Computer-Aided Drug Design Applied to Secondary Metabolites as Anticancer Agents

Rodrigo    Santos Aquino    de Araújo; Edeildo    Ferreira    da Silva-Junior; Thiago    Mendonça    de Aquino; Marcus    Tullius    Scotti; Hamilton    M.    Ishiki; Luciana       Scotti; Francisco    Jaime Bezerra    Mendonça-Junior
doi:10.2174/1568026620666200607191838
Abstract

Computer-Aided Drug Design (CADD) techniques have garnered a great deal of attention in academia and industry because of their great versatility, low costs, possibilities of cost reduction in in vitro screening and in the development of synthetic steps; these techniques are compared with highthroughput screening, in particular for candidate drugs. The secondary metabolism of plants and other organisms provide substantial amounts of new chemical structures, many of which have numerous biological and pharmacological properties for virtually every existing disease, including cancer. In oncology, compounds such as vimblastine, vincristine, taxol, podophyllotoxin, captothecin and cytarabine are examples of how important natural products enhance the cancer-fighting therapeutic arsenal.
In this context, this review presents an update of Ligand-Based Drug Design and Structure-Based Drug Design techniques applied to flavonoids, alkaloids and coumarins in the search of new compounds or fragments that can be used in oncology.
A systematical search using various databases was performed. The search was limited to articles published in the last 10 years.
The great diversity of chemical structures (coumarin, flavonoids and alkaloids) with cancer properties, associated with infinite synthetic possibilities for obtaining analogous compounds, creates a huge chemical environment with potential to be explored, and creates a major difficulty, for screening studies to select compounds with more promising activity for a selected target. CADD techniques appear to be the least expensive and most efficient alternatives to perform virtual screening studies, aiming to selected compounds with better activity profiles and better “drugability”.
Keywords: Cancer, Natural products, Computer-Aided drug design, Docking, Ligand-based drug design, Structure-based drug design.
« Previous Next »
Graphical Abstract

[1] 
World Health Organization / International Agency for Research on Cancer (IARC). Latest global cancer data: Cancer burden rises to18.1 million new cases and 9.6 million cancer deaths in 2018.Available from: 2018.https://www.iarc.fr/wp-content/uploads/2018/09/pr263_E.pdf
[2] 
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin.,  2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402] 
[3] 
Santos, M de O Estimate 2018: Incidence of cancer in Brazil. Rev. Brasileira.De.Cancerologia,,  2018, 64(1), 119-120.
[4] 
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell,  2000, 100(1), 57-70.
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931] 
[5] 
Foster, I. Cancer: A cell cycle defect. Radiography,  2008, 14, 144-149.
[http://dx.doi.org/10.1016/j.radi.2006.12.001] 
[6] 
Costa-Lotufo, L.V.; Montenegro, R.C.; Alves, A.P.N.N.; Madeira, S.V.F.; Pessoa, C.; Moraes, M.E.A.; Moraes, M.O. A contribuição dos produtos naturais como fonte de novos fármacos anticâncer: estudos no laboratório de oncologia experimental da Universidade Federal do Ceará. Rev. Virtual Quim.,  2010, 2, 47-58.
[http://dx.doi.org/10.5935/1984-6835.20100006] 
[7] 
Vermeulen, K.; Van Bockstaele, D.R.; Berneman, Z.N. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif.,  2003, 36(3), 131-149.
[http://dx.doi.org/10.1046/j.1365-2184.2003.00266.x] [PMID: 12814430] 
[8] 
Birudukota, N.; Madan Mudgal, M.; Shanbhag, V. Discovery and development of azasteroids as anticancer agents. Steroids,  2019, 152108505
[http://dx.doi.org/10.1016/j.steroids.2019.108505] 
[9] 
Butler, M.S. Natural products to drugs: natural product-derived compounds in clinical trials. Nat. Prod. Rep.,  2008, 25(3), 475-516.
[http://dx.doi.org/10.1039/b514294f] [PMID: 18497896] 
[10] 
Harvey, A.L. Natural products in drug discovery. Drug Discov. Today,  2008, 13(19-20), 894-901.
[http://dx.doi.org/10.1016/j.drudis.2008.07.004] [PMID: 18691670] 
[11] 
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod.,  2007, 70(3), 461-477.
[http://dx.doi.org/10.1021/np068054v] [PMID: 17309302] 
[12] 
Amaral, R.G.; dos Santos, S.A.; Andrade, L.N.; Severino, P.; Carvalho, A.A. Natural products as treatment against cancer: a historical and current vision. Clin. Oncol. (R. Coll. Radiol.),  2019, 4, 1562-1566.
[13] 
Cragg, G.M.; Pezzuto, J.M. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med. Princ. Pract.,  2016, 25(Suppl. 2), 41-59.
[http://dx.doi.org/10.1159/000443404] [PMID: 26679767] 
[14] 
Mann, J. Natural products in cancer chemotherapy: past, present and future. Nat. Rev. Cancer,  2002, 2(2), 143-148.
[http://dx.doi.org/10.1038/nrc723] [PMID: 12635177] 
[15] 
Newman, D.J.; Cragg, G.M. Marine-sourced anti-cancer and cancer pain control agents in clinical and late preclinical development. Mar. Drugs,  2014, 12(1), 255-278.
[http://dx.doi.org/10.3390/md12010255] [PMID: 24424355] 
[16] 
Surabhi; Singh, B.K. Computer aided drug design: an overview. J. Drug Deliv. Ther.,  2018, 8, 504-509.
[http://dx.doi.org/10.22270/jddt.v8i5.1894] 
[17] 
Kapetanovic, I.M. Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach. Chem. Biol. Interact.,  2008, 171(2), 165-176.
[http://dx.doi.org/10.1016/j.cbi.2006.12.006] [PMID: 17229415] 
[18] 
Scotti, L.; Yarla, N.S.; Mendonça-Filho, F.J.B.; Barbosa-Filho, J.M.; da Silva, M.S.; Tavares, J.F.; Scotti, M.T. CADD studiesapplied to secondary metaboiltes in the anticancer drug research. In:Anticancer Plants: Mechanism and Molecular; Akhtar, M.S.;Swamy, M.K., Eds; Springer Nature Singapore Pvt Ltd: Singapore, CADD studies applied to secondary metaboiltes in the anticancer drug research., 2018; 4, pp. 209-226.
[19] 
Luis, J.A.S.; Souza, H.D.S.; Lira, B.F.; Alves, F.S.; Athayde-Filho, P.F.; Lima, T.K.S.; Rocha, J.C.; Mendonça, F.J.B. Junior; Scotti, L.; Scotti, M.T. Combined structure- and ligand-based virtual screening aiding discovery of selenoglycolicamides as potential multitarget agents against Leishmania species. J. Mol. Struct.,  2019, 1198, 126872-126883.
[http://dx.doi.org/10.1016/j.molstruc.2019.126872] 
[20] 
Herrera Acevedo, C.; Scotti, L.; Feitosa Alves, M.; Formiga Melo Diniz, M.F.; Scotti, M.T. Computer-aided drug design using sesquiterpene lactones as sources of new structures with potential activity against infectious neglected diseases. Molecules,  2017, 22(1)E79
[http://dx.doi.org/10.3390/molecules22010079] [PMID: 28054952] 
[21] 
Ferla, S.; Netzler, N.E.; Ferla, S.; Veronese, S.; Tuipulotu, D.E.; Guccione, S.; Brancale, A.; White, P.A.; Bassetto, M. In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase. Sci. Rep.,  2018, 8(1), 4129-4145.
[http://dx.doi.org/10.1038/s41598-018-22303-y] [PMID: 29515206] 
[22] 
Lionta, E.; Spyrou, G.; Vassilatis, D.K.; Cournia, Z. Structure-based virtual screening for drug discovery: principles, applications and recent advances. Curr. Top. Med. Chem.,  2014, 14(16), 1923-1938.
[http://dx.doi.org/10.2174/1568026614666140929124445] [PMID: 25262799] 
[23] 
da Silva Rocha, S.F.L.; Olanda, C.G.; Fokoue, H.H.; Sant’Anna, C.M.R. Virtual screening techiniques in drug discovery: review and recente applications. Curr. Top. Med. Chem.,  2019, 19(19), 1751-1767.
[http://dx.doi.org/10.2174/1568026619666190816101948] [PMID: 31418662] 
[24] 
Wang, X.; Song, K.; Li, L.; Chen, L. Structure-based drug design strategies and challenges. Curr. Top. Med. Chem.,  2018, 18(12), 998-1006.
[http://dx.doi.org/10.2174/1568026618666180813152921] [PMID: 30101712] 
[25] 
Viskupicova, J.; Ondrejovič, M.; Sturdik, E. Bioavailability and metabolism of flavonoids. Food Nutr. Res.,  2008, 47, 151-162.
[26] 
Chahar, M.K.; Sharma, N.; Dobhal, M.P.; Joshi, Y.C. Flavonoids: A versatile source of anticancer drugs. Pharmacogn. Rev.,  2011, 5(9), 1-12.
[http://dx.doi.org/10.4103/0973-7847.79093] [PMID: 22096313] 
[27] 
Harborne, J.B.; Grayer, R.J. Flavonoids and insects. in:The flavonoids: advances in research since 1986; Harborne, J.B., Ed.; Chapman & Hall: London, 1994, pp. 589-618.
[http://dx.doi.org/10.1007/978-1-4899-2911-2] 
[28] 
Harborne, J.B.; Williams, C.A. Advances in Flavonoid Researchsince 1992 Phytochemistry, 2000, 55, 481-504.
[29] 
McNally, D.J.; Wurms, K.V.; Labbé, C.; Quideau, S.; Bélanger, R.R. Complex C-glycosyl flavonoid phytoalexins from Cucumis sativus. J. Nat. Prod.,  2003, 66(9), 1280-1283.
[http://dx.doi.org/10.1021/np030150y] [PMID: 14510618] 
[30] 
Hostetler, G.L.; Ralston, R.A.; Schwartz, S.J. Flavones: Food Sources, Bioavailability, Metabolism, and Bioactivity. Adv. Nutr.,  2017, 8(3), 423-435.
[http://dx.doi.org/10.3945/an.116.012948] [PMID: 28507008] 
[31] 
Wang, C-Z.; Mehendale, S.R.; Calway, T.; Yuan, C-S. Botanical flavonoids on coronary heart disease. Am. J. Chin. Med.,  2011, 39(4), 661-671.
[http://dx.doi.org/10.1142/S0192415X1100910X] [PMID: 21721147] 
[32] 
Jiang, W.; Wei, H.; He, B. Dietary flavonoids intake and the risk of coronary heart disease: A dose-response meta-analysis of 15 prospective studies. Thromb. Res.,  2015, 135, 459-463.
[http://dx.doi.org/10.1016/j.thromres.2014.12.016] 
[33] 
Zhao, J.; Zhu, M.; Kumar, M.; Ngo, F.Y.; Li, Y.; Lao, L.; Rong, J. A pharmacological appraisal of neuroprotective and neurorestorative flavonoids against neurodegenerative diseases. CNS Neurol. Disord. Drug Targets,  2019, 18(2), 103-114.
[http://dx.doi.org/10.2174/1871527317666181105093834] [PMID: 30394219] 
[34] 
Airoldi, C.; La Ferla, B.D.; Orazio, G.; Ciaramelli, C.; Palmioli, A. Flavonoids in the treatment of Alzheimer’s and other neurodegenerative diseases. Curr. Med. Chem.,  2018, 25(27), 3228-3246.
[http://dx.doi.org/10.2174/0929867325666180209132125] [PMID: 29424298] 
[35] 
Sarbu, L.G.; Bahrin, L.G.; Babii, C.; Stefan, M.; Birsa, M.L. Synthetic flavonoids with antimicrobial activity: a review. J. Appl. Microbiol.,  2019, 127(5), 1282-1290.
[http://dx.doi.org/10.1111/jam.14271] [PMID: 30934143] 
[36] 
Guan, Y.; Shen, H.J.; Shen, J.; Jia, Y.L.; Dong, X.W.; Jin, Y.C.; Xie, Q.M. Anti-allergic activities of 5,7-dimethoxy-3,4′-dihydroxyflavone via inhalation in rat allergic models. Eur. J. Pharmacol.,  2019, 848, 55-61.
[http://dx.doi.org/10.1016/j.ejphar.2019.01.046] [PMID: 30707957] 
[37] 
Mateeva, N.; Eyunni, S.V.K.; Redda, K.K.; Ononuju, U.; Hansberry, T.D., II; Aikens, C.; Nag, A. Functional evaluation of synthetic flavonoids and chalcones for potential antiviral and anticancer properties. Bioorg. Med. Chem. Lett.,  2017, 27(11), 2350-2356.
[http://dx.doi.org/10.1016/j.bmcl.2017.04.034] [PMID: 28442256] 
[38] 
Jung, Y.C.; Kim, M.E.; Yoon, J.H.; Park, P.R.; Youn, H.Y.; Lee, H.W.; Lee, J.S. Anti-inflammatory effects of galangin on lipopolysaccharide-activated macrophages via ERK and NF-κB pathway regulation. Immunopharmacol. Immunotoxicol.,  2014, 36(6), 426-432.
[http://dx.doi.org/10.3109/08923973.2014.968257] [PMID: 25270721] 
[39] 
de Lima Glória, L.; Barreto de Souza Arantes, M.; Menezes de Faria Pereira, S.; de Souza Vieira, G.; Xavier Martins, C.; Ribeiro de Carvalho, A., Junior; Antunes, F.; Braz-Filho, R.; José Curcino Vieira, I.; Leandro da Cruz, L.; Siqueira de Almeida Chaves, D.; de Paiva Freitas, S.; Barros de Oliveira, D. Phenolic compounds present schinus terebinthifolius raddi influence the lowering of blood pressure in rats. Molecules,  2017, 22(10)E1792
[http://dx.doi.org/10.3390/molecules22101792] [PMID: 29065547] 
[40] 
Djeradi, H.; Rahmouni, A.; Cheriti, A. Antioxidant activity of flavonoids: a QSAR modeling using Fukui indices descriptors. J. Mol. Model.,  2014, 20(10), 2476.
[http://dx.doi.org/10.1007/s00894-014-2476-1] [PMID: 25311723] 
[41] 
Ravishankar, D.; Rajora, A.K.; Greco, F.; Osborn, H.M. Flavonoids as prospective compounds for anti-cancer therapy. Int. J. Biochem. Cell Biol.,  2013, 45(12), 2821-2831.
[http://dx.doi.org/10.1016/j.biocel.2013.10.004] [PMID: 24128857] 
[42] 
Batra, P.; Sharma, A.K. Anti-cancer potential of flavonoids: recenttrends and future perspectives 3 Biotech., 2013, 3, 439-459.
[43] 
Sak, K. Cytotoxicity of dietary flavonoids on different human cancer types. Pharmacogn. Rev.,  2014, 8(16), 122-146.
[http://dx.doi.org/10.4103/0973-7847.134247] [PMID: 25125885] 
[44] 
Awasthi, M.; Singh, S.; Pandey, V.P.; Dwivedi, U.N. Molecular docking and 3D-QSAR-based virtual screening of flavonoids as potential aromatase inhibitors against estrogen-dependent breast cancer. J. Biomol. Struct. Dyn.,  2015, 33(4), 804-819.
[http://dx.doi.org/10.1080/07391102.2014.912152] [PMID: 24702656] 
[45] 
Brueggemeier, R.W.; Hackett, J.C.; Diaz-Cruz, E.S. Aromatase inhibitors in the treatment of breast cancer. Endocr. Rev.,  2005, 26(3), 331-345.
[http://dx.doi.org/10.1210/er.2004-0015] [PMID: 15814851] 
[46] 
Karkola, S.; Wähälä, K. The binding of lignans, flavonoids and coumestrol to CYP450 aromatase: a molecular modelling study. Mol. Cell. Endocrinol.,  2009, 301(1-2), 235-244.
[http://dx.doi.org/10.1016/j.mce.2008.10.003] [PMID: 19000737] 
[47] 
Balunas, M.J.; Su, B.; Brueggemeier, R.W.; Kinghorn, A.D. Natural products as aromatase inhibitors. Anticancer. Agents Med. Chem.,  2008, 8(6), 646-682.
[http://dx.doi.org/10.2174/187152008785133092] [PMID: 18690828] 
[48] 
Aouidate, A.; Ghaleb, A.; Ghamali, M.; Chtita, S.; Ousaa, A.; Choukrad, M.; Sbai, A.; Bouachrine, M.; Lakhlifi, T. Furanone derivatives as new inhibitors of CDC7 kinase: development of structure activity relationship model using 3D QSAR, molecular docking, and in silico ADMET. Struct. Chem.,  2018, 29, 1031-1043.
[http://dx.doi.org/10.1007/s11224-018-1086-4] 
[49] 
Kulkarni, A.A.; Kingsbury, S.R.; Tudzarova, S.; Hong, H-K.; Loddo, M.; Rashid, M.; Rodriguez-Acebes, S.; Prevost, A.T.; Ledermann, J.A.; Stoeber, K.; Williams, G.H. Cdc7 kinase is a predictor of survival and a novel therapeutic target in epithelial ovarian carcinoma. Clin. Cancer Res.,  2009, 15(7), 2417-2425.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1276] [PMID: 19318489] 
[50] 
Choschzick, M.; Lebeau, A.; Marx, A.H.; Tharun, L.; Terracciano, L.; Heilenkötter, U.; Jaenicke, F.; Bokemeyer, C.; Simon, R.; Sauter, G.; Schwarz, J. Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer. Hum. Pathol.,  2010, 41(3), 358-365.
[http://dx.doi.org/10.1016/j.humpath.2009.08.008] [PMID: 19896697] 
[51] 
Huggett, M.T.; Tudzarova, S.; Proctor, I.; Loddo, M.; Keane, M.G.; Stoeber, K.; Williams, G.H.; Pereira, S.P. Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint. Oncotarget,  2016, 7(14), 18495-18507.
[http://dx.doi.org/10.18632/oncotarget.7611] [PMID: 26921250] 
[52] 
Kim, J.M.; Kakusho, N.; Yamada, M.; Kanoh, Y.; Takemoto, N.; Masai, H. Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint. Oncogene,  2008, 27(24), 3475-3482.
[http://dx.doi.org/10.1038/sj.onc.1210994] [PMID: 18084324] 
[53] 
Holder, S.; Lilly, M.; Brown, M.L. Comparative molecular field analysis of flavonoid inhibitors of the PIM-1 kinase. Bioorg. Med. Chem.,  2007, 15(19), 6463-6473.
[http://dx.doi.org/10.1016/j.bmc.2007.06.025] [PMID: 17637507] 
[54] 
Gomes, M.N.; Muratov, E.N.; Pereira, M.; Peixoto, J.C.; Rosseto, L.P.; Cravo, P.V.L.; Andrade, C.H.; Neves, B.J. Chalcone derivatives: promising starting points for drug design. Molecules,  2017, 22E1210
[55] 
Bukhari, S.N.A.; Jasamai, M.; Jantan, I. Synthesis and biological evaluation of chalcone derivatives (mini review). Mini Rev. Med. Chem.,  2012, 12(13), 1394-1403.
[http://dx.doi.org/10.2174/13895575112091394] [PMID: 22876958] 
[56] 
Wu, X-F.; Neumann, H.; Spannenberg, A.; Schulz, T.; Jiao, H.; Beller, M. Development of a general palladium-catalyzed carbonylative Heck reaction of aryl halides. J. Am. Chem. Soc.,  2010, 132(41), 14596-14602.
[http://dx.doi.org/10.1021/ja1059922] [PMID: 20866089] 
[57] 
Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. A convenient synthesis of ethynylarenes and diethynylarenes. Synthesis,  1980, 1980, 627-630.
[http://dx.doi.org/10.1055/s-1980-29145] 
[58] 
Hsieh, C-T.; Ötvös, S.B.; Wu, Y-C.; Mándity, I.M.; Chang, F-R.; Fülöp, F. Highly selective continuous-flow synthesis of potentially bioactive deuterated chalcone derivatives. ChemPlusChem,  2015, 80(5), 859-864.
[http://dx.doi.org/10.1002/cplu.201402426] [PMID: 31973339] 
[59] 
Selepe, M.A.; Van Heerden, F.R. Application of the Suzuki-Miyaura reaction in the synthesis of flavonoids. Molecules,  2013, 18(4), 4739-4765.
[http://dx.doi.org/10.3390/molecules18044739] [PMID: 23609624] 
[60] 
Mahapatra, D.K.; Bharti, S.K.; Asati, V. Chalcone scaffolds as anti-infective agents: structural and molecular target perspectives. Eur. J. Med. Chem.,  2015, 101, 496-524.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.052] [PMID: 26188621] 
[61] 
Rueping, M.; Bootwicha, T.; Baars, H.; Sugiono, E. Continuous-flow hydration-condensation reaction: Synthesis of α,β-unsaturated ketones from alkynes and aldehydes by using a heterogeneous solid acid catalyst. Beilstein J. Org. Chem.,  2011, 7, 1680-1687.
[http://dx.doi.org/10.3762/bjoc.7.198] [PMID: 22238547] 
[62] 
Niu, M.M.; Qin, J.Y.; Tian, C.P.; Yan, X.F.; Dong, F.G.; Cheng, Z.Q.; Fida, G.; Yang, M.; Chen, H.Y.; Gu, Y.Q. Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking. Acta Pharmacol. Sin.,  2014, 35(7), 967-979.
[http://dx.doi.org/10.1038/aps.2014.34] [PMID: 24909516] 
[63] 
Zhou, J.; Li, M.; Chen, N.; Wang, S.; Luo, H-B.; Zhang, Y.; Wu, R. Computational design of a time-dependent histone deacetylase 2 selective inhibitor. ACS Chem. Biol.,  2015, 10(3), 687-692.
[http://dx.doi.org/10.1021/cb500767c] [PMID: 25546141] 
[64] 
Cabrera, N.; Mora, J.R.; Marquez, E.A. Computational molecular modeling of Pin1 inhibition activity of quinazoline, benzophenone, and pyrimidine derivatives. J. Chem.,  2019, 19ID2954250
[http://dx.doi.org/10.1155/2019/2954250] 
[65] 
Lee, T.H.; Pastorino, L.; Lu, K.P. Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Expert Rev. Mol. Med.,  2011, 13e21
[http://dx.doi.org/10.1017/S1462399411001906] [PMID: 21682951] 
[66] 
Yeh, E.S.; Means, A.R. PIN1, the cell cycle and cancer. Nat. Rev. Cancer,  2007, 7(5), 381-388.
[http://dx.doi.org/10.1038/nrc2107] [PMID: 17410202] 
[67] 
Fan, X.; He, H.; Li, J.; Luo, G.; Zheng, Y.; Zhou, J.K.; He, J.; Pu, W.; Zhao, Y. Discovery of 4,6-bis(benzyloxy)-3-phenylbenzofuran as a novel Pin1 inhibitor to suppress hepatocellular carcinoma via upregulating microRNA biogenesis. Bioorg. Med. Chem.,  2019, 27(11), 2235-2244.
[http://dx.doi.org/10.1016/j.bmc.2019.04.028] [PMID: 31027708] 
[68] 
Zhu, L.; Jin, J.; Liu, C.; Zhang, C.; Sun, Y.; Guo, Y.; Fu, D.; Chen, X.; Xu, B. Synthesis and biological evaluation of novel quinazoline-derived human Pin1 inhibitors. Bioorg. Med. Chem.,  2011, 19(9), 2797-2807.
[http://dx.doi.org/10.1016/j.bmc.2011.03.058] [PMID: 21504850] 
[69] 
Liu, C.; Jin, J.; Chen, L.; Zhou, J.; Chen, X.; Fu, D.; Song, H.; Xu, B. Synthesis and biological evaluation of novel human Pin1 inhibitors with benzophenone skeleton. Bioorg. Med. Chem.,  2012, 20(9), 2992-2999.
[http://dx.doi.org/10.1016/j.bmc.2012.03.005] [PMID: 22459212] 
[70] 
Cui, G.; Jin, J.; Chen, H.; Cao, R.; Chen, X.; Xu, B. Synthesis and biological evaluation of pyrimidine derivatives as novel human Pin1 inhibitors. Bioorg. Med. Chem.,  2018, 26(8), 2186-2197.
[http://dx.doi.org/10.1016/j.bmc.2018.03.024] [PMID: 29576270] 
[71] 
García-Jacas, C.R.; Marrero-Ponce, Y.; Acevedo-Martínez, L.; Barigye, S.J.; Valdés-Martiní, J.R.; Contreras-Torres, E. QuBiLS-MIDAS: a parallel free-software for molecular descriptors computation based on multilinear algebraic maps. J. Comput. Chem.,  2014, 35(18), 1395-1409.
[http://dx.doi.org/10.1002/jcc.23640] [PMID: 24889018] 
[72] 
Flores-Sumoza, M.; Alcázar, J.; Márquez, E.; Mora, J.; Lezama, J.; Puello, E. Classical QSAR and docking simulation of 4-pyridone derivatives for their antimalarial activity. Molecules,  2018, 23, 3166.
[73] 
Hall, M.; Frank, E.; Holmes, G.; Pfahringer, B.; Reutemann, P.; Witten, I.H. The WEKA data mining software: An uptade. SIGKDD Explor.,  2009, 11, 10-18.
[http://dx.doi.org/10.1145/1656274.1656278] 
[74] 
Li, C.; Jiang, L. Using locally weighted learning to improve SMOreg for regression. Trends in Artificial Intelligence; Yang, Q; Webb, G., Ed.; PRICAI: Berlin, Heidelberg, 2006, pp. 375-384.
[75] 
Vijayasarathy, S.; Chatterjee, J. Comparison of MLR, isotonic regression and KNN based QSAR models for the prediction of inhibitory activity of HDAC6 inhibitors. Int. J. Life Sci. Biotechnol. Pharma Res.,  2015, 4, 127-131.
[76] 
Svetnik, V.; Liaw, A.; Tong, C.; Culberson, J.C.; Sheridan, R.P.; Feuston, B.P. Random forest: a classification and regression tool for compound classification and QSAR modeling. J. Chem. Inf. Comput. Sci.,  2003, 43(6), 1947-1958.
[http://dx.doi.org/10.1021/ci034160g] [PMID: 14632445] 
[77] 
Lee, K.; Lee, M.; Kim, D. Utilizing random Forest QSAR models with optimized parameters for target identification and its application to target-fishing server. BMC Bioinformatics,  2017, 18(Suppl. 16), 567.
[http://dx.doi.org/10.1186/s12859-017-1960-x] [PMID: 29297315] 
[78] 
Zhao, H.; Cui, G.; Jin, J.; Chen, X.; Xu, B. Synthesis and Pin1 inhibitory activity of thiazole derivatives. Bioorg. Med. Chem.,  2016, 24(22), 5911-5920.
[http://dx.doi.org/10.1016/j.bmc.2016.09.049] [PMID: 27692510] 
[79] 
Singh, S.; Awasthi, M.; Pandey, V.P.; Dwivedi, U.N. Natural products as anticancerous therapeutic molecules with special reference to enzymatic targets topoisomerase, COX, LOX and aromatase. Curr. Protein Pept. Sci.,  2018, 19(3), 238-274.
[http://dx.doi.org/10.2174/1389203718666170106102223] [PMID: 28059043] 
[80] 
Safarzadeh, E.; Sandoghchian Shotorbani, S.; Baradaran, B. Herbal medicine as inducers of apoptosis in cancer treatment. Adv. Pharm. Bull.,  2014, 4(Suppl. 1), 421-427.
[http://dx.doi.org/10.5681/apb.2014.062] [PMID: 25364657] 
[81] 
Wheat, J.; Currie, G. Herbal medicine for cancer patients: An evidence based review. Int. J. Altern. Med.,  2008, 5, 1-20.
[http://dx.doi.org/10.5580/502] 
[82] 
Perrone, M.G.; Scilimati, A.; Simone, L.; Vitale, P. Selective COX-1 inhibition: A therapeutic target to be reconsidered. Curr. Med. Chem.,  2010, 17(32), 3769-3805.
[http://dx.doi.org/10.2174/092986710793205408] [PMID: 20858219] 
[83] 
Ramachandran, C.; Rodriguez, S.; Ramachandran, R.; Raveendran Nair, P.K.; Fonseca, H.; Khatib, Z.; Escalon, E.; Melnick, S.J. Expression profiles of apoptotic genes induced by curcumin in human breast cancer and mammary epithelial cell lines. Anticancer Res.,  2005, 25(5), 3293-3302.
[PMID:  16101141] 
[84] 
Ahamed, T.K.S.; Muraleedharan, K. A ligand-based comparative molecular field analysis (CoMFA) and homology model based molecular docking studies on 3′, 4′-dihydroxyflavones as rat 5-lipoxygenase inhibitors: Design of new inhibitors. Comput. Biol. Chem.,  2017, 71, 188-200.
[http://dx.doi.org/10.1016/j.compbiolchem.2017.08.010] [PMID: 29112937] 
[85] 
Gilbert, N.C.; Bartlett, S.G.; Waight, M.T.; Neau, D.B.; Boeglin, W.E.; Brash, A.R.; Newcomer, M.E. The structure of human 5-lipoxygenase. Science,  2011, 331(6014), 217-219.
[http://dx.doi.org/10.1126/science.1197203] [PMID: 21233389] 
[86] 
Melstrom, L.G.; Bentrem, D.J.; Salabat, M.R.; Kennedy, T.J.; Ding, X.Z.; Strouch, M.; Rao, S.M.; Witt, R.C.; Ternent, C.A.; Talamonti, M.S.; Bell, R.H.; Adrian, T.A. Overexpression of 5-lipoxygenase in colon polyps and cancer and the effect of 5-LOX inhibitors in vitro and in a murine model. Clin. Cancer Res.,  2008, 14(20), 6525-6530.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4631] [PMID: 18927292] 
[87] 
Hennig, R.; Grippo, P.; Ding, X.Z.; Rao, S.M.; Buchler, M.W.; Friess, H.; Talamonti, M.S.; Bell, R.H.; Adrian, T.E. 5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions. Cancer Res.,  2005, 65(14), 6011-6016.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-4090] [PMID: 16024599] 
[88] 
Ghosh, J. Inhibition of arachidonate 5-lipoxygenase triggers prostate cancer cell death through rapid activation of c-Jun N-terminal kinase. Biochem. Biophys. Res. Commun.,  2003, 307(2), 342-349.
[http://dx.doi.org/10.1016/S0006-291X(03)01201-4] [PMID: 12859962] 
[89] 
Chen, Y.; Hu, Y.; Zhang, H.; Peng, C.; Li, S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat. Genet.,  2009, 41(7), 783-792.
[http://dx.doi.org/10.1038/ng.389] [PMID: 19503090] 
[90] 
Horie, T.; Tsukayama, M.; Kourai, H.; Yokoyama, C.; Furukawa, M.; Yoshimoto, T.; Yamamoto, S.; Watanabe-Kohno, S.; Ohata, K. Syntheses of 5,6,7- and 5,7,8-trioxygenated 3′,4′-dihydroxyflavones having alkoxy groups and their inhibitory activities against arachidonate 5-lipoxygenase. J. Med. Chem.,  1986, 29(11), 2256-2262.
[http://dx.doi.org/10.1021/jm00161a021] [PMID: 3783588] 
[91] 
Alam, S.; Khan, F. 3D-QSAR, Docking, ADME/Tox studies on Flavone analogs reveal anticancer activity through Tankyrase inhibition. Sci. Rep.,  2019, 9(1), 5414.
[http://dx.doi.org/10.1038/s41598-019-41984-7] [PMID: 30932078] 
[92] 
Zaleska, M.; Pollock, K.; Collins, I.; Guettler, S.; Pfuhl, M. Solution NMR assignment of the ARC4 domain of human tankyrase 2. Biomol. NMR Assign.,  2019, 13(1), 255-260.
[http://dx.doi.org/10.1007/s12104-019-09887-w] [PMID: 30847846] 
[93] 
Lehtiö, L.; Chi, N.W.; Krauss, S. Tankyrases as drug targets. FEBS J.,  2013, 280(15), 3576-3593.
[http://dx.doi.org/10.1111/febs.12320] [PMID: 23648170] 
[94] 
Riffell, J.L.; Lord, C.J.; Ashworth, A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat. Rev. Drug Discov.,  2012, 11(12), 923-936.
[http://dx.doi.org/10.1038/nrd3868] [PMID: 23197039] 
[95] 
Polakis, P. Drugging Wnt signalling in cancer. EMBO J.,  2012, 31(12), 2737-2746.
[http://dx.doi.org/10.1038/emboj.2012.126] [PMID: 22617421] 
[96] 
Xia, M.; Fang, Y.; Cao, W.; Liang, F.; Pan, S.; Xu, X. Quantitative Structure−Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells. Molecules,  2019, 24(9)E1661
[http://dx.doi.org/10.3390/molecules24091661] [PMID: 31035631] 
[97] 
Gadhe, C.G.; Cho, S.J. Flavonoids: An Emerging Lead in the P-glycoprotein Inhibition. J. Chosun Nat. Sci.,  2016, 12, 2458-2470.
[http://dx.doi.org/10.13160/ricns.2012.5.2.072] 
[98] 
Zhang, S.; Morris, M.E. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J. Pharmacol. Exp. Ther.,  2003, 304(3), 1258-1267.
[http://dx.doi.org/10.1124/jpet.102.044412] [PMID: 12604704] 
[99] 
Ferreira, A.; Rodrigues, M.; Fortuna, A.; Falcão, A.; Alves, G. Flavonoid compounds as reversing agents of the P-glycoprotein-mediated multidrug resistance: An in vitro evaluation with focus on antiepileptic drugs. Food Res. Int.,  2018, 103, 110-120.
[http://dx.doi.org/10.1016/j.foodres.2017.10.010] [PMID: 29389596] 
[100] 
Limtrakul, P.; Khantamat, O.; Pintha, K. Inhibition of P-glycoprotein function and expression by kaempferol and quercetin. J. Chemother.,  2005, 17(1), 86-95.
[http://dx.doi.org/10.1179/joc.2005.17.1.86] [PMID: 15828450] 
[101] 
Ofer, M.; Wolffram, S.; Koggel, A.; Spahn-Langguth, H.; Langguth, P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur. J. Pharm. Sci.,  2005, 25(2-3), 263-271.
[http://dx.doi.org/10.1016/j.ejps.2005.03.001] [PMID: 15911222] 
[102] 
Lies, B.; Martens, S.; Schmidt, S.; Boll, M.; Wenzel, U. Flavone potently stimulates an apical transporter for flavonoids in human intestinal Caco-2 cells. Mol. Nutr. Food Res.,  2012, 56(11), 1627-1635.
[http://dx.doi.org/10.1002/mnfr.201200370] [PMID: 22965487] 
[103] 
Feng, S.L.; Yuan, Z.W.; Yao, X.J.; Ma, W.Z.; Liu, L.; Liu, Z.Q.; Xie, Y. Tangeretin, a citrus pentamethoxyflavone, antagonizes ABCB1-mediated multidrug resistance by inhibiting its transport function. Pharmacol. Res.,  2016, 110, 193-204.
[http://dx.doi.org/10.1016/j.phrs.2016.04.003] [PMID: 27058921] 
[104] 
Di Pietro, A.; Conseil, G.; Pérez-Victoria, J.M.; Dayan, G.; Baubichon-Cortay, H.; Trompier, D.; Steinfels, E.; Jault, J.M.; de Wet, H.; Maitrejean, M.; Comte, G.; Boumendjel, A.; Mariotte, A.M.; Dumontet, C.; McIntosh, D.B.; Goffeau, A.; Castanys, S.; Gamarro, F.; Barron, D. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell. Mol. Life Sci.,  2002, 59(2), 307-322.
[http://dx.doi.org/10.1007/s00018-002-8424-8] [PMID: 11915946] 
[105] 
Rampogu, S.; Park, C.; Son, M.; Baek, A.; Zeb, A.; Lee, G.; Lee, K.W. Modulation of aromatase by natural compounds - A pharmacophore guided molecular modelling simulations. S. Afr. J. Bot.,  2019, 120, 230-240.
[http://dx.doi.org/10.1016/j.sajb.2018.06.019] 
[106] 
Chumsri, S.; Howes, T.; Bao, T.; Sabnis, G.; Brodie, A. Aromatase, aromatase inhibitors, and breast cancer. J. Steroid Biochem. Mol. Biol.,  2011, 125(1-2), 13-22.
[http://dx.doi.org/10.1016/j.jsbmb.2011.02.001] [PMID: 21335088] 
[107] 
Hong, Y.; Chen, S. Aromatase inhibitors: structural features and biochemical characterization. Ann. N. Y. Acad. Sci.,  2006, 1089, 237-251.
[http://dx.doi.org/10.1196/annals.1386.022] [PMID: 17261771] 
[108] 
Mangal, M.; Sagar, P.; Singh, H.; Raghava, G.P.S.; Agarwal, S.M. NPACT: naturally occurring plant-based anti-cancer compound-activity-target database. Nucleic Acids Res.,  2013, 41(Database issue), D1124-D1129.
[http://dx.doi.org/10.1093/nar/gks1047] [PMID: 23203877] 
[109] 
Musa, M.A.; Cooperwood, J.S.; Khan, M.O. A review of coumarin derivatives in pharmacotherapy of breast cancer. Curr. Med. Chem.,  2008, 15(26), 2664-2679.
[http://dx.doi.org/10.2174/092986708786242877] [PMID: 18991629] 
[110] 
Venugopala, K.N.; Rashmi, V.; Odhav, B. Review on natural coumarin lead compounds for their pharmacological activity. BioMed Res. Int.,  2013, 2013963248
[http://dx.doi.org/10.1155/2013/963248] [PMID: 23586066] 
[111] 
Lv, H.N.; Wang, S.; Zeng, K.W.; Li, J.; Guo, X.Y.; Ferreira, D.; Zjawiony, J.K.; Tu, P.F.; Jiang, Y. Anti-inflammatory coumarin and benzocoumarin derivatives from Murraya alata. J. Nat. Prod.,  2015, 78(2), 279-285.
[http://dx.doi.org/10.1021/np500861u] [PMID: 25621853] 
[112] 
Ntie-Kang, F.; Zofou, D.; Babiaka, S.B.; Meudom, R.; Scharfe, M.; Lifongo, L.L.; Mbah, J.A.; Mbaze, L.M.; Sippl, W.; Efange, S.M.N. AfroDb: a select highly potent and diverse natural product library from African medicinal plants. PLoS One,  2013, 8(10)e78085
[http://dx.doi.org/10.1371/journal.pone.0078085] [PMID: 24205103] 
[113] 
Shin, S.Y.; Lee, Y.; Kim, B.S.; Lee, J.; Ahn, S.; Koh, D.; Lim, Y.; Lee, Y.H. Inhibitory effect of synthetic flavone derivatives on pan-aurora kinases: induction of G2/M cell-cycle arrest and apoptosis in HCT116 human colon cancer cells. Int. J. Mol. Sci.,  2018, 19(12) E4086.
[PMID: 30562979] [http://dx.doi.org/10.3390/ijms19124086]] 
[114] 
Franken, N.A.; Rodermond, H.M.; Stap, J.; Haveman, J.; van Bree, C. Clonogenic assay of cells in vitro. Nat. Protoc.,  2006, 1(5), 2315-2319.
[http://dx.doi.org/10.1038/nprot.2006.339] [PMID: 17406473] 
[115] 
Moreira, J.; Ribeiro, D.; Silva, P.M.A.; Nazareth, N.; Monteiro, M.; Palmeira, A.; Saraiva, L.; Pinto, M.; Bousbaa, H.; Cidade, H. New alkoxy flavone derivatives targeting caspases: synthesis and antitumor activity evaluation. Molecules,  2018, 24(1), 129.
[http://dx.doi.org/10.3390/molecules24010129] [PMID: 30602686] 
[116] 
McIlwain, D.R.; Berger, T.; Mak, T.W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol.,  2013, 5(4) a008656.
[http://dx.doi.org/10.1101/cshperspect.a008656] [PMID: 23545416] 
[117] 
Peterson, Q.P.; Hsu, D.C.; Goode, D.R.; Novotny, C.J.; Totten, R.K.; Hergenrother, P.J. Procaspase-3 activation as an anti-cancer strategy: structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3. J. Med. Chem.,  2009, 52(18), 5721-5731.
[http://dx.doi.org/10.1021/jm900722z] [PMID: 19708658] 
[118] 
Worachartcheewan, A.; Nantasenamat, C.; Isarankura-Na-Ayudhya, C.; Prachayasittikul, V. Probing the origins of anticancer activity of chrysin derivatives. Med. Chem. Res.,  2015, 24, 1884-1892.
[http://dx.doi.org/10.1007/s00044-014-1260-1] 
[119] 
Kubo, I.; Kinst-Hori, I.; Chaudhuri, S.K.; Kubo, Y.; Sánchez, Y.; Ogura, T. Flavonols from Heterotheca inuloides: tyrosinase inhibitory activity and structural criteria. Bioorg. Med. Chem.,  2000, 8(7), 1749-1755.
[http://dx.doi.org/10.1016/S0968-0896(00)00102-4] [PMID: 10976523] 
[120] 
Sun, L.P.; Chen, A.L.; Hung, H.C.; Chien, Y.H.; Huang, J.S.; Huang, C.Y.; Chen, Y.W.; Chen, C.N. Chrysin: a histone deacetylase 8 inhibitor with anticancer activity and a suitable candidate for the standardization of Chinese propolis. J. Agric. Food Chem.,  2012, 60(47), 11748-11758.
[http://dx.doi.org/10.1021/jf303261r] [PMID: 23134323] 
[121] 
Mohammed, H.A.; Ba, L.A.; Burkholz, T.; Schumann, E.; Diesel, B.; Zapp, J.; Kiemer, A.K.; Ries, C.; Hartmann, R.W.; Hosny, M.; Jacob, C. Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors. Nat. Prod. Commun.,  2011, 6(1), 31-34.
[http://dx.doi.org/10.1177/1934578X1100600108] [PMID: 21366040] 
[122] 
Zhang, T.; Chen, X.; Qu, L.; Wu, J.; Cui, R.; Zhao, Y. Chrysin and its phosphate ester inhibit cell proliferation and induce apoptosis in Hela cells. Bioorg. Med. Chem.,  2004, 12(23), 6097-6105.
[http://dx.doi.org/10.1016/j.bmc.2004.09.013] [PMID: 15519155] 
[123] 
Woo, K.J.; Jeong, Y.J.; Park, J.W.; Kwon, T.K. Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem. Biophys. Res. Commun.,  2004, 325(4), 1215-1222.
[http://dx.doi.org/10.1016/j.bbrc.2004.09.225] [PMID: 15555556] 
[124] 
Ishihara, M.; Yokote, Y.; Sakagami, H. Quantitative structure-cytotoxicity relationship analysis of coumarin and its derivatives by semiempirical molecular orbital method. Anticancer Res.,  2006, 26(4B), 2883-2886.
[PMID:  16886609] 
[125] 
Ishihara, M.; Kawase, M.; Westman, G.; Samuelsson, K.; Motohashi, N.; Sakagami, H. Quantitative structure-cytotoxicity relationship analysis of phenoxazine derivatives by semiempirical molecular-orbital method. Anticancer Res.,  2007, 27(6B), 4053-4057.
[PMID:  18225570] 
[126] 
Anand, P.; Singh, B.; Singh, N. A review on coumarins as acetylcholinesterase inhibitors for Alzheimer’s disease. Bioorg. Med. Chem.,  2012, 20(3), 1175-1180.
[http://dx.doi.org/10.1016/j.bmc.2011.12.042] [PMID: 22257528] 
[127] 
Tyagi, B.; Mishra, M.K.; Jasra, R.V. Microwave-assisted solvent free synthesis of hydroxyl derivatives of 4-methyl coumarin using nano-crystalline sulfated-zirconia catalyst. J. Mol. Catal. Chem.,  2008, 286, 41-46.
[http://dx.doi.org/10.1016/j.molcata.2008.01.035] 
[128] 
Prashanth, T.; Avin, B.R.V.; Thirusangu, P.; Ranganatha, V.L.; Prabhakar, B.T.; Sharath Chandra, J.N.N.; Khanum, S.A. Synthesis of coumarin analogs appended with quinoline and thiazole moiety and their apoptogenic role against murine ascitic carcinoma. Biomed. Pharmacother.,  2019, 112108707
[http://dx.doi.org/10.1016/j.biopha.2019.108707] [PMID: 30970513] 
[129] 
Kulkarni, M.V.; Kulkarni, G.M.; Lin, C-H.; Sun, C-M. Recent advances in coumarins and 1-azacoumarins as versatile biodynamic agents. Curr. Med. Chem.,  2006, 13(23), 2795-2818.
[http://dx.doi.org/10.2174/092986706778521968] [PMID: 17073630] 
[130] 
Nawrot-Modranka, J.; Nawrot, E.; Graczyk, J. In vivo antitumor, in vitro antibacterial activity and alkylating properties of phosphorohydrazine derivatives of coumarin and chromone. Eur. J. Med. Chem.,  2006, 41(11), 1301-1309.
[http://dx.doi.org/10.1016/j.ejmech.2006.06.004] [PMID: 16904795] 
[131] 
Čačič, M.; Trkovnik, M.; Cacic, F.; Has-Schon, E. Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide. Molecules,  2006, 11(2), 134-147.
[http://dx.doi.org/10.3390/11010134] [PMID: 17962784] 
[132] 
Dhawan, S.; Kerru, N.; Awolade, P.; Singh-Pillay, A.; Saha, S.T.; Kaur, M.; Jonnalagadda, S.B.; Singh, P. Synthesis, computational studies and antiproliferative activities of coumarin-tagged 1,3,4-oxadiazole conjugates against MDA-MB-231 and MCF-7 human breast cancer cells. Bioorg. Med. Chem.,  2018, 26(21), 5612-5623.
[http://dx.doi.org/10.1016/j.bmc.2018.10.006] [PMID: 30360952] 
[133] 
Xue, H.; Lu, X.; Zheng, P.; Liu, L.; Han, C.; Hu, J.; Liu, Z.; Ma, T.; Li, Y.; Wang, L.; Chen, Z.; Liu, G. Highly suppressing wild-type HIV-1 and Y181C mutant HIV-1 strains by 10-chloromethyl-11-demethyl-12-oxo-calanolide A with druggable profile. J. Med. Chem.,  2010, 53(3), 1397-1401.
[http://dx.doi.org/10.1021/jm901653e] [PMID: 20050672] 
[134] 
Mahajan, D.H.; Pannecouque, C.; De Clercq, E.; Chikhalia, K.H. Synthesis and studies of new 2-(coumarin-4-yloxy)-4,6-(substituted)-S-triazine derivatives as potential anti-HIV agents. Arch. Pharm. (Weinheim),  2009, 342(5), 281-290.
[http://dx.doi.org/10.1002/ardp.200800149] [PMID: 19415671] 
[135] 
Al-Majedy, Y.K.; Kadhum, A.A.H.; Al-Amiery, A.A.; Mohamad, A.B. Coumarins: the antimicrobial agents. Sys. Rev. Pharm.,  2017, 8, 62-70.
[http://dx.doi.org/10.5530/srp.2017.1.11] 
[136] 
Shi, Y.; Zhou, C.H. Synthesis and evaluation of a class of new coumarin triazole derivatives as potential antimicrobial agents. Bioorg. Med. Chem. Lett.,  2011, 21(3), 956-960.
[http://dx.doi.org/10.1016/j.bmcl.2010.12.059] [PMID: 21215620] 
[137] 
Piazzi, L.; Cavalli, A.; Colizzi, F.; Belluti, F.; Bartolini, M.; Mancini, F.; Recanatini, M.; Andrisano, V.; Rampa, A. Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. Bioorg. Med. Chem. Lett.,  2008, 18(1), 423-426.
[http://dx.doi.org/10.1016/j.bmcl.2007.09.100] [PMID: 17998161] 
[138] 
Duarte, Y.; Fonseca, A.; Gutiérrez, M.; Adasme-Carreño, F.; Muñoz-Gutierrez, C.; Alzate-Morales, J.; Santana, L.; Uriarte, E.; Álvarez, R.; Matos, M.J. Novel coumarin-quinoline hybrids: design of multarget compounds for Alzheimer’s disease. Chem. Select.,  2019, 4, 551-558.
[http://dx.doi.org/10.1002/slct.201803222] 
[139] 
Fylaktakidou, K.C.; Hadjipavlou-Litina, D.J.; Litinas, K.E.; Nicolaides, D.N. Natural and synthetic coumarin derivatives with anti-inflammatory/antioxidant activities. Curr. Pharm. Des.,  2004, 10(30), 3813-3833.
[http://dx.doi.org/10.2174/1381612043382710] [PMID: 15579073] 
[140] 
Kurt, B.Z.; Kandas, N.O.; Dag, A.; Sonmez, F.; Kucukislamoglu, M. Synthesis and biological evaluation of novel coumarin-chalcone derivatives containing urea moiety as potential anticancer agents. Arab. J. Chem.,  2020, 13(1), 1120-1129.
[http://dx.doi.org/10.1016/j.arabjc.2017.10.001] 
[141] 
Hwu, J.R.; Singha, R.; Hong, S.C.; Chang, Y.H.; Das, A.R.; Vliegen, I.; De Clercq, E.; Neyts, J. Synthesis of new benzimidazole-coumarin conjugates as anti-hepatitis C virus agents. Antiviral Res.,  2008, 77(2), 157-162.
[http://dx.doi.org/10.1016/j.antiviral.2007.09.003] [PMID: 17977606] 
[142] 
Kostova, I.; Bhatia, S.; Grigorov, P.; Balkansky, S.; Parmar, V.S.; Prasad, A.K.; Saso, L. Coumarins as antioxidants. Curr. Med. Chem.,  2011, 18(25), 3929-3951.
[http://dx.doi.org/10.2174/092986711803414395] [PMID: 21824098] 
[143] 
He, H.; Wang, C.; Wang, T.; Zhou, N.; Wen, Z.; Wang, S.; He, L. Synthesis, characterization and biological evaluation of fluorescent biphenyl-1-furocoumarin derivatives. Dyes Pigm.,  2015, 113, 174-180.
[http://dx.doi.org/10.1016/j.dyepig.2014.07.011] 
[144] 
Wang, G.; Lu, M.; Yao, Y.; Wang, J.; Li, J. Esculetin exerts antitumor effect on human gastric cancer cells through IGF-1/PI3K/Akt signaling pathway. Eur. J. Pharmacol.,  2017, 814, 207-215.
[http://dx.doi.org/10.1016/j.ejphar.2017.08.025] [PMID: 28847482] 
[145] 
Xu, X.; Liu, X.; Zhang, Y. Osthole inhibits gastric cancer cell proliferation through regulation of PI3K/AKT. PLoS One,  2018, 13(3)e0193449
[http://dx.doi.org/10.1371/journal.pone.0193449] [PMID: 29590128] 
[146] 
Abdelhafez, O.M.; Amin, K.M.; Batran, R.Z.; Maher, T.J.; Nada, S.A.; Sethumadhavan, S. Synthesis, anticoagulant and PIVKA-II induced by new 4-hydroxycoumarin derivatives. Bioorg. Med. Chem.,  2010, 18(10), 3371-3378.
[http://dx.doi.org/10.1016/j.bmc.2010.04.009] [PMID: 20435480] 
[147] 
Yang, Y-Z.; Ranz, A.; Pan, H.Z.; Zhang, Z-N.; Lin, X-B.; Meshnick, S.R. Daphnetin: a novel antimalarial agent with in vitro and in vivo activity. Am. J. Trop. Med. Hyg.,  1992, 46(1), 15-20.
[http://dx.doi.org/10.4269/ajtmh.1992.46.15] [PMID: 1311154] 
[148] 
Ramesh, B.; Pugalendi, K.V. Antihyperglycemic effect of umbelliferone in streptozotocin-diabetic rats. J. Med. Food,  2006, 9(4), 562-566.
[http://dx.doi.org/10.1089/jmf.2006.9.562] [PMID: 17201645] 
[149] 
Ghate, M.; Kusanur, R.A.; Kulkarni, M.V. Synthesis and in vivo analgesic and anti-inflammatory activity of some bi heterocyclic coumarin derivatives. Eur. J. Med. Chem.,  2005, 40(9), 882-887.
[http://dx.doi.org/10.1016/j.ejmech.2005.03.025] [PMID: 16140424] 
[150] 
Emami, S.; Dadashpour, S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur. J. Med. Chem.,  2015, 102, 611-630.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.033] [PMID: 26318068] 
[151] 
Riveiro, M.E.; De Kimpe, N.; Moglioni, A.; Vázquez, R.; Monczor, F.; Shayo, C.; Davio, C. Coumarins: old compounds with novel promising therapeutic perspectives. Curr. Med. Chem.,  2010, 17(13), 1325-1338.
[http://dx.doi.org/10.2174/092986710790936284] [PMID: 20166938] 
[152] 
Kaur, M.; Kohli, S.; Sandhu, S.; Bansal, Y.; Bansal, G. Coumarin: a promising scaffold for anticancer agents. Anticancer. Agents Med. Chem.,  2015, 15(8), 1032-1048.
[http://dx.doi.org/10.2174/1871520615666150101125503] [PMID: 25553437] 
[153] 
Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr. Med. Chem.,  2005, 12(8), 887-916.
[http://dx.doi.org/10.2174/0929867053507315] [PMID: 15853704] 
[154] 
Yong, J-P.; Lu, C-Z.; Wu, X. Potential anticancer agents. I. Synthesis of isoxazole moiety containing quinazoline derivatives and preliminarily in vitro anticancer activity. Anticancer. Agents Med. Chem.,  2015, 15(1), 131-136.
[http://dx.doi.org/10.2174/1871520614666140812105445] [PMID: 25142319] 
[155] 
Bronikowska, J.; Szliszka, E.; Jaworska, D.; Czuba, Z.P.; Krol, W. The coumarin psoralidin enhances anticancer effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Molecules,  2012, 17(6), 6449-6464.
[http://dx.doi.org/10.3390/molecules17066449] [PMID: 22643355] 
[156] 
Dandriyal, J.; Singla, R.; Kumar, M.; Jaitak, V. Recent developments of C-4 substituted coumarin derivatives as anticancer agents. Eur. J. Med. Chem.,  2016, 119, 141-168.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.087] [PMID: 27155469] 
[157] 
Bheemanapalli, L.N.; Balakumar, C.; Kaki, V.R.; Kaur, R.; Akkinepally, R.R. Pharmacophore based 3D-QSAR study of biphenyl derivatives as nonsteroidal aromatase inhibitors in JEG-3 cell lines. Med. Chem.,  2013, 9(7), 974-984.
[http://dx.doi.org/10.2174/1573406411309070011] [PMID: 22974288] 
[158] 
Niinivehmas, S.P.; Manivannan, E.; Rauhamäki, S.; Huuskonen, J.; Pentikäinen, O.T. Identification of estrogen receptor α ligands with virtual screening techniques. J. Mol. Graph. Model.,  2016, 64, 30-39.
[http://dx.doi.org/10.1016/j.jmgm.2015.12.006] [PMID: 26774287] 
[159] 
Postila, P.A.; Swanson, G.T.; Pentikäinen, O.T. Exploring kainate receptor pharmacology using molecular dynamics simulations. Neuropharmacology,  2010, 58(2), 515-527.
[http://dx.doi.org/10.1016/j.neuropharm.2009.08.019] [PMID: 19737573] 
[160] 
Kumalo, H.M.; Bhakat, S.; Soliman, M.E. Theory and applications of covalent docking in drug discovery: merits and pitfalls. Molecules,  2015, 20(2), 1984-2000.
[http://dx.doi.org/10.3390/molecules20021984] [PMID: 25633330] 
[161] 
Yang, F.; Zhao, N.; Song, J.; Zhu, K.; Jiang, C.S.; Shan, P.; Zhang, H. Design, synthesis and biological evaluation of novel coumarin-based hydroxamate derivatives as histone deacetylase (Hdac) inhibitors with antitumor activities. Molecules,  2019, 24(14)e2569
[http://dx.doi.org/10.3390/molecules24142569] [PMID: 31311163] 
[162] 
Parcha, P.; Sarvagalla, S.; Madhuri, B.; Pajaniradje, S.; Baskaran, V.; Coumar, M.S.; Rajasekaran, B. Identification of natural inhibitors of Bcr-Abl for the treatment of chronic myeloid leukemia. Chem. Biol. Drug Des.,  2017, 90(4), 596-608.
[http://dx.doi.org/10.1111/cbdd.12983] [PMID: 28338290] 
[163] 
Liu, X-H.; Liu, H-F.; Chen, J.; Yang, Y.; Song, B-A.; Bai, L-S.; Liu, J-X.; Zhu, H-L.; Qi, X-B. Synthesis and molecular docking study of novel coumarin derivatives containing 4,5-dihydropyrazole moiety as potential antitumor agents. Bioorg. Med. Chem. Lett.,  2010, 20(19), 5705-5708.
[http://dx.doi.org/10.1016/j.bmcl.2010.08.017] [PMID: 20800480] 
[164] 
Paul, K.; Bindal, S.; Luxami, V. Synthesis of new conjugated coumarin-benzimidazole hybrids and their anticancer activity. Bioorg. Med. Chem. Lett.,  2013, 23(12), 3667-3672.
[http://dx.doi.org/10.1016/j.bmcl.2012.12.071] [PMID: 23642480] 
[165] 
Hao, S-Y.; Feng, S-L.; Wang, X-R.; Wang, Z.; Chen, S-W.; Hui, L. Novel conjugates of podophyllotoxin and coumarin: Synthesis, cytotoxicities, cell cycle arrest, binding CT DNA and inhibition of Topo IIβ. Bioorg. Med. Chem. Lett.,  2019, 29(16), 2129-2135.
[http://dx.doi.org/10.1016/j.bmcl.2019.06.063] [PMID: 31278032] 
[166] 
Debbabi, K.F.; Al-Harbi, S.A.; Al-Saidi, H.M.; Aljuhani, E.H.; Abd El-Gilil, S.M.; Bashandy, M.S. Debbabi, K.F.; Al-Harbi, S.A.; Al-Saidi, H.M.; Aljuhani, E.H.; AbdEl-Gilil, S.M.; Bashandy, M.S. Study of reactivity ofcyanoacetohydrazonoethyl-N-ethyl-N-methyl benzenesulfonamide:preparation of novel anticancer and antimicrobial activeheterocyclic benzenesulfonamide derivatives and their moleculardocking against dihydrofolate reductase. J. Enzyme Inhib. Med.Chem., 2016, 31(super4), 7-19.
[167] 
Khomenko, T.; Zakharenko, A.; Odarchenko, T.; Arabshahi, H.J.; Sannikova, V.; Zakharova, O.; Korchagina, D.; Reynisson, J.; Volcho, K.; Salakhutdinov, N.; Lavrik, O. New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties. Bioorg. Med. Chem.,  2016, 24(21), 5573-5581.
[http://dx.doi.org/10.1016/j.bmc.2016.09.016] [PMID: 27658793] 
[168] 
Abdizadeh, T.; Kalani, M.R.; Abnous, K.; Tayarani-Najaran, Z.; Khashyarmanesh, B.Z.; Abdizadeh, R.; Ghodsi, R.; Hadizadeh, F. Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents. Eur. J. Med. Chem.,  2017, 132, 42-62.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.024] [PMID: 28340413] 
[169] 
Mira, A.; Shimizu, K. In vitro cytotoxic activities and molecular mechanisms of Angelica shikokiana extract and its isolated compounds. Pharmacogn. Mag.,  2015, 11(Suppl. 4), S564-S569.
[http://dx.doi.org/10.4103/0973-1296.172962] [PMID: 27013795] 
[170] 
Beena, T.; Sudha, L.; Nataraj, A.; Balachandran, V.; Kannan, D.; Ponnuswamy, M.N. Synthesis, spectroscopic, dielectric, molecular docking and DFT studies of (3E)-3-(4-methylbenzylidene)-3,4-dihydro-2H-chromen-2-one: an anticancer agent. Chem. Cent. J.,  2017, 11, 6.
[http://dx.doi.org/10.1186/s13065-016-0230-8] [PMID: 28119762] 
[171] 
Alam, M.; Khan, A.; Wadood, A.; Khan, A.; Bashir, S.; Aman, A.; Jan, A.K.; Rauf, A.; Ahmad, B.; Khan, A.R.; Farooq, U. Bioassay-guided isolation of sesquiterpene coumarins from Ferula narthex bioss: A new anticancer agent. Front. Pharmacol.,  2016, 7, 26.
[http://dx.doi.org/10.3389/fphar.2016.00026] [PMID: 26909039] 
[172] 
Zhang, Z.; Gu, L.; Wang, B.; Huang, W.; Zhang, Y.; Ma, Z.; Zeng, S.; Shen, Z. Discovery of novel coumarin derivatives as potent and orally bioavailable BRD4 inhibitors based on scaffold hopping. J. Enzyme Inhib. Med. Chem.,  2019, 34(1), 808-817.
[http://dx.doi.org/10.1080/14756366.2019.1587417] [PMID: 30879350] 
[173] 
Khan, S.; Malla, A.M.; Zafar, A.; Naseem, I. Synthesis of novel coumarin nucleus-based DPA drug-like molecular entity: In vitro DNA/Cu(II) binding, DNA cleavage and pro-oxidant mechanism for anticancer action. PLoS One,  2017, 12(8)e0181783
[http://dx.doi.org/10.1371/journal.pone.0181783] [PMID: 28763458] 
[174] 
Sangwan, R.; Rajan, R.; Mandal, P.K. HDAC as onco target: Reviewing the synthetic approaches with SAR study of their inhibitors. Eur. J. Med. Chem.,  2018, 158, 620-706.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.073] [PMID: 30245394] 
[175] 
Gao, S.; Li, X.; Zang, J.; Xu, W.; Zhang, Y. Preclinical and Clinical studies of Chidamide (CS055/HBI-8000), an orally available subtype-selective HDAC inhibitor for cancer therapy. Anticancer. Agents Med. Chem.,  2017, 17(6), 802-812.
[http://dx.doi.org/10.2174/1871520616666160901150427] [PMID: 27592546] 
[176] 
Jin, P.; Chen, X. Current status of epigenetics and anticancer drug discovery. Anticancer. Agents Med. Chem.,  2016, 16(6), 699-712.
[http://dx.doi.org/10.2174/1871520616666151116124432] [PMID: 26567620] 
[177] 
Neelgundmath, M.; Dinesh, K.R.; Mohan, C.D.; Li, F.; Dai, X.; Siveen, K.S.; Paricharak, S.; Mason, D.J.; Fuchs, J.E.; Sethi, G.; Bender, A.; Rangappa, K.S.; Kotresh, O. Basappa, Novel synthetic coumarins that targets NF-κB in Hepatocellular carcinoma. Bioorg. Med. Chem. Lett.,  2015, 25(4), 893-897.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.065] [PMID: 25592709] 
[178] 
Cai, G.; Yu, W.; Song, D.; Zhang, W.; Guo, J.; Zhu, J.; Ren, Y.; Kong, L. Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors. Eur. J. Med. Chem.,  2019, 174, 236-251.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.024] [PMID: 31048139] 
[179] 
Zhang, Y.; Wang, L.; Deng, Y.; Zhao, P.; Deng, W.; Zhang, J.; Luo, J.; Li, R. Fraxetin suppresses proliferation of non-small-cell lung cancer cells via preventing activation of signal transducer and activator of transcription 3. Tohoku J. Exp. Med.,  2019, 248(1), 3-12.
[http://dx.doi.org/10.1620/tjem.248.3] [PMID: 31080186] 
[180] 
Lee, J.Y.; Talhi, O.; Jang, D.; Cerella, C.; Gaigneaux, A.; Kim, K.W.; Lee, J.W.; Dicato, M.; Bachari, K.; Han, B.W.; Silva, A.M.S.; Orlikova, B.; Diederich, M. Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer. Cancer Lett.,  2018, 416, 94-108.
[http://dx.doi.org/10.1016/j.canlet.2017.12.007] [PMID: 29247826] 
[181] 
Mokale, S.N.; Begum, A.; Sakle, N.S.; Shelke, V.R.; Bhavale, S.A. Design, synthesis and anticancer screening of 3-(3-(substituted phenyl) acryloyl)-2H-chromen-2ones as selective anti-breast cancer agent. Biomed. Pharmacother.,  2017, 89, 966-972.
[http://dx.doi.org/10.1016/j.biopha.2017.02.089] [PMID: 28292025] 
[182] 
Dube, P.N.; Mokale, S.N. Design and synthesis of some novel estrogen receptor modulators as anti-breast cancer agents: In vitro & In vivo screening, docking analysis. Anticancer. Agents Med. Chem.,  2016, 16(11), 1461-1467.
[http://dx.doi.org/10.2174/1871520616666160211124617] [PMID: 26863879] 
[183] 
Dhawan, S.; Kerru, N.; Awolade, P.; Singh-Pillay, A.; Saha, S.T.; Kaur, M.; Jonnalagadda, S.B.; Singh, P. Synthesis, computationalstudies and antiproliferative activities of coumarin-tagged 1,3,4-oxadiazole conjugates against MDA-MB-231 and MCF-7 humanbreast cancer cells 2018, 26, 5612-5623.
[184] 
Dube, P.N.; Waghmare, M.N.; Mokale, S.N. Synthesis, in vitro, and in vivo biological evaluation and molecular docking analysis of novel 3-(3-oxo-substituted phenyl-3-)4-(2-(piperidinyl)ethoxy) phenyl)propyl)-2H-chromen-2-one derivatives as anti-breast cancer agents. Chem. Biol. Drug Des.,  2016, 87(4), 608-617.
[http://dx.doi.org/10.1111/cbdd.12696] [PMID: 26643017] 
[185] 
Niinivehmas, S.; Postila, P.A.; Rauhamäki, S.; Manivannan, E.; Kortet, S.; Ahinko, M.; Huuskonen, P.; Nyberg, N.; Koskimies, P.; Lätti, S.; Multamäki, E.; Juvonen, R.O.; Raunio, H.; Pasanen, M.; Huuskonen, J.; Pentikäinen, O.T. Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives. J. Enzyme Inhib. Med. Chem.,  2018, 33(1), 743-754.
[http://dx.doi.org/10.1080/14756366.2018.1452919] [PMID: 29620427] 
[186] 
Luo, G.; Li, X.; Zhang, G.; Wu, C.; Tang, Z.; Liu, L.; You, Q.; Xiang, H. Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer. Eur. J. Med. Chem.,  2017, 140, 252-273.
[http://dx.doi.org/10.1016/j.ejmech.2017.09.015] [PMID: 28942113] 
[187] 
Tugcu, G.; Sipahi, H.; Aydin, A. Application of a validated QSTR model for repurposing COX-2 inhibitor coumarin derivatives as potential antitumor agents. Curr. Top. Med. Chem.,  2019, 19(13), 1121-1128.
[http://dx.doi.org/10.2174/1568026619666190618143552] [PMID: 31210111] 
[188] 
Thomas, V.; Giles, D.; Basavarajaswamy, G.P.M.; Das, A.K.; Patel, A. Coumarin derivatives as anti-inflammatory and anticancer agents. Anticancer. Agents Med. Chem.,  2017, 17(3), 415-423.
[http://dx.doi.org/10.2174/1871520616666160902094739] [PMID: 27592545] 
[189] 
Elhenawy, A.A.; Al-Harbi, L.M.; El-Gazzar, M.A.; Khowdiary, M.M.; Moustfa, A. Synthesis, molecular properties and comparative docking and QSAR of new 2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetic acid derivatives as possible anticancer agents. Spectrochim. Acta A Mol. Biomol. Spectrosc.,  2019, 218, 248-262.
[http://dx.doi.org/10.1016/j.saa.2019.02.074] [PMID: 31003050] 
[190] 
Lu, X.Y.; Wang, Z.C.; Ren, S.Z.; Shen, F.Q.; Man, R.J.; Zhu, H.L. Coumarin sulfonamides derivatives as potent and selective COX-2 inhibitors with efficacy in suppressing cancer proliferation and metastasis. Bioorg. Med. Chem. Lett.,  2016, 26(15), 3491-3498.
[http://dx.doi.org/10.1016/j.bmcl.2016.06.037] [PMID: 27349331] 
[191] 
Shen, F-Q.; Wang, Z-C.; Wu, S-Y.; Ren, S-Z.; Man, R-J.; Wang, B-Z.; Zhu, H-L. Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX. Bioorg. Med. Chem. Lett.,  2017, 27(16), 3653-3660.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.020] [PMID: 28720504] 
[192] 
Worachartcheewan, A.; Suvannang, N.; Prachayasittikul, S.; Prachayasittikul, V.; Nantasenamat, C. Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking. EXCLI J.,  2014, 13, 1259-1274.
[PMID:  26417339] 
[193] 
Gould, N.S.; Pooladanda, V.; Mahammad, S.G.; Jekkula, P.; Gatreddi, S.; Qureshi, I.A.; Alvala, R.; Godugu, C.; Alvala, M. Synthesis and biological evaluation of morpholines linked coumarin-triazole hybrids as anticancer agents. Chem. Biol. Drug Des.,  2019, 94(5), 1919-1929.
[http://dx.doi.org/10.1111/cbdd.13578] 
[194] 
Han, H-W.; Zheng, C-S.; Chu, S-J.; Sun, W-X.; Han, L-J.; Yang, R-W.; Qi, J-L.; Lu, G-H.; Wang, X-M.; Yang, Y-H. The evaluation of potent antitumor activities of shikonin coumarin-carboxylic acid, PMMB232 through HIF-1α-mediated apoptosis. Biomed. Pharmacother.,  2018, 97, 656-666.
[http://dx.doi.org/10.1016/j.biopha.2017.10.159] [PMID: 29101810] 
[195] 
Rahman, M.M. Evaluation of hymenodictyon excelsum Phytochemical’s therapeutic value against prostate cancer by molecular docking study. Jundishapur J. Nat. Pharm. Prod.,  2015, 10(1) e18216.
[PMID: 25866716] [http://dx.doi.org/10.17795/jjnpp-18216]] 
[196] 
Mohamed, T.K.; Batran, R.Z.; Elseginy, S.A.; Ali, M.M.; Mahmoud, A.E. Synthesis, anticancer effect and molecular modeling of new thiazolylpyrazolyl coumarin derivatives targeting VEGFR-2 kinase and inducing cell cycle arrest and apoptosis. Bioorg. Chem.,  2019, 85, 253-273.
[http://dx.doi.org/10.1016/j.bioorg.2018.12.040] [PMID: 30641320] 
[197] 
Yu, H.; Hou, Z.; Yang, X.; Mou, Y.; Guo, C. Design, synthesis, and mechanism of dihydroartemisinin-coumarin hybrids as potential anti-neuroinflammatory agents. Molecules,  2019, 24(9), 1672-1691.
[http://dx.doi.org/10.3390/molecules24091672] [PMID: 31035404] 
[198] 
Lee, S-Y.; Lim, T-G.; Chen, H.; Jung, S.K.; Lee, H.J.; Lee, M-H.; Kim, D.J.; Shin, A.; Lee, K.W.; Bode, A.M.; Surh, Y-J.; Dong, Z. Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin. Cancer Prev. Res. (Phila.),  2013, 6(12), 1356-1364.
[http://dx.doi.org/10.1158/1940-6207.CAPR-13-0241] [PMID: 24104353] 
[199] 
Lakshmi Ranganatha, V.; Zameer, F.; Meghashri, S.; Rekha, N.D.; Girish, V.; Gurupadaswamy, H.D.; Khanum, S.A. Design, synthesis, and anticancer properties of novel benzophenone-conjugated coumarin analogs. Arch. Pharm. (Weinheim),  2013, 346(12), 901-911.
[http://dx.doi.org/10.1002/ardp.201300298] [PMID: 24170414] 
[200] 
Abroun, S.; Saki, N.; Ahmadvand, M.; Asghari, F.; Salari, F.; Rahim, F. STATs: an old story, yet mesmerizing. Cell J.,  2015, 17(3), 395-411.
[http://dx.doi.org/10.22074/cellj.2015.1] [PMID: 26464811] 
[201] 
Laudisi, F.; Cherubini, F.; Monteleone, G.; Stolfi, C. STAT interactions as potential therapeutic targets for cancer treatment. Int. J. Mol. Sci.,  2018, 19(6)e1787
[http://dx.doi.org/10.3390/ijms19061787] [PMID: 29914167] 
[202] 
Channar, P.A.; Irum, H.; Mahmood, A.; Shabir, G.; Zaib, S.; Saeed, A.; Ashraf, Z.; Larik, F.A.; Lecka, J.; Sévigny, J.; Iqbal, J. Design, synthesis and biological evaluation of trinary benzocoumarin-thiazoles-azomethines derivatives as effective and selective inhibitors of alkaline phosphatase. Bioorg. Chem.,  2019, 91103137
[http://dx.doi.org/10.1016/j.bioorg.2019.103137] [PMID: 31400554] 
[203] 
Ibrar, A.; Zaib, S.; Jabeen, F.; Iqbal, J.; Saeed, A. Unraveling the alkaline phasphatase inhibition, anticancer, and antileishmanial potential of coumarin-triazolothiadiazine hybrids: design, synthesis, and molecular docking analysis. Arch. Pharm. (Weinheim),  2016, 349(7), 553-565.
[http://dx.doi.org/10.1002/ardp.201500392] [PMID: 27214743] 
[204] 
Cavalcanti, E.B.V.S.; Félix, M.B.; Scotti, L.; Scotti, M.T. Virtual screening of natural products to select compounds with potential anticancer activity. Anticancer. Agents Med. Chem.,  2019, 19(2), 154-171.
[http://dx.doi.org/10.2174/1871520618666181119110934] [PMID: 30451120] 
[205] 
Abd El-Karim, S.S.; Syam, Y.M.; El Kerdawy, A.M.; Abdelghany, T.M. New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies. Bioorg. Chem.,  2019, 86, 80-96.
[http://dx.doi.org/10.1016/j.bioorg.2019.01.026] [PMID: 30685646] 
[206] 
Morsy, S.A.; Farahat, A.A.; Nasr, M.N.A.; Tantawy, A.S. Synthesis, molecular modeling and anticancer activity of new coumarin containing compounds. Saudi Pharm. J.,  2017, 25(6), 873-883.
[http://dx.doi.org/10.1016/j.jsps.2017.02.003] [PMID: 28951673] 
[207] 
Batran, R.Z.; Dawood, D.H.; El-Seginy, S.A.; Ali, M.M.; Maher, T.J.; Gugnani, K.S.; Rondon-Ortiz, A.N. New coumarin derivatives as anti-breast and anti-cervical cancer agents targeting VEGFR-2 and p38α MAPK. Arch. Pharm. (Weinheim),  2017, 350(9)e1700064
[http://dx.doi.org/10.1002/ardp.201700064] [PMID: 28787092] 
[208] 
Huang, X.Y.; Shan, Z.J.; Zhai, H.L.; Su, L.; Zhang, X.Y. Study on the anticancer activity of coumarin derivatives by molecular modeling. Chem. Biol. Drug Des.,  2011, 78(4), 651-658.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01195.x] [PMID: 21791009] 
[209] 
Mah, S.; Jang, J.; Song, D.; Shin, Y.; Latif, M.; Jung, Y.; Hong, S. Discovery of fluorescent 3-heteroarylcoumarin derivatives as novel inhibitors of anaplastic lymphoma kinase. Org. Biomol. Chem.,  2018, 17(1), 186-194.
[http://dx.doi.org/10.1039/C8OB02874E] [PMID: 30534706] 
[210] 
Parthasarathy, K.; Praveen, C.; Jeyaveeran, J.C.; Prince, A.A. Gold catalyzed double condensation reaction: Synthesis, antimicrobial and cytotoxicity of spirooxindole derivatives. Bioorg. Med. Chem. Lett.,  2016, 26(17), 4310-4317.
[http://dx.doi.org/10.1016/j.bmcl.2016.07.036] [PMID: 27476145] 
[211] 
Vaarla, K.; Kesharwani, R.K.; Santosh, K.; Vedula, R.R.; Kotamraju, S.; Toopurani, M.K. Synthesis, biological activity evaluation and molecular docking studies of novel coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes. Bioorg. Med. Chem. Lett.,  2015, 25(24), 5797-5803.
[http://dx.doi.org/10.1016/j.bmcl.2015.10.042] [PMID: 26542964] 
[212] 
Liu, J.; Pham, P.T.; Skripnikova, E.V.; Zheng, S.; Lovings, L.J.; Wang, Y.; Goyal, N.; Bellow, S.M.; Mensah, L.M.; Chatters, A.J.; Bratton, M.R.; Wiese, T.E.; Zhao, M.; Wang, G.; Foroozesh, M. A ligand-based drug design. Discovery of 4-trifluoromethyl-7,8-pyranocoumarin as a selective inhibitor of human cytochrome P450 1A2. J. Med. Chem.,  2015, 58(16), 6481-6493.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00494] [PMID: 26222195] 
[213] 
Nolan, K.A.; Zhao, H.; Faulder, P.F.; Frenkel, A.D.; Timson, D.J.; Siegel, D.; Ross, D.; Burke, T.R., Jr; Stratford, I.J.; Bryce, R.A. Coumarin-based inhibitors of human NAD(P)H:quinone oxidoreductase-1. Identification, structure-activity, off-target effects and in vitro human pancreatic cancer toxicity. J. Med. Chem.,  2007, 50(25), 6316-6325.
[http://dx.doi.org/10.1021/jm070472p] [PMID: 17999461] 
[214] 
Nolan, K.A.; Doncaster, J.R.; Dunstan, M.S.; Scott, K.A.; Frenkel, A.D.; Siegel, D.; Ross, D.; Barnes, J.; Levy, C.; Leys, D.; Whitehead, R.C.; Stratford, I.J.; Bryce, R.A. Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: quinone oxidoreductase-1 (NQO1). J. Med. Chem.,  2009, 52(22), 7142-7156.
[http://dx.doi.org/10.1021/jm9011609] [PMID: 19877692] 
[215] 
Kawai, J.; Ota, M.; Ohki, H.; Toki, T.; Suzuki, M.; Shimada, T.; Matsui, S.; Inoue, H.; Sugihara, C.; Matsuhashi, N.; Matsui, Y.; Takaishi, S.; Nakayama, K. Structure-based design and synthesis of an isozyme-selective MTHFD2 inhibitor with a tricyclic coumarin scaffold. ACS Med. Chem. Lett.,  2019, 10(6), 893-898.
[http://dx.doi.org/10.1021/acsmedchemlett.9b00069] [PMID: 31223444] 
[216] 
Daśko, M.; Przybyłowska, M.; Rachon, J.; Masłyk, M.; Kubiński, K.; Misiak, M.; Składanowski, A.; Demkowicz, S. Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors. Eur. J. Med. Chem.,  2017, 128, 79-87.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.028] [PMID: 28152429] 
[217] 
Daśko, M.; Demkowicz, S.; Biernacki, K.; Harrous, A.; Rachon, J.; Kozak, W.; Martyna, A.; Masłyk, M.; Kubiński, K.; Boguszewska-Czubara, A. Novel steroid sulfatase inhibitors based on N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates. Drug Dev. Res.,  2019, 80(6), 857-866.
[http://dx.doi.org/10.1002/ddr.21569] [PMID: 31301181] 
[218] 
Ferlay, J.; Shin, H.R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer,  2010, 127(12), 2893-2917.
[http://dx.doi.org/10.1002/ijc.25516] [PMID: 21351269] 
[219] 
Jin, X.; Mo, Q.; Zhang, Y.; Gao, Y.; Wu, Y.; Li, J.; Hao, X.; Ma, D.; Gao, Q.; Chen, P. The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer. Cancer Biol. Ther.,  2016, 17(5), 566-576.
[http://dx.doi.org/10.1080/15384047.2016.1177676] [PMID: 27082306] 
[220] 
Taheri, S.; Nazifi, M.; Mansourian, M.; Hosseinzadeh, L.; Shokoohinia, Y. Ugi efficient synthesis, biological evaluation and molecular docking of coumarin-quinoline hybrids as apoptotic agents through mitochondria-related pathways. Bioorg. Chem.,  2019, 91103147
[http://dx.doi.org/10.1016/j.bioorg.2019.103147] [PMID: 31377390] 
[221] 
Kamath, P.R.; Sunil, D.; Ajees, A.A.; Pai, K.S.R.; Biswas, S.N. ′-((2-(6-bromo-2-oxo-2H-chromen-3-yl)-1H-indol-3-yl)methylene)benzohydrazide as a probable Bcl-2/Bcl-xL inhibitor with apoptotic and anti-metastatic potential. Eur. J. Med. Chem.,  2016, 120, 134-147.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.010] [PMID: 27187865] 
[222] 
Kamath, P.R.; Sunil, D.; Joseph, M.M.; Abdul Salam, A.A. T T, S. Indole-coumarin-thiadiazole hybrids: An appraisal of their MCF-7 cell growth inhibition, apoptotic, antimetastatic and computational Bcl-2 binding potential. Eur. J. Med. Chem.,  2017, 136, 442-451.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.032] [PMID: 28525842] 
[223] 
Perumalsamy, H.; Sankarapandian, K.; Veerappan, K.; Natarajan, S.; Kandaswamy, N.; Thangavelu, L.; Balusamy, S.R. In silico and in vitro analysis of coumarin derivative induced anticancer effects by undergoing intrinsic pathway mediated apoptosis in human stomach cancer. Phytomedicine,  2018, 46, 119-130.
[http://dx.doi.org/10.1016/j.phymed.2018.04.021] [PMID: 30097112] 
[224] 
Chuang, J-Y.; Huang, Y-F.; Lu, H-F.; Ho, H-C.; Yang, J-S.; Li, T-M.; Chang, N-W.; Chung, J-G. Coumarin induces cell cycle arrest and apoptosis in human cervical cancer HeLa cells through a mitochondria- and caspase-3 dependent mechanism and NF-kappaB down-regulation. In Vivo,  2007, 21(6), 1003-1009.
[PMID:  18210747] 
[225] 
Santhosh Kumar, S.; Sajeli Begum, A.; Hira, K.; Niazi, S.; Prashantha Kumar, B.R.; Araya, H.; Fujimoto, Y. Structure-based design and synthesis of new 4-methylcoumarin-based lignans as pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) inhibitors. Bioorg. Chem.,  2019, 89102991
[http://dx.doi.org/10.1016/j.bioorg.2019.102991] [PMID: 31153100] 
[226] 
Wang, Z-C.; Qin, Y-J.; Wang, P-F.; Yang, Y-A.; Wen, Q.; Zhang, X.; Qiu, H-Y.; Duan, Y-T.; Wang, Y-T.; Sang, Y-L.; Zhu, H-L. Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis. Eur. J. Med. Chem.,  2013, 66, 1-11.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.035] [PMID: 23777898] 
[227] 
Buran, K.; Bua, S.; Poli, G.; Önen Bayram, F.E.; Tuccinardi, T.; Supuran, C.T. Novel 8-substituted coumarins that selectively inhibit human carbonic anhydrase IX and XII. Int. J. Mol. Sci.,  2019, 20(5), 1208-1223.
[http://dx.doi.org/10.3390/ijms20051208] [PMID: 30857344] 
[228] 
An, R.; Hou, Z.; Li, J-T.; Yu, H-N.; Mou, Y-H.; Guo, C. Design, synthesis and biological evaluation of novel 4-substituted coumarin derivatives as antitumor agents. Molecules,  2018, 23(9), 2281-2292.
[http://dx.doi.org/10.3390/molecules23092281] [PMID: 30200625] 
[229] 
Rajabi, M.; Hossaini, Z.; Khalilzadeh, M.A.; Datta, S.; Halder, M.; Mousa, S.A. Synthesis of a new class of furo[3,2-c]coumarins and its anticancer activity. J. Photochem. Photobiol. B,  2015, 148, 66-72.
[http://dx.doi.org/10.1016/j.jphotobiol.2015.03.027] [PMID: 25889947] 
[230] 
Pingaew, R.; Saekee, A.; Mandi, P.; Nantasenamat, C.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V. Synthesis, biological evaluation and molecular docking of novel chalcone-coumarin hybrids as anticancer and antimalarial agents. Eur. J. Med. Chem.,  2014, 85, 65-76.
[http://dx.doi.org/10.1016/j.ejmech.2014.07.087] [PMID: 25078311] 
[231] 
Yan, W.; Yang, T.; Yang, J.; Wang, T.; Yu, Y.; Wang, Y.; Chen, Q.; Bai, P.; Li, D.; Ye, H.; Qiu, Q.; Zhou, Y.; Hu, Y.; Yang, S.; Wei, Y.; Li, W.; Chen, L. SKLB060 reversibly binds to colchicines site of tubulin and possesses efficacy in multidrug-resistant cell lines. Cell. Physiol. Biochem.,  2018, 47(2), 489-504.
[http://dx.doi.org/10.1159/000489983] [PMID: 29794416] 
[232] 
Batran, R.Z.; Kassem, A.F.; Abbas, E.M.H.; Elseginy, S.A.; Mounier, M.M. Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells. Bioorg. Med. Chem.,  2018, 26(12), 3474-3490.
[http://dx.doi.org/10.1016/j.bmc.2018.05.022] [PMID: 29793751] 
[233] 
Singh, H.; Singh, J.V.; Gupta, M.K.; Saxena, A.K.; Sharma, S.; Nepali, K.; Bedi, P.M.S. Triazole tethered isatin-coumarin based molecular hybrids as novel antitubulin agents: Design, synthesis, biological investigation and docking studies. Bioorg. Med. Chem. Lett.,  2017, 27(17), 3974-3979.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.069] [PMID: 28797799] 
[234] 
Soualmia, F.; Bosc, E.; Amiri, S.A.; Stratmann, D.; Magdolen, V.; Darmoul, D.; Reboud-Ravaux, M.; El Amri, C. Insights into the activity control of the kallikrein-related peptidase 6: small-molecule modulators and allosterism. Biol. Chem.,  2018, 399(9), 1073-1078.
[http://dx.doi.org/10.1515/hsz-2017-0336] [PMID: 29641412] 
[235] 
Singh, M.; Chaudhry, P.; Fabi, F.; Asselin, E. Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance. BMC Cancer,  2013, 13, 233.
[http://dx.doi.org/10.1186/1471-2407-13-233] [PMID: 23663432] 
[236] 
Wang, Y.; Wu, C.; Zhang, Q.; Shan, Y.; Gu, W.; Wang, S. Design, synthesis and biological evaluation of novel β-pinene-based thiazole derivatives as potential anticancer agents via mitochondrial-mediated apoptosis pathway. Bioorg. Chem.,  2019, 84, 468-477.
[http://dx.doi.org/10.1016/j.bioorg.2018.12.010] [PMID: 30576910] 
[237] 
Jordan, M.A.; Kamath, K. How do microtubule-targeted drugs work? An overview. Curr. Cancer Drug Targets,  2007, 7(8), 730-742.
[http://dx.doi.org/10.2174/156800907783220417] [PMID: 18220533] 
[238] 
Kim, L.J.; Chamberlain, M.C.; Zhu, J.; Raizer, J.J.; Grimm, S.A.; Phuphanich, S.; Fadul, C.E.; Rosenfeld, S.; Balch, A.H.; Pope, C.C.; Brulotte, M.; Beelen, A.A.P.; Recht, L.D. Phase II study of verubulin (MPC-6827) for the treatment of subjects with recurrent glioblastoma naïve to treatment with bevacizumab. J. Clin. Oncol.,  2011, 29, 2088.
[http://dx.doi.org/10.1200/jco.2011.29.15_suppl.2088] 
[239] 
Tripathi, A.; Misra, K. Inhibition of P-glycoprotein mediated efflux of paclitaxel by coumarin derivatives in cancer stem cells: An in silico approach. Comb. Chem. High Throughput Screen.,  2016, 19(6), 497-506.
[http://dx.doi.org/10.2174/1386207319666160517115158] [PMID: 27185570] 
[240] 
Robert, M.F.; Wink, M. Alkaloids : Biochemistry, Ecology, and Medicinal Applications, 1st ed; Springer US: Boston, 1998. 
[241] 
Manske, R.H.F. The Alkaloids. Chemistry and Physiology, 1st ed; Academic Press: New York, 1965. 
[242] 
Plemenkov, V.V. Introduction to the Chemistry of Natural Compounds; MPIK: Kazan, 2001. 
[243] 
Gournelis, D.C.; Laskaris, G.G.; Verpoorte, R. Cyclopeptide alkaloids. Nat. Prod. Rep.,  1997, 14(1), 75-82.
[http://dx.doi.org/10.1039/np9971400075] [PMID: 9121730] 
[244] 
Aniszewski, T. Alkaloids – secrets of life, 1st ed; Elsevier: Amsterdam, 2007. 
[245] 
Shityakov, S.; Bigdelian, E.; Hussein, A.A.; Hussain, M.B.; Tripathi, Y.C.; Khan, M.U.; Shariati, M.A. Phytochemical and pharmacological attributes of piperine: A bioactive ingredient of black pepper. Eur. J. Med. Chem.,  2019, 176, 149-161.
[http://dx.doi.org/10.1016/j.ejmech.2019.04.002] [PMID: 31103896] 
[246] 
Parrino, B.; Schillaci, D.; Carnevale, I.; Giovannetti, E.; Diana, P.; Cirrincione, G.; Cascioferro, S. Synthetic small molecules as anti-biofilm agents in the struggle against antibiotic resistance. Eur. J. Med. Chem.,  2019, 161, 154-178.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.036] [PMID: 30347328] 
[247] 
Deng, Y.; Wu, T.; Zhai, S-Q.; Li, C-H. Recent progress on anti-Toxoplasma drugs discovery: Design, synthesis and screening. Eur. J. Med. Chem.,  2019, 183111711
[http://dx.doi.org/10.1016/j.ejmech.2019.111711] [PMID: 31585276] 
[248] 
Hou, X-M.; Wang, C-Y.; Gerwick, W.H.; Shao, C-L. Marine natural products as potential anti-tubercular agents. Eur. J. Med. Chem.,  2019, 165, 273-292.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.026] [PMID: 30685527] 
[249] 
Yang, T.; Chen, Y-Y.; Liu, J-R.; Zhao, H.; Vaziri, N.D.; Guo, Y.; Zhao, Y.Y. Natural products against renin-angiotensin system for antifibrosis therapy. Eur. J. Med. Chem.,  2019, 179, 623-633.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.091] [PMID: 31279295] 
[250] 
Yin, B.; Fang, D-M.; Zhou, X-L.; Gao, F. Natural products as important tyrosine kinase inhibitors. Eur. J. Med. Chem.,  2019, 182111664
[http://dx.doi.org/10.1016/j.ejmech.2019.111664] [PMID: 31494475] 
[251] 
Kishore, N.; Kumar, P.; Shanker, K.; Verma, A.K. Human disorders associated with inflammation and the evolving role of natural products to overcome. Eur. J. Med. Chem.,  2019, 179, 272-309.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.034] [PMID: 31255927] 
[252] 
Turnaturi, R.; Chiechio, S.; Salerno, L.; Rescifina, A.; Pittalà, V.; Cantarella, G.; Tomarchio, E.; Parenti, C.; Pasquinucci, L. Progress in the development of more effective and safer analgesics for pain management. Eur. J. Med. Chem.,  2019, 183111701
[http://dx.doi.org/10.1016/j.ejmech.2019.111701] [PMID: 31550662] 
[253] 
Wan, Y.; Li, Y.; Yan, C.; Yan, M.; Tang, Z. Indole: A privileged scaffold for the design of anti-cancer agents. Eur. J. Med. Chem.,  2019, 183111691
[http://dx.doi.org/10.1016/j.ejmech.2019.111691] [PMID: 31536895] 
[254] 
Kumar, A.; Jaitak, V. Natural products as multidrug resistance modulators in cancer. Eur. J. Med. Chem.,  2019, 176, 268-291.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.027] [PMID: 31103904] 
[255] 
Yang, X.; Gao, J.; Guo, J.; Zhao, Z.; Zhang, S-L.; He, Y. Anti-lung cancer activity and inhibitory mechanisms of a novel Calothrixin A derivative. Life Sci.,  2019, 219, 20-30.
[http://dx.doi.org/10.1016/j.lfs.2018.12.052] [PMID: 30605652] 
[256] 
Kumari, S.; Kaladhar, D.S.V.G.K.; Solmon, K.S.; Malla, R.R.; Kishore, G. Anti-proliferative and metastatic protease inhibitory activities of protoberberines : An in silico and in vitro approaches. Process Biochem.,  2013, 48, 1565-1571.
[http://dx.doi.org/10.1016/j.procbio.2013.06.027] 
[257] 
Jabbarzadeh Kaboli, P.; Leong, M.P-Y.; Ismail, P.; Ling, K-H. Antitumor effects of berberine against EGFR, ERK1/2, P38 and AKT in MDA-MB231 and MCF-7 breast cancer cells using molecular modelling and in vitro study. Pharmacol. Rep.,  2019, 71(1), 13-23.
[http://dx.doi.org/10.1016/j.pharep.2018.07.005] [PMID: 30343043] 
[258] 
Abdelfatah, S.A.; Efferth, T. Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells. Phytomedicine,  2015, 22(2), 308-318.
[http://dx.doi.org/10.1016/j.phymed.2015.01.002] [PMID: 25765838] 
[259] 
Saha, S.K.; Khuda-Bukhsh, A.R. Berberine alters epigenetic modifications, disrupts microtubule network, and modulates HPV-18 E6-E7 oncoproteins by targeting p53 in cervical cancer cell HeLa: a mechanistic study including molecular docking. Eur. J. Pharmacol.,  2014, 744, 132-146.
[http://dx.doi.org/10.1016/j.ejphar.2014.09.048] [PMID: 25448308] 
[260] 
Tyagi, G.; Charak, S.; Mehrotra, R. Binding of an indole alkaloid, vinblastine to double stranded DNA: a spectroscopic insight in to nature and strength of interaction. J. Photochem. Photobiol. B,  2012, 108, 48-52.
[http://dx.doi.org/10.1016/j.jphotobiol.2011.12.009] [PMID: 22280878] 
[261] 
Pandya, P.; Agarwal, L.K.; Gupta, N.; Pal, S. Molecular recognition pattern of cytotoxic alkaloid vinblastine with multiple targets. J. Mol. Graph. Model.,  2014, 54, 1-9.
[http://dx.doi.org/10.1016/j.jmgm.2014.09.001] [PMID: 25241127] 
[262] 
Sai Murali, R.S.; Sai Siddhardha, R.S.; Rajesh Babu, D.; Venketesh, S.; Basavaraju, R.; Nageswara Rao, G. Interaction of vasicine with calf thymus DNA: Molecular docking, spectroscopic and differential scanning calorimetric insights. Spectrochim. Acta A Mol. Biomol. Spectrosc.,  2017, 180, 217-223.
[http://dx.doi.org/10.1016/j.saa.2017.03.016] [PMID: 28315618] 
[263] 
Sharma, S.; Yadav, M.; Gupta, S.P.; Pandav, K.; Kumar, S. Spectroscopic and structural studies on the interaction of an anticancer β-carboline alkaloid, harmine with GC and AT specific DNA oligonucleotides. Chem. Biol. Interact.,  2016, 260, 256-262.
[http://dx.doi.org/10.1016/j.cbi.2016.08.025] [PMID: 27590873] 
[264] 
Islam, M.M.; Pandya, P.; Chowdhury, S.R.; Kumar, S.; Kumar, G.S. Binding of DNA-binding alkaloids berberine and palmatine to tRNA and comparison to ethidium : Spectroscopic and molecular modeling studies. J. Mol. Struct.,  2008, 891, 498-507.
[http://dx.doi.org/10.1016/j.molstruc.2008.04.043] 
[265] 
Basu, A.; Kumar, G.S. Nucleic acids binding strategies of small molecules: Lessons from alkaloids. Biochim. Biophys. Acta, Gen. Subj.,  2018, 1862(9), 1995-2016.
[http://dx.doi.org/10.1016/j.bbagen.2018.06.010] [PMID: 29908208] 
[266] 
Wang, N.; Zhang, J.; Li, Q.; Xu, H.; Chen, G.; Li, Z.; Liu, D.; Yang, X. Discovery of potent indoleamine 2,3-dioxygenase (IDO) inhibitor from alkaloids in Picrasma quassioides by virtual screening and in vitro evaluation. Fitoterapia,  2019, 133, 137-145.
[http://dx.doi.org/10.1016/j.fitote.2019.01.005] [PMID: 30654128] 
[267] 
Shawky, E.; Takla, S.S.; Hammoda, H.M.; Darwish, F.A. Evaluation of the influence of green extraction solvents on the cytotoxic activities of Crinum (Amaryllidaeae) alkaloid extracts using in-vitro-in-silico approach. J. Ethnopharmacol.,  2018, 227, 139-149.
[http://dx.doi.org/10.1016/j.jep.2018.08.040] [PMID: 30179713] 
[268] 
Subhani, S.; Jayaraman, A.; Jamil, K. Homology modelling and molecular docking of MDR1 with chemotherapeutic agents in non-small cell lung cancer. Biomed. Pharmacother.,  2015, 71, 37-45.
[http://dx.doi.org/10.1016/j.biopha.2015.02.009] [PMID: 25960213] 
[269] 
Thiyagarajan, V.; Lin, S.H.; Chang, Y.C.; Weng, C.F. Identification of novel FAK and S6K1 dual inhibitors from natural compounds via ADMET screening and molecular docking. Biomed. Pharmacother.,  2016, 80, 52-62.
[http://dx.doi.org/10.1016/j.biopha.2016.02.020] [PMID: 27133039] 
[270] 
Mohan, L.; Raghav, D.; Ashraf, S.M.; Sebastian, J.; Rathinasamy, K. Indirubin, a bis-indole alkaloid binds to tubulin and exhibits antimitotic activity against HeLa cells in synergism with vinblastine. Biomed. Pharmacother.,  2018, 105, 506-517.
[http://dx.doi.org/10.1016/j.biopha.2018.05.127] [PMID: 29883946] 
[271] 
Zou, P.; Xia, Y.; Ji, J.; Chen, W.; Zhang, J.; Chen, X.; Rajamanickam, V.; Chen, G.; Wang, Z.; Chen, L.; Wang, Y.; Yang, S.; Liang, G. Piperlongumine as a direct TrxR1 inhibitor with suppressive activity against gastric cancer. Cancer Lett.,  2016, 375(1), 114-126.
[http://dx.doi.org/10.1016/j.canlet.2016.02.058] [PMID: 26963494] 
Rights & Permissions Print Cite
Article Metrics
55
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568026620666200607191838	Print ISSN 1568-0266
Publisher Name Bentham Science Publisher	Online ISSN 1873-4294
Current Topics in Medicinal Chemistry

Computer-Aided Drug Design Applied to Secondary Metabolites as Anticancer Agents

Abstract Play Pause

Graphical Abstract

Related Journals

Related Books

Related Articles

Abstract
