was used as positive control and the results are presented in Table 1. doi:10.1111/j.2042-7158.2012.01526.x, Wang, H. T., Hu, Y., Tong, D., Huang, J., Gu, L., Wu, X. R., et al. 5 (49), 3889238905. PMC The incubated tumor cells were planted into 96-well plates (4103 cells/well). Yield: 65.9%. To realize both the characteristics and functions of these 81 predicted targets, GO enrichment and KEGG pathway enrichment analysis were performed, and the GO terms and KEGG pathways with p-value <0.01 were significantly enriched. (A) The wound was captured at different time points (0 h and 24h). In addition, the coumarin-3-hydrazide derivatives (Figure 1F) were developed as new lactate transport inhibitors with low toxicity to normal cells, which induced intracellular lactate accumulation and inhibited lactate uptake (Ji et al., 2021). KB cells (5105 cells/well) were seeded into six-well plates. The https:// ensures that you are connecting to the 21 (1), 8492. 2'-Benzoyloxycinnamaldehyde inhibits nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 cells via regulation of AP-1 pathway. M. p. 199C201C. Clipboard, Search History, and several other advanced features are temporarily unavailable. (B) Quantification of the cell scrape results (n > 3). sharing sensitive information, make sure youre on a federal The .gov means its official. Chem. The precipitated yellow solid was filtered off, washed with deionized water and dried under vacuum to give pure yellow powder. The protein content was determined by BCA reagent (Beyotime, China) according to the standard curve. doi:10.1016/j.jes.2016.08.028, Kowshik, J., Nivetha, R., Ranjani, S., Venkatesan, P., Selvamuthukumar, S., Veeravarmal, V., et al. (2012). M. p. 217C219 C. Introduction Cancer is considered as a one of the most serious life-threatening diseases. Neurotox Res. Eur. doi:10.1016/j.bmcl.2012.03.059, Singh, A. K., Patel, P. K., Choudhary, K., Joshi, J., Yadav, D., and Jin, J. O. This site needs JavaScript to work properly. MMP was determined using the JC-1 mitochondria staining Kit (Aladdin, China). Coumarins as privileged scaffold for anti-inflammatory drug development. J. Clin. 152, 104605. doi:10.1016/j.phrs.2019.104605, Yu, H., Hou, Z., Tian, Y., Mou, Y., and Guo, C. (2018). The absorbance was determined at the wavelength of 540nm and 655nm using a microplate reader (BioTek Epoch, America). 2015 Sep 18;102:611-30. doi: 10.1016/j.ejmech.2015.08.033. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Targets for the anticancer activities of each coumarin derivative have been unveiled. The former detected the planar movement ability of monolayer cells after external stimulation, while the latter detected spatial migration ability of cells. 13C NMR (100MHz, DMSO-d6) 192.13, 164.20, 157.50, 155.73, 146.32, 144.61, 132.22, 126.61, 115.73, 114.48, 111.24, 101.68. Several studies suggested that network pharmacology might be helpful to promote the efficiency of drug discovery and development (Pei et al., 2022). After washing with Phosphate Buffered Saline (PBS), the cells were incubated with compound 6e in different concentrations (0.5 IC50, IC50, 2 IC50) for 24h. Images of cells were photographed with the inverted fluorescence microscope (Leica DMi8, Germany) at 0 h and 24h. The areas that were not covered by cells in the scratch wound were quantified by using ImageJ. Total protein was separated with 20% SDS polyacrylamide gels for 1h at 120V, transferred to PVDF membranes, and blocked with rapid blocking solution for 1hour at room temperature. Design, synthesis and biological evaluation of new carbohydrate-based coumarin derivatives as selective carbonic anhydrase IX inhibitors via "click" reaction. Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors. https://gco.iarc.fr/tomorrow/graphic-isotype?type=0&population=900&mode= 21776021/National Natural Science Foundation of China. Rep. 24 (3), 273284. It was found that the three derivatives had nearly equivalent activity to compound 5a against KB cells. doi:10.1093/toxsci/57.1.6, Kern, J. C., and Kehrer, J. P. (2002). 1H-NMR (400MHz, CDCl3) 10.27 (d, J = 6.9 Hz, 1H), 8.37 (s, 1H), 7.67 (d, J = 6.9 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 6.64 (dd, J = 9.0, 2.5 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.46 (d, J = 7.2 Hz, 4H), 1.24 (d, J = 7.1 Hz, 6H). Pharmacol. IR (KBr) max (cm-1) 3069, 2969, 2880, 1725, 1662, 1615. 2018, 68, 329. Synthesis and biological evaluation of coumarin-quinone hybrids as multifunctional bioactive agents. Infect. (2021). W. Zheng, Y. Zhao, Q. Luo, Y. Zhang, K. Wu, F. Wang, Curr. UniProt knowledge database (https://www.uniprot.org/) was used to transform the targets and select Homo sapiens as the target species. (2003). Coupling constant (J) is expressed in Hertz (Hz). 29, 115870. doi:10.1016/j.bmc.2020.115870, Justus, C. R., Leffler, N., Ruiz-Echevarria, M., and Yang, L. V. (2014). Hela, MCF-7 and LO2 cells were cultured in DMEM medium (Gibco, America). FIGURE 2. (A) The expression levels of the PI3K, AKT and pAKT in KB cells treated with compound 6e. 2021;21(18):1692-1709. doi: 10.2174/1568026621666210303145430. MeSH 2020 Aug;353(8):e2000025. The gene targets of cancers (human oral epidermoid carcinoma, cervical cancer, non-small cell lung cancer and breast cancer) were collected from GeneCards (http://www.genecards.org/). Acrolein-induced cell death: A caspase-influenced decision between apoptosis and oncosis/necrosis. Integrating network pharmacology and pharmacological evaluation for deciphering the action mechanism of herbal formula zuojin pill in suppressing hepatocellular carcinoma. Finally, the underlying molecular mechanisms were further verified through in vitro experiments. (accessed: November 16, 2019). Interestingly, when the hydrogen at C-7 position of compound 5a was substituted with bromine, the resulting compound 5d was 10-fold more potent than 5a and 5-FU against A549, and had activity equivalent to or greater than that of compound 5a and 5-FU against KB, Hela and MCF-7 cells. Coumarin derivatives are ubiquitous in nature and can readily interact with diverse enzymes and receptors in cancer cells via weak bond interactions; hence, coumarin is a highly privileged pharmacophore for the development of novel anticancer agents. In recent years, our group has been dedicated to the synthesis and development of new coumarin derivatives as anticancer agents. 48, 128258. doi:10.1016/j.bmcl.2021.128258, PubMed Abstract | CrossRef Full Text | Google Scholar, Badawy, M. E., and Rabea, E. I. IR (KBr) max (cm-1) 3058, 1714, 1655, 1594. Biotechnol. Front. Yield: 75.2%. **** (p < 0.0001), *** (p < 0.001), ** (p < 0.01), * (p < 0.05), ns (not significant). IR (KBr) max (cm-1) 3066, 1725, 1658, 1595, 1082. 63 (11), 10811091. and transmitted securely. doi:10.1016/s0009-2797(01)00295-2, Kharroubi, W., Haj Ahmed, S., Nury, T., Andreoletti, P., Sakly, R., Hammami, M., et al. (2019). Yellow solid. In the present study, network pharmacology-based prediction showed that PI3K-AKT signaling pathway was the top signaling pathway involved in the underlying mechanisms of compound 6e. Therefore, JC-1 staining was used to investigate the effect of compound 6e on the MMP (m) of KB cells. HRMS-ESI: m/z Calcd for C12H7BrClO3 [M + H]+: 312.9267; Found: 312.9258. The cells trapped on the bottom side of the membrane were fixed with methanol for 1h and stained with crystal violet solution for 2h. Subsequently, the chambers thoroughly washed with PBS. The top 10 enriched GO terms in biological process, cellular component and molecular function were shown in Figure 7A, among which the response to reactive oxygen species, oxidative stress and protein kinase B (AKT) signaling had significant correlations with oral epidermoid carcinoma. Epub 2015 Aug 17. (B) PPI network of the overlapping targets of predicted compound 6e targets and cancer targets obtained from Venn analysis. (2022). The analysis of Annexin V-FITC/PI dual staining assay proved that compound 6e induced apoptosis of KB cells in a dose dependent manner. Therefore, mitochondrial depolarization is manifested by a decrease in the ratio of red to green fluorescence intensity. As the concentration of compound 6e increased, the number of KB cells with red fluorescence decreased in a concentration-dependent manner (Figures 8A, B), and the results also showed a significant decrease in the JC-1 ratio (Figure 8C). Because of their outstanding antitumor activity and relatively low side effects (Cai et al., 2013; Ahmed et al., 2021; de la Cruz-Concepcin et al., 2021; Chu et al., 2022; Song et al., 2022), coumarin derivatives have attracted tremendous research interest. J. Med. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Redox Biol. (2017). The precipitated yellow solid was filtered off and washed with deionized water. IR (KBr) max (cm-1) 3197, 3072, 1743, 1716, 1648. In this review, current developments of coumarin-based anticancer agents viz simple coumarin, furanocoumarin, pyranocoumarin, pyrone-substituted coumarin, and . Coumarins have a tremendous ability to regulate diverse range of cellular pathways that can be explored for selective anticancer activity. It is a highly reactive , -unsaturated carbonyl serving as a Michael acceptor which has the ability of reacting with glutathione, DNA, some enzymes or receptors as electrophiles, thus disrupts the function of cells (Kehrer and Biswal, 2000; Kern and Kehrer, 2002; Feng et al., 2006; Tang et al., 2011; Wang et al., 2012). M. p. 167C169 C. Compound 6e inhibited invasion of KB cells. Human umbilical vein endothelial cell (HUVEC) and human normal hepatocytes (LO2) cells were provided by Guangzhou Medical University (Guangzhou, China).

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