Abstract
Background: Pyrrole compounds having a heterocyclic structure are the most researched and biological activities such as antioxidant and anticancer activities.
Objective: Herein is a first effort to study the significance of heterocyclic compounds to include pyrrole and triazolidine-3,5-dion moiety, on the pharmacokinetic, antioxidant activity and cytotoxic activity on MCF-7 and MCF-12A cell lines.
Method: The molecular structures of compounds I-XIV were simulated by the theoretical B3- LYP/DFT method. Pharmacokinetic studies of PhTAD-substituted heterocyclic compounds (IXIV) were analyzed to show Lipinski's rules via in-silico methods of Swiss-ADME. The drug likeness calculations were carried out in Molinspiration analyses. Some toxicity risk parameter can be quantified using Osiris. Antioxidant activities determined by DPPH, Fe+2 ions chelating and reducing. Cytotoxic activity measured by MTT and RTCA
Results: Compared with the DPPH activity, the metal chelating activity exhibited serious similar antioxidant effects by PhTAD substituted pyrrole compounds. The same compounds showed the highest activity among the two antioxidant activities. The IC50 values of the compounds are in the range of 12 and 290 μM in the MCF-7 cell line. In the MTT and RTCA assays, All compounds showed cytotoxic activity, but about half of the fourteen compounds showed high cytotoxicity. IC50 values of the compounds are in the range of 5 and 54 μM for MTT and range of 1.5 and 44 μM for RTCA.
Conclusion: Data of the antioxidant and cytotoxic activity of PhTAD-substituted dihydropyrrole- derived compounds in MCF-7 and MCF-12A cell lines confirmed that the compounds are biologically active compound and are notable for anti-cancer researches.
Keywords: Breast cancer, PhTAD-Dihydropyrrole, antioxidant activity, RTCA, swiss-ADME, molinspiration, osiris.
Graphical Abstract
[1]
Fatahala, SS; Mohamed, MS; Youns, M Synthesis and evaluation of cytotoxic activity of some pyrroles and fused pyrroles. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 2017, 17, 1014-1025..
[2]
Kaur, R; Rani, V; Abbot, V Recent synthetic and medicinal perspectives of pyrroles: An overview. J Pharm Chem Chem Sci, 2017, 1(1), 17-32.
[3]
Nakano, H.; Umio, S.; Kariyone, K.; Tanaka, K.; Kishimoto, T.; Noguchi, H. Total synthesis of pyrrolnitrin, a new antibiotic. Tetrahedron Lett., 1966, 7, 737-740.
[http://dx.doi.org/10.1016/S0040-4039(00)90255-7] [PMID: 5955096]
[http://dx.doi.org/10.1016/S0040-4039(00)90255-7] [PMID: 5955096]
[4]
Bhardwaj, V.; Gumber, D.; Abbot, V. Pyrrole: a resourceful small molecule in key medicinal hetero-aromatics. RSC Advances, 2015, 5, 15233-15266.
[http://dx.doi.org/10.1039/C4RA15710A]
[http://dx.doi.org/10.1039/C4RA15710A]
[6]
Saluja, P.; Khurana, J.M.; Nikhil, K. Task-specific ionic liquid catalyzed synthesis of novel naphthoquinone–urazole hybrids and evaluation of their antioxidant and in vitro anticancer activity. RSC Advances, 2014, 4, 34594-34603.
[http://dx.doi.org/10.1039/C4RA02917H]
[http://dx.doi.org/10.1039/C4RA02917H]
[7]
Jacobson, C.R.; Adamo, A.D.; Cosgrove, C.E. Urazoles and their production; Google Patents, 1972.
[8]
Izydore, R.A.; Hall, I.H. Compounds for the control of hyperlipidemia using N-substituted isoxazolidine-3, 5-diones; Google Patents, 1990.
[9]
Von Bredow, B.; Brechbuehler, H. Ger Offen. 2,343,347; file date, March 14, 1974. In: Chem Abstr; , 1974; p. 140210s.
[10]
Valadez-Vega, C.; Delgado-Olivares, L.; González, J.A.M. The role of natural antioxidants in cancer disease. Oxidative Stress and Chronic Degenerative Diseases-A Role for Antioxidants; IntechOpen, 2013.
[11]
Harris, I.S.; DeNicola, G.M. The Complex Interplay between Antioxidants and ROS in Cancer. Trends Cell Biol., 2020, 30(6), 440-451.
[http://dx.doi.org/10.1016/j.tcb.2020.03.002] [PMID: 32303435]
[http://dx.doi.org/10.1016/j.tcb.2020.03.002] [PMID: 32303435]
[12]
Martinez-Serra, J.; Gutierrez, A.; Muñoz-Capó, S.; Navarro-Palou, M.; Ros, T.; Amat, J.C.; Lopez, B.; Marcus, T.F.; Fueyo, L.; Suquia, A.G.; Gines, J.; Rubio, F.; Ramos, R.; Besalduch, J. xCELLigence system for real-time label-free monitoring of growth and viability of cell lines from hematological malignancies. OncoTargets Ther., 2014, 7, 985-994.
[http://dx.doi.org/10.2147/OTT.S62887] [PMID: 24959085]
[http://dx.doi.org/10.2147/OTT.S62887] [PMID: 24959085]
[13]
Mycek, M.J.; Finkel, R.; Clark, M.A. Pharmacology; Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.
[14]
Elmore, S. Apoptosis: a review of programmed cell death. Toxicol. Pathol., 2007, 35(4), 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[15]
Gul, M.; Elemes, Y.; Pelit, E. Synthesis of PhTAD-substituted dihydropyrrole derivatives via stereospecific C–H amination. Res. Chem. Intermed., 2017, 43, 1031-1045.
[http://dx.doi.org/10.1007/s11164-016-2681-x]
[http://dx.doi.org/10.1007/s11164-016-2681-x]
[16]
Gul, M.; Eryılmaz, S. Synthesis, Antioxidant Activity and Theoretical Investigation of Isoxazolines Derivatives of Monoterpenoids. Lett. Org. Chem., 2019, 16, 501-510.
[http://dx.doi.org/10.2174/1570178616666181226154540]
[http://dx.doi.org/10.2174/1570178616666181226154540]
[17]
Eryılmaz, S.; Türk Çelikoğlu, E.; İdil, Ö.; İnkaya, E.; Kozak, Z.; Mısır, E.; Gül, M. Derivatives of pyridine and thiazole hybrid: Synthesis, DFT, biological evaluation via antimicrobial and DNA cleavage activity. Bioorg. Chem., 2020, 95103476
[http://dx.doi.org/10.1016/j.bioorg.2019.103476] [PMID: 31838288]
[http://dx.doi.org/10.1016/j.bioorg.2019.103476] [PMID: 31838288]
[18]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[19]
Santra, S; Kaittanis, C; Grimm, J Drug/dye‐loaded, multifunctional iron oxide nanoparticles for combined targeted cancer therapy and dual optical/magnetic resonance imaging. small, 2009, 5, 1862-1868..
[20]
Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B Condens. Matter, 1988, 37(2), 785-789.
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[http://dx.doi.org/10.1103/PhysRevB.37.785] [PMID: 9944570]
[21]
Miehlich, B.; Savin, A.; Stoll, H. Results obtained with the correlation energy density functionals of Becke and Lee, Yang and Parr. Chem. Phys. Lett., 1989, 157, 200-206.
[http://dx.doi.org/10.1016/0009-2614(89)87234-3]
[http://dx.doi.org/10.1016/0009-2614(89)87234-3]
[22]
Foresman, J.; Frisch, A. Exploring Chemistry with Electronic Structure Methods. Gaussian, Inc., Pittsburg, PA (USA). J. Am. Chem. Soc., 1995, 2, 136.
[24]
Parr, R.G.; Donnelly, R.A.; Levy, M. Electronegativity: the density functional viewpoint. J. Chem. Phys., 1978, 68, 3801-3807.
[http://dx.doi.org/10.1063/1.436185]
[http://dx.doi.org/10.1063/1.436185]
[25]
Parr, R.G.; Pearson, R.G. Absolute hardness: companion parameter to absolute electronegativity. J. Am. Chem. Soc., 1983, 105, 7512-7516.
[http://dx.doi.org/10.1021/ja00364a005]
[http://dx.doi.org/10.1021/ja00364a005]
[26]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[27]
Weininger, D. SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules. J. Chem. Inf. Comput. Sci., 1988, 28, 31-36.
[http://dx.doi.org/10.1021/ci00057a005]
[http://dx.doi.org/10.1021/ci00057a005]
[28]
Kotchevar, A.T.; Ghosh, P.; Uckun, F.M. Interactions of vanadocene (IV)-chelated complexes with artificial membranes. J. Phys. Chem. B, 1998, 102, 10925-10930.
[http://dx.doi.org/10.1021/jp9831637]
[http://dx.doi.org/10.1021/jp9831637]
[29]
Brand-Williams, W.; Cuvelier, M-E.; Berset, C. Use of a free radical method to evaluate antioxidant activity. Lebensm. Wiss. Technol., 1995, 28, 25-30.
[http://dx.doi.org/10.1016/S0023-6438(95)80008-5]
[http://dx.doi.org/10.1016/S0023-6438(95)80008-5]
[30]
Decker, E.A.; Welch, B. Role of ferritin as a lipid oxidation catalyst in muscle food. J. Agric. Food Chem., 1990, 38, 674-677.
[http://dx.doi.org/10.1021/jf00093a019]
[http://dx.doi.org/10.1021/jf00093a019]
[31]
Oyaizu, M. Studies on products of browning reaction: antioxidative activity of products of browning reaction. Jpn J Nutr, 1986, 44, 307-315.
[http://dx.doi.org/10.5264/eiyogakuzashi.44.307]
[http://dx.doi.org/10.5264/eiyogakuzashi.44.307]
[32]
Cree, I.A. Principles of cancer cell culture. Cancer cell culture; Springer, 2011, pp. 13-26.
[http://dx.doi.org/10.1007/978-1-61779-080-5_2]
[http://dx.doi.org/10.1007/978-1-61779-080-5_2]
[33]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[34]
Ma, H.; Yang, S.; Lu, H.; Zhang, Y. Bioassay-guided separation of anti-tumor components from Euphorbia kansui by means of two-dimensional preparative high performance liquid chromatography and real-time cell analysis. Anal. Sci., 2016, 32(5), 581-586.
[http://dx.doi.org/10.2116/analsci.32.581] [PMID: 27169660]
[http://dx.doi.org/10.2116/analsci.32.581] [PMID: 27169660]
[35]
Georgiou, D.; Toutountzoglou, V.; Muir, K.W.; Hadjipavlou-Litina, D.; Elemes, Y. Synthesis of sulfur containing dihydro-pyrrolo derivatives and their biological evaluation as antioxidants. Bioorg. Med. Chem., 2012, 20(17), 5103-5109.
[http://dx.doi.org/10.1016/j.bmc.2012.07.014] [PMID: 22858299]
[http://dx.doi.org/10.1016/j.bmc.2012.07.014] [PMID: 22858299]
[36]
Chohan, Z.H.; Sumrra, S.H.; Youssoufi, M.H.; Hadda, T.B. Metal based biologically active compounds: design, synthesis, and antibacterial/antifungal/cytotoxic properties of triazole-derived Schiff bases and their oxovanadium(IV) complexes. Eur. J. Med. Chem., 2010, 45(7), 2739-2747.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.053] [PMID: 20338672]
[http://dx.doi.org/10.1016/j.ejmech.2010.02.053] [PMID: 20338672]
[37]
Kidwai, M.; Venkataramanan, R.; Mohan, R.; Sapra, P. Cancer chemotherapy and heterocyclic compounds. Curr. Med. Chem., 2002, 9(12), 1209-1228.
[http://dx.doi.org/10.2174/0929867023370059] [PMID: 12052173]
[http://dx.doi.org/10.2174/0929867023370059] [PMID: 12052173]
[38]
Zhou, C.H.; Wang, Y. Recent researches in triazole compounds as medicinal drugs. Curr. Med. Chem., 2012, 19(2), 239-280.
[http://dx.doi.org/10.2174/092986712803414213] [PMID: 22320301]
[http://dx.doi.org/10.2174/092986712803414213] [PMID: 22320301]
[39]
Hiremath, S.B.; Devendrappa, S.L. Safety and efficacy of tirapazamine as anti-cancer drug: a meta-analysis of randomized controlled trials. Int. J. Basic Clin. Pharmacol., 2018, 7, 783.
[http://dx.doi.org/10.18203/2319-2003.ijbcp20181187]
[http://dx.doi.org/10.18203/2319-2003.ijbcp20181187]
[40]
Shi, F.; Tao, Z-L.; Yu, J. Highly enantioselective synthesis of biologically important 2, 5-dihydropyrroles via phosphoric acid-catalyzed three-component reactions and evaluation of their cytotoxicity. Tetrahedron Asymmetry, 2011, 22, 2056-2064.
[http://dx.doi.org/10.1016/j.tetasy.2011.11.020]
[http://dx.doi.org/10.1016/j.tetasy.2011.11.020]
[41]
Bavadi, M.; Niknam, K.; Shahraki, O. Novel pyrrole derivatives bearing sulfonamide groups: Synthesis in vitro cytotoxicity evaluation, molecular docking and DFT study. J. Mol. Struct., 2017, 1146, 242-253.
[http://dx.doi.org/10.1016/j.molstruc.2017.06.003]
[http://dx.doi.org/10.1016/j.molstruc.2017.06.003]
[42]
Kaur, M.; Singh, P. Targeting tyrosine kinase: Development of acridone - pyrrole - oxindole hybrids against human breast cancer. Bioorg. Med. Chem. Lett., 2019, 29(1), 32-35.
[http://dx.doi.org/10.1016/j.bmcl.2018.11.021] [PMID: 30446310]
[http://dx.doi.org/10.1016/j.bmcl.2018.11.021] [PMID: 30446310]
[43]
Khanam, H.; Mashrai, A.; Siddiqui, N. Structural elucidation, density functional calculations and contribution of intermolecular interactions in cholest-4-en-3-one crystals: Insights from X-ray and Hirshfeld surface analysis. J. Mol. Struct., 2015, 1084, 274-283.
[http://dx.doi.org/10.1016/j.molstruc.2014.12.027]
[http://dx.doi.org/10.1016/j.molstruc.2014.12.027]
[44]
Bendjeddou, A.; Abbaz, T.; Gouasmia, A. Molecular structure, HOMO-LUMO, MEP and Fukui function analysis of some TTFdonor substituted molecules using DFT (B3LYP) calculations. Int. Res. J. Pure Appl. Chem., 2016, 12(1), 1-9.
[http://dx.doi.org/10.9734/IRJPAC/2016/27066]
[http://dx.doi.org/10.9734/IRJPAC/2016/27066]
[45]
Irwin, J.J.; Duan, D.; Torosyan, H.; Doak, A.K.; Ziebart, K.T.; Sterling, T.; Tumanian, G.; Shoichet, B.K. An aggregation advisor for ligand discovery. J. Med. Chem., 2015, 58(17), 7076-7087.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01105] [PMID: 26295373]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01105] [PMID: 26295373]
[46]
Fatahala, S.S.; Shalaby, E.A.; Kassab, S.E.; Mohamed, M.S. A promising anti-cancer and anti-oxidant agents based on the pyrrole and fused pyrrole: synthesis, docking studies and biological evaluation. Anticancer. Agents Med. Chem., 2015, 15(4), 517-526.
[http://dx.doi.org/10.2174/1871520615666150105113946] [PMID: 25929576]
[http://dx.doi.org/10.2174/1871520615666150105113946] [PMID: 25929576]
[47]
Beale, T.M.; Bond, P.J.; Brenton, J.D.; Charnock-Jones, D.S.; Ley, S.V.; Myers, R.M. Increased endothelial cell selectivity of triazole-bridged dihalogenated A-ring analogues of combretastatin A-1. Bioorg. Med. Chem., 2012, 20(5), 1749-1759.
[http://dx.doi.org/10.1016/j.bmc.2012.01.010] [PMID: 22304851]
[http://dx.doi.org/10.1016/j.bmc.2012.01.010] [PMID: 22304851]
[48]
Diaz-Perez, S; Kane, N; Kurmis, AA Interference with DNA repair after ionizing radiation by a pyrrole-imidazole polyamide. PLoS One, 2018 May;13, e0196803.
[http://dx.doi.org/10.1371/journal.pone.0196803]
[http://dx.doi.org/10.1371/journal.pone.0196803]
[49]
Abd El Hameid, M.K.; Mohammed, M.R. Design, synthesis, and cytotoxicity screening of 5-aryl-3-(2-(pyrrolyl) thiophenyl)-1, 2, 4-oxadiazoles as potential antitumor molecules on breast cancer MCF-7 cells. Bioorg. Chem., 2019, 86, 609-623.
[http://dx.doi.org/10.1016/j.bioorg.2019.01.067] [PMID: 30807934]
[http://dx.doi.org/10.1016/j.bioorg.2019.01.067] [PMID: 30807934]
[50]
Schwartz-Roberts, J.L.; Shajahan, A.N.; Cook, K.L.; Wärri, A.; Abu-Asab, M.; Clarke, R. GX15-070 (obatoclax) induces apoptosis and inhibits cathepsin D- and L-mediated autophagosomal lysis in antiestrogen-resistant breast cancer cells. Mol. Cancer Ther., 2013, 12(4), 448-459.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0617] [PMID: 23395885]
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0617] [PMID: 23395885]
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