Cytotoxicity, Molecular Docking, ADMET and DFT Analysis of Alkaloids
from the Roots and Fruits of Vepris dainelli

Mathewos      Anza; Milkyas      Endale; Luz      Cardona; Diego      Cortes; Nuria      Cabedo; Rajalakshmanan      Eswaramoorthy; Belen      Abarca; Inés      Domingo-Ortí; Martina      Palomino-Schätzlein

Abstract

Background: Vepris dainelli (Rutaceae) is an endemic medicinal plant of Ethiopia, traditionally used for the treatment of abdominal cramps, intestinal worms, skin diseases, and tooth pain.

Methods: Roots and fruit extracts were subjected to silica gel column chromatographic separation to afford five alkaloids, reported for the first time from the species. The cytotoxic effects of alkaloids (2-4) were evaluated in vitro against the estrogen-responsive MCF-7 and estrogen-unresponsive MDA-MB-231 human breast cancer cell lines by MTS assay.

Results: The results revealed that alkaloids (2-4) induced a significant reduction in cell growth of both breast cancer cell lines in a dose-dependent manner. Evodiamine (4) showed the highest potency against the aggressive metastatic MDA-MB-231 cell line at low micromolar concentrations. In addition, it highly arrested the cells in the G2/M phase, especially the MCF-7 cell line. By contrast, evoxanthine (2) and arborinine (3) exhibited higher cytotoxicity against MCF-7 than MDA-MB- 231 and influenced the cell cycle in both cell lines by arresting some cells in the G2/M phase, preventing cells with damaged DNA from entering mitosis. Molecular docking analysis showed that all alkaloids inhibit human topoisomerase II α, compared with vosaroxin’s anti-cancer agent under clinical trial. The ADMET studies revealed that the alkaloids showed the highest drug-likeness properties, suggesting that these alkaloids act as a drug and exhibit remarkable biological activities, except (5). DFT calculations indicated that the studied alkaloids showed the lowest gap energy and were chemically reactive.

Conclusion: The results obtained from molecular docking, drug-likeness properties, ADMET analysis, and DFT calculation are in good agreement with experimental studies. Hence, evoxanthine (2), arborinine (3), and evodiamine (4) may serve as lead molecules that could be developed into potent topoisomerase II α inhibitors against human breast cancer cells.

Keywords: Vepris dainelli, alkaloids, cytotoxicity, molecular docking, ADMET, DFT.

Graphical Abstract

[1] 
Tao, Z.; Shi, A.; Lu, C.; Song, T.; Zhang, Z.; Zhao, J. Breast cancer: epidemiology and etiology. Cell Biochem. Biophys.,  2015, 72(2), 333-338.
[http://dx.doi.org/10.1007/s12013-014-0459-6] [PMID: 25543329] 
[2] 
Dumitrescu, R.G.; Cotarla, I. Understanding breast cancer risk - where do we stand in 2005? J. Cell. Mol. Med.,  2005, 9(1), 208-221.
[http://dx.doi.org/10.1111/j.1582-4934.2005.tb00350.x] [PMID: 15784178] 
[3] 
Foroodi, F.; Duivenvoorden, W.C.; Singh, G. Interactions of doxycycline with chemotherapeutic agents in human breast adenocarcinoma MDA-MB-231 cells. Anticancer Drugs,  2009, 20(2), 115-122.
[http://dx.doi.org/10.1097/CAD.0b013e32831c14ec] [PMID: 19209028] 
[4] 
Razak, N.A.; Abu, N.; Ho, W.Y.; Zamberi, N.R.; Tan, S.W.; Alitheen, N.B.; Long, K.; Yeap, S.K. Cytotoxicity of eupatorin in MCF-7 and MDA-MB-231 human breast cancer cells via cell cycle arrest, anti-angiogenesis and induction of apoptosis. Sci. Rep.,  2019, 9(1), 1514.
[http://dx.doi.org/10.1038/s41598-018-37796-w] [PMID: 30728391] 
[5] 
Liu, M.; Zhang, J.; Li, X.; Cai, C.; Cao, X.; Shi, X.; Guo, R. A polydopamine-coated LAPONITE®-stabilized iron oxide nanoplatform for targeted multimodal imaging-guided photothermal cancer therapy. J. Mater. Chem. B Mater. Biol. Med.,  2019, 7(24), 3856-3864.
[http://dx.doi.org/10.1039/C9TB00398C] [PMID: 33629981] 
[6] 
Lu, S.; Li, X.; Zhang, J.; Peng, C.; Shen, M.; Shi, X. dendrimer-stabilized gold nanoflowers embedded with ultrasmall iron oxide nanoparticles for multimode imaging-guided combination therapy of tumors. Adv. Sci. (Weinh.),  2018, 5(12), 1801612.
[http://dx.doi.org/10.1002/advs.201801612] [PMID: 30581720] 
[7] 
Li, H.; Wu, X.; Li, X.; Cao, X.; Li, Y.; Cao, H.; Men, Y. Multistage extraction of star anise and black pepper derivatives for antibacterial, antioxidant, and anticancer activity. Front Chem.,  2021, 9(9), 660138.
[http://dx.doi.org/10.3389/fchem.2021.660138] [PMID: 34055736] 
[8] 
Greenwell, M.; Rahman, P.K.S.M. Medicinal plants: their use in anticancer treatment. Int. J. Pharm. Sci. Res.,  2015, 6(10), 4103-4112.
[http://dx.doi.org/10.13040/IJPSR.0975-8232.6(10).4103-12] [PMID: 26594645] 
[9] 
Dagne, E.; Yenesew, A.; Waterman, P.G.; Gray, A.I. the chemical systematics of the rutaceae, subfamily toddalioideae, in Africa. Biochem. Syst. Ecol.,  1988, 16, 179-188.
[http://dx.doi.org/10.1016/0305-1978(88)90093-2] 
[10] 
Chhabra, S.C.; Mahunnah, R.L.; Mshiu, E.N. Plants used in traditional medicine in eastern Tanzania. V. Angiosperms (Passifloraceae to Sapindaceae). J. Ethnopharmacol.,  1991, 33(1-2), 143-157.
[http://dx.doi.org/10.1016/0378-8741(91)90173-B] [PMID: 1943163] 
[11] 
Palmer, S.I.; Eric, K.O.; Naji, S.A.; Japheth, O.O.; Peter, K. C A review on chemistry of some species of genus Vepris (Rutaceae). Int. j. sci. innov. Res,  2014, 3(3), 357-362.
[12] 
Hedberg, I.; Hedberg, O.; Madati, P.J.; Mshigeni, K.E.; Mshiu, E.N.; Samuelsson, G. Inventory of plants used in traditional medicine in Tanzania. II. Plants of the families Dilleniaceae- Opiliaceae. J. Ethnopharmacol.,  1983, 9(1), 105-127.
[http://dx.doi.org/10.1016/0378-8741(83)90030-2] [PMID: 6668952] 
[13] 
Gurib-Fakim, A.; Sewraj, M.; Gueho, J.; Dulloo, E. Medicalethnobotany of some weeds of Mauritius and rodrigues. J. Ethnopharmacol.,  1993, 39(3), 175-185.
[http://dx.doi.org/10.1016/0378-8741(93)90034-3] [PMID: 8258975] 
[14] 
Moshi, M.J.; Mbwambo, Z.H.; Nondo, R.S.O.; Masimba, P.J.; Kamuhabwa, A.; Kapingu, M.C.; Thomas, P.; Richard, M. Evaluation of ethnomedical claims and brine shrimp toxicity of some plants used in Tanzania as traditional medicines. Afr. J. Tradit. Complement. Altern. Med.,  2006, 3, 48-58.
[15] 
Innocent, E.; Moshi, M.J.; Masimba, P.J.; Mbwambo, Z.H.; Kapingu, M.C.; Kamuhabwa, A. Screening of traditionally used plants for in vivo antimalarial activity in mice. Afr. J. Tradit. Complement. Altern. Med.,  2009, 6(2), 163-167.
[PMID: 20209008] 
[16] 
Arnold, H.J.; Gulumian, M. Pharmacopoeia of traditional medicine in Venda. J. Ethnopharmacol.,  1984, 12(1), 35-74.
[http://dx.doi.org/10.1016/0378-8741(84)90086-2] [PMID: 6521492] 
[17] 
Poitou, F.; Masotti, V.; Viano, J.; Gaydou, E.M.; Andriamahavo, N.R.; Mamitiana, A.; Rabemanantsoa, A.; Razanamahefa, B.V.; Andriantsiferana, M. Chemical compositon of vepris elliotii essential oil. J. Essent. Oil Res.,  1995, 7, 447-449.
[http://dx.doi.org/10.1080/10412905.1995.9698560] 
[18] 
Rasoanaivo, P.; Federici, E.; Palazzino, G.; Galeffi, C. Acridones of Vepris sclerophylla: their 13C-NMR data. Fitoterapia,  1999, 70, 625-627.
[http://dx.doi.org/10.1016/S0367-326X(99)00095-7] 
[19] 
Nordeng, H.; Al-Zayadi, W.; Diallo, D.; Ballo, N.; Paulsen, B.S. Traditional medicine practitioners’ knowledge and views on treatment of pregnant women in three regions of Mali. J. Ethnobiol. Ethnomed.,  2013, 9(1), 67.
[http://dx.doi.org/10.1186/1746-4269-9-67] [PMID: 24041441] 
[20] 
Hamzah, A.S.; Lajis, N.H.; Sargent, M.V. Kaempferitrin from the leaves of Hedyotis verticillata and its biological activity. Planta Med.,  1994, 60(4), 388-389.
[http://dx.doi.org/10.1055/s-2006-959513] [PMID: 7938277] 
[21] 
Emmanuel, T.; Djibo, D.; Jean-noël, N.; Laurent, S.; Luce, V.E.; Bernard, D.; Joseph, M. Two new compounds from stem barks of Vepris heterophylla (Engl) R. Let. (Rutaceae). J. Chem. Pharm. Res.,  2015, 7, 553-557.
[22] 
Tesfaye, A.; Sebsebe, D. Ethnobotanical study of medicinal plants in Kafficho people, southwestern Ethiopia. The 16th International Conference of Ethiopian Studies,  2009, pp. 711-726.
[23] 
Kebebew, M.R.; Mohammed, E.E. Distribution, abundance and population status of four indigenous threatened tree species in the arba minch natural forest, Southern Ethiopia. Int. J. Nat. Res. Ecol Manag,  2013, 2, 1-8.
[24] 
Fouda, A.; Aristide, F.; Toze, A.; Langat, M.K.; Ngeufa, E.; Leonard, L.M.M.; Mulholland, D.A.; Waffo, K.F.A.; Sewald, N.; Duplex, J. Acridone alkaloids from Vepris verdoorniana (Excell & Mendonça) Mziray (Rutaceae). Phytochem. Lett.,  2017, 19, 191-195.
[http://dx.doi.org/10.1016/j.phytol.2017.01.001] 
[25] 
Larsen, A.K.; Escargueil, A.E.; Skladanowski, A. Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol. Ther.,  2003, 99(2), 167-181.
[http://dx.doi.org/10.1016/S0163-7258(03)00058-5] [PMID: 12888111] 
[26] 
Müller, I.; Niethammer, D.; Bruchelt, G. Anthracycline-derived chemotherapeutics in apoptosis and free radical cytotoxicity (Review). Int. J. Mol. Med.,  1998, 1(2), 491-494.
[http://dx.doi.org/10.3892/ijmm.1.2.491] [PMID: 9852255] 
[27] 
Andoh, T.; Ishida, R. Catalytic inhibitors of DNA topoisomerase II. Biochim. Biophys. Acta,  1998, 1400(1-3), 155-171.
[http://dx.doi.org/10.1016/S0167-4781(98)00133-X] [PMID: 9748552] 
[28] 
Sarker, D.S.; Latif, Z.; Alexander, I.G. Natural Products Isolation, 2nd ed; Humana Press Inc: Totowa, New Jersey, 2006, pp. 1-26.
[29] 
Narramore, S.; Stevenson, C.E.M.; Maxwell, A.; Lawson, D.M.; Fishwick, C.W.G. New insights into the binding mode of pyridine-3-carboxamide inhibitors of E. coli DNA gyrase. Bioorg. Med. Chem.,  2019, 27(16), 3546-3550.
[http://dx.doi.org/10.1016/j.bmc.2019.06.015] [PMID: 31257079] 
[30] 
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem.,  2010, 31(2), 455-461.
[PMID: 19499576] 
[31] 
Seeliger, D.; de Groot, B.L. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J. Comput. Aided Mol. Des.,  2010, 24(5), 417-422.
[http://dx.doi.org/10.1007/s10822-010-9352-6] [PMID: 20401516] 
[32] 
Lipinski, A.C.; Lombardo, F.; IDominy, W. B.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.,  1997, 23, 3-23.
[http://dx.doi.org/10.1016/S0169-409X(96)00423-1] 
[33] 
Oduselu, G.O.; Ajani, O.O.; Ajamma, Y.U.; Brors, B.; Adebiyi, E. Homology modelling and molecular docking studies of selected substituted benzo[d]imidazol-1-yl)methyl)benzimidamide scaffolds on plasmodium falciparum adenylosuccinate lyase receptor. Bioinform. Biol. Insights,  2019, 13, 1177932219865533.
[http://dx.doi.org/10.1177/1177932219865533] [PMID: 31391779] 
[34] 
Behrouz, S.; Soltani Rad, M.N.; Taghavi Shahraki, B.; Fathalipour, M.; Behrouz, M.; Mirkhani, H.; Mirkhani, H. Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their β-adrenoceptor blocking property. Mol. Divers.,  2019, 23(1), 147-164.
[http://dx.doi.org/10.1007/s11030-018-9867-7] [PMID: 30094501] 
[35] 
Sulpizi, M.; Folkers, G.; Rothlisberger, U.; Carloni, P.; Scapozza, L. Applications of density functional theory-based methods in medicinal chemistry. Quant. Struct.-. Act. Relat,  2002, 21, 173-181.
[http://dx.doi.org/10.1002/1521-3838(200207)21:2<173::AID-QSAR173>3.0.CO;2-B] 
[36] 
Abu-Melha, S. Design, synthesis and DFT/DNP modeling study of new 2-amino-5-arylazothiazole derivatives as potential antibacterial agents. Molecules,  2018, 23(2), 1-11.
[http://dx.doi.org/10.3390/molecules23020434] [PMID: 29462895] 
[37] 
Pegel, K.H.; Wright, W.G. South African plant extractives. part ii. alkaloids of Teclea natalensis. J. Chem. Soc.,  1969, 2327-2329.
[38] 
Bowie, J.H.; Cooks, R.R.G.; Prager, H.; Thredgo, H.M. The mass spectra of acridones. Aust. J. Chem.,  1967, 20, 1179-1193.
[http://dx.doi.org/10.1071/CH9671179] 
[39] 
Kenmogne Kouam, A.D.; Kenmogne, S.B.; Songue Lobe, J.; Ngeufa Happi, E.; Stammler, H.G.; Kamdem Waffo, A.F.; Sewald, N.; Wansi, J.D. A rotameric tryptamide alkaloid from the roots of Vepris lecomteana (Pierre) Cheek & T. Heller (Rutaceae). Fitoterapia,  2019, 135, 9-14.
[http://dx.doi.org/10.1016/j.fitote.2019.03.028] [PMID: 30946943] 
[40] 
Joshi, B.S.; Moore, K.M.; Pelletier, S.W.; Puar, M.S. Alkaloids of Zanthoxylum budrunga wall: nmr assignments of dihydrochelerythrine, (±)-evodiamine and zanthobungeanine. Phytochem. Anal.,  1991, 2, 20-25.
[http://dx.doi.org/10.1002/pca.2800020105] 
[41] 
Shoji, N.; Umeyama, A.; Takemoto, T.; Kajiwara, A.; Ohizumi, Y. Isolation of evodiamine, a powerful cardiotonic principle, from Evodia rutaecarpa Bentham (Rutaceae). J. Pharm. Sci.,  1986, 75(6), 612-613.
[http://dx.doi.org/10.1002/jps.2600750619] [PMID: 3735108] 
[42] 
Khaljd, A.S.; Waterman, P.G. Furoquinoline and pyrano-2-quinolone alkaloids. J. Nat. Prod.,  1982, 45, 343-346.
[http://dx.doi.org/10.1021/np50021a017] 
[43] 
Abdelrheem, D.A.; Rahman, A.A.; Elsayed, K.N.M.; Abd El- Mageed, H.R.; Mohamed, H.S.; Ahmed, S.A. Isolation, characterization, in vitro anticancer activity, dft calculations, molecular docking, bioactivity score, drug-likeness and admet studies of eight phytoconstituents from brown alga sargassum platycarpum. J. Mol. Struct.,  2021, 1225, 129245.
[http://dx.doi.org/10.1016/j.molstruc.2020.129245] 
[44] 
Pan, X.; Hartley, J.M.; Hartley, J.A.; White, K.N.; Wang, Z.; Bligh, S.W.A. Evodiamine, a dual catalytic inhibitor of type I and II topoisomerases, exhibits enhanced inhibition against camptothecin resistant cells. Phytomedicine,  2012, 19(7), 618-624.
[http://dx.doi.org/10.1016/j.phymed.2012.02.003] [PMID: 22402246] 
[45] 
Wang, J.C. Cellular roles of DNA topoisomerases: a molecular perspective. Nat. Rev. Mol. Cell Biol.,  2002, 3(6), 430-440.
[http://dx.doi.org/10.1038/nrm831] [PMID: 12042765] 
[46] 
Eswaramoorthy, R.; Hailekiros, H.; Kedir, F.; Endale, M. In silico molecular docking, DFT Analysis and ADMET studies of carbazole alkaloid and coumarins from roots of Clausena anisata: a potent inhibitor for quorum sensing. Adv. Appl. Bioinform. Chem.,  2021, 14, 13-24.
[http://dx.doi.org/10.2147/AABC.S290912] [PMID: 33584098] 
[47] 
Rodriguez-Antona, C.; Ingelman-Sundberg, M. Cytochrome P450 pharmacogenetics and cancer. Oncogene,  2006, 25(11), 1679-1691.
[http://dx.doi.org/10.1038/sj.onc.1209377] [PMID: 16550168] 
[48] 
Mumit, M.A.; Pal, T.K.; Alam, M.A.; Islam, M.A.A.A.A.; Paul, S.; Sheikh, M.C. DFT studies on vibrational and electronic spectra, HOMO-LUMO, MEP, HOMA, NBO and molecular docking analysis of benzyl-3-N-(2,4,5-trimethoxyphenylmethylene)hydrazinecarbodithioate. J. Mol. Struct.,  2020, 1220, 128715.
[http://dx.doi.org/10.1016/j.molstruc.2020.128715] [PMID: 32834109] 

Rights & Permissions Print Cite

Article Metrics

43

1

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1573407218666220117100141	Print ISSN 1573-4072
Publisher Name Bentham Science Publisher	Online ISSN 1875-6646

Current Bioactive Compounds

Cytotoxicity, Molecular Docking, ADMET and DFT Analysis of Alkaloids from the Roots and Fruits of Vepris dainelli

Abstract

Graphical Abstract

Related Journals

Related Books