Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Benzophenone Sulfonamide Derivatives as Interacting Partners and Inhibitors of Human P-glycoprotein

Author(s): Saira Farman, Aneela Javed, Arshia, Khalid M. Khan, Abdul Nasir, Asif Ullah Khan, Muhammad A. Lodhi, Humaira Gul, Faisal Khan, Muhammad Asad and Zahida Parveen*

Volume 20, Issue 14, 2020

Page: [1739 - 1751] Pages: 13

DOI: 10.2174/1871520620666200516144403

Price: $65

Abstract

Background: Human P-glycoprotein (P-gp) is a transmembrane protein that belongs to the ATPBinding Cassette (ABC) transporters family. Physiologically, it exports toxins out of the cell, however, its overexpression leads to the phenomena of Multidrug-Resistance (MDR) by exporting a diverse range of compounds, which are structurally and chemically different from each other, thus creating a hurdle in the treatment of various diseases including cancer. The current study was designed to screen benzophenone sulfonamide derivatives as a class of inhibitors and potential anticancer agents for P-gp.

Methods: A total number of 15 compounds were evaluated. These compounds were screened in daunorubicin efflux inhibition assays using CCRF-CEM Vcr1000 cell line that overexpressed human P-gp. Cytotoxicity assay was also performed for active compounds 11, 14, and 13. These scaffolds were then docked in the homology model of human P-gp using mouse P-gp as a template (PDB ID: 4MIM) and the recently published Cryo Electron Microscopy (CEM) structure of human mouse chimeric P-gp to find their interactions with specified residues in the binding pocket. Analysis was performed using Labview VI and Graph pad prism version 5.0.

Results: Results revealed the potency of all these compounds in low nanomolar range whereas, compound 14 was found to be most active with IC50 value of 18.35nM±4.90 followed by 11 and 13 having IC50 values of 30.66nM±5.49 and 46.12nM±3.06, respectively. Moreover, IC50 values calculated for 14, 11 and 13 in cytotoxicity assay were found to be 22.97μM±0.026, 583.1μM±0.027 and 117.8μM±0.062, respectively. Docking results showed the interaction of these scaffolds in transmembrane helices (TM) where Tyr307, Tyr310, Tyr953, Met986 and Gln946 were found to be the major interaction partners, thus they might play a significant role in the transport of these scaffolds.

Conclusion: Benzophenone sulfonamide derivatives showed IC50 values in low nanomolar range comparable to the standard inhibitor Verapamil, therefore they can be good inhibitors of P-gp and can serve as anticancer agents. Also, they have shown interactions in the transmembrane region sharing the same binding region of verapamil and zosuquidar.

Keywords: P-gp, benzophenone sulfonamide, docking, inhibition, ABCB1, MDR.

« Previous
Graphical Abstract

[1]
Moitra, K.; Dean, M. Evolution of ABC transporters by gene duplication and their role in human disease. Biol. Chem., 2011, 392(1-2), 29-37.
[http://dx.doi.org/10.1515/bc.2011.006] [PMID: 21194360]
[2]
Dean, M.; Hamon, Y.; Chimini, G. The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res., 2001, 42(7), 1007-1017.
[PMID: 11441126]
[3]
Sarkadi, B.; Homolya, L.; Szakács, G.; Váradi, A. Human multidrug resistance ABCB and ABCG transporters: Participation in a chemoimmunity defense system. Physiol. Rev., 2006, 86(4), 1179-1236.
[http://dx.doi.org/10.1152/physrev.00037.2005] [PMID: 17015488]
[4]
Schinkel, A.H.; Jonker, J.W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv. Drug Deliv. Rev., 2003, 55(1), 3-29.
[http://dx.doi.org/10.1016/S0169-409X(02)00169-2] [PMID: 12535572]
[5]
Hoffmann, U.; Kroemer, H.K. The ABC transporters MDR1 and MRP2: multiple functions in disposition of xenobiotics and drug resistance. Drug Metab. Rev., 2004, 36(3-4), 669-701.
[http://dx.doi.org/10.1081/DMR-200033473] [PMID: 15554242]
[6]
Lee, C.H. Reversing agents for ATP-Binding Cassette (ABC) transporters: Application in modulating Multidrug Resistance (MDR). Curr. Med. Chem. Anticancer Agents, 2004, 4(1), 43-52.
[http://dx.doi.org/10.2174/1568011043482197] [PMID: 14754411]
[7]
Pascaud, C.; Garrigos, M.; Orlowski, S. Multidrug resistance transporter P-glycoprotein has distinct but interacting binding sites for cytotoxic drugs and reversing agents. Biochem. J., 1998, 333(Pt 2), 351-358.
[http://dx.doi.org/10.1042/bj3330351] [PMID: 9657975]
[8]
Loo, T.W.; Clarke, D.M. Defining the drug-binding site in the human multidrug resistance P-glycoprotein using a methanethiosulfonate analog of verapamil, MTS-verapamil. J. Biol. Chem., 2001, 276(18), 14972-14979.
[http://dx.doi.org/10.1074/jbc.M100407200] [PMID: 11279063]
[9]
Loo, T.W.; Bartlett, M.C.; Clarke, D.M. Disulfide cross-linking analysis shows that transmembrane segments 5 and 8 of human P-glycoprotein are close together on the cytoplasmic side of the membrane. J. Biol. Chem., 2004, 279(9), 7692-7697.
[http://dx.doi.org/10.1074/jbc.M311825200] [PMID: 14670948]
[10]
Litman, T.; Zeuthen, T.; Skovsgaard, T.; Stein, W.D. Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity. Biochim. Biophys. Acta, 1997, 1361(2), 169-176.
[http://dx.doi.org/10.1016/S0925-4439(97)00027-6] [PMID: 9300798]
[11]
Parveen, Z.; Stockner, T.; Bentele, C.; Pferschy, S.; Kraupp, M.; Freissmuth, M.; Ecker, G.F.; Chiba, P. Molecular dissection of dual pseudosymmetric solute translocation pathways in human P-glycoprotein. Mol. Pharmacol., 2011, 79(3), 443-452.
[12]
Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer, 2005, 5(4), 275-284.
[http://dx.doi.org/10.1038/nrc1590] [PMID: 15803154]
[13]
Marchetti, S.; Mazzanti, R.; Beijnen, J.H.; Schellens, J.H. Concise review: Clinical relevance of drug drug and herb drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist, 2007, 12(8), 927-941.
[http://dx.doi.org/10.1634/theoncologist.12-8-927] [PMID: 17766652]
[14]
Khaleel, S.A.; Al-Abd, A.M.; Ali, A.A.; Abdel-Naim, A.B. Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity. Sci. Rep., 2016, 6, 36855.
[http://dx.doi.org/10.1038/srep36855] [PMID: 27841296]
[15]
Qiu, Q.; Liu, B.; Cui, J.; Li, Z.; Deng, X.; Qiang, H.; Li, J.; Liao, C.; Zhang, B.; Shi, W.; Pan, M.; Huang, W.; Qian, H. Design, synthesis, and pharmacological characterization of N-(4-(2 (6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)yl)ethyl)phenyl)quinazolin-4-amine derivatives: Novel inhibitors reversing P-glycoprotein-mediated multidrug resistance. J. Med. Chem., 2017, 60(8), 3289-3302.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01787] [PMID: 28355069]
[16]
Xue, G.M.; Xia, Y.Z.; Wang, Z.M.; Li, L.N.; Luo, J.G.; Kong, L.Y. neo-Clerodane diterpenoids from Scutellaria barbata mediated inhibition of P-glycoprotein in MCF-7/ADR cells. Eur. J. Med. Chem., 2016, 121, 238-249.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.045] [PMID: 27240278]
[17]
Kannan, P.; John, C.; Zoghbi, S.S.; Halldin, C.; Gottesman, M.M.; Innis, R.B.; Hall, M.D. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin. Pharmacol. Ther., 2009, 86(4), 368-377.
[http://dx.doi.org/10.1038/clpt.2009.138] [PMID: 19625998]
[18]
Hsieh, H.P.; Liou, J.P.; Lin, Y.T.; Mahindroo, N.; Chang, J.Y.; Yang, Y.N.; Chern, S.S.; Tan, U.K.; Chang, C.W.; Chen, T.W.; Lin, C.H.; Chang, Y.Y.; Wang, C.C. Structure-activity and crystallographic analysis of benzophenone derivatives-the potential anticancer agents. Bioorg. Med. Chem. Lett., 2003, 13(1), 101-105.
[http://dx.doi.org/10.1016/S0960-894X(02)00850-8] [PMID: 12467626]
[19]
Nakagawa, Y.; Suzuki, T. Metabolism of 2-hydroxy-4-methoxybenzophenone in isolated rat hepatocytes and xenoestrogenic effects of its metabolites on MCF-7 human breast cancer cells. Chem. Biol. Interact., 2002, 139(2), 115-128.
[http://dx.doi.org/10.1016/S0009-2797(01)00293-9] [PMID: 11823001]
[20]
Schlitzer, M.; Böhm, M.; Sattler, I. Non-thiol farnesyltransferase inhibitors: structure-activity relationships of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors. Bioorg. Med. Chem., 2002, 10(3), 615-620.
[http://dx.doi.org/10.1016/S0968-0896(01)00312-1] [PMID: 11814849]
[21]
Revesz, L.; Blum, E.; Di Padova, F.E.; Buhl, T.; Feifel, R.; Gram, H.; Hiestand, P.; Manning, U.; Rucklin, G. SAR of benzoylpyridines and benzophenones as p38α MAP kinase inhibitors with oral activity. Bioorg. Med. Chem. Lett., 2004, 14(13), 3601-3605.
[http://dx.doi.org/10.1016/j.bmcl.2004.03.111] [PMID: 15177483]
[22]
Supuran, C.T.; Scozzafava, A.; Menabuoni, L.; Mincione, F.; Briganti, F.; Mincione, G. Carbonic anhydrase inhibitors. Part 71. Synthesis and ocular pharmacology of a new class of water-soluble, topically effective intraocular pressure lowering sulfonamides incorporating picolinoyl moieties. Eur. J. Pharm. Sci., 1999, 8(4), 317-328.
[http://dx.doi.org/10.1016/S0928-0987(99)00022-6] [PMID: 10425382]
[23]
Remko, M.; von der Lieth, C.W. Theoretical study of gas-phase acidity, pKa, lipophilicity, and solubility of some biologically active sulfonamides. Bioorg. Med. Chem., 2004, 12(20), 5395-5403.
[http://dx.doi.org/10.1016/j.bmc.2004.07.049] [PMID: 15388166]
[24]
Perlovich, G.L.; Strakhova, N.N.; Kazachenko, V.P.; Volkova, T.V.; Tkachev, V.V.; Schaper, K.J.; Raevsky, O.A. Sulfonamides as a subject to study molecular interactions in crystals and solutions: sublimation, solubility, solvation, distribution and crystal structure. Int. J. Pharm., 2008, 349(1-2), 300-313.
[http://dx.doi.org/10.1016/j.ijpharm.2007.07.034] [PMID: 17913412]
[25]
Gadad, A.K.; Mahajanshetti, C.S.; Nimbalkar, S.; Raichurkar, A. Synthesis and antibacterial activity of some 5-guanylhydrazone/thiocyanato-6-arylimidazo[2,1-b]-1,3, 4-thiadiazole-2-sulfonamide derivatives. Eur. J. Med. Chem., 2000, 35(9), 853-857.
[http://dx.doi.org/10.1016/S0223-5234(00)00166-5] [PMID: 11006486]
[26]
Li, J.; Jaimes, K.F.; Aller, S.G. Refined structures of mouse P-glycoprotein. Protein Sci., 2014, 23(1), 34-46.
[http://dx.doi.org/10.1002/pro.2387] [PMID: 24155053]
[27]
Alam, A.; Küng, R.; Kowal, J.; McLeod, R.A.; Tremp, N.; Broude, E.V.; Roninson, I.B.; Stahlberg, H.; Locher, K.P. Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1. Proc. Natl. Acad. Sci. USA, 2018, 115(9), E1973-E1982.
[http://dx.doi.org/10.1073/pnas.1717044115] [PMID: 29440498]
[28]
Gekeler, V.; Frese, G.; Noller, A.; Handgretinger, R.; Wilisch, A.; Schmidt, H.; Muller, C.P.; Dopfer, R.; Klingebiel, T.; Diddens, H. Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias. Br. J. Cancer, 1992, 66(3), 507-517.
[http://dx.doi.org/10.1038/bjc.1992.304] [PMID: 1355660]
[29]
Arshia.; Begum, F.; Almandil, N.B.; Lodhi, M.A.; Khan, K.M.; Hameed, A.; Perveen, S. Synthesis and urease inhibitory potential of benzophenone sulfonamide hybrid in vitro and in silico. Bioorg. Med. Chem., 2019, 27(6), 1009-1022.
[http://dx.doi.org/10.1016/j.bmc.2019.01.043] [PMID: 30738655]
[30]
Altschul, S.F.; Gish, W.; Miller, W.; Myers, E.W.; Lipman, D.J. Basic local alignment search tool. J. Mol. Biol., 1990, 215(3), 403-410.
[http://dx.doi.org/10.1016/S0022-2836(05)80360-2] [PMID: 2231712]
[31]
Syed, S.B.; Arya, H.; Fu, I.H.; Yeh, T.K.; Periyasamy, L.; Hsieh, H.P.; Coumar, M.S. Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer. Sci. Rep., 2017, 7(1), 7972.
[http://dx.doi.org/10.1038/s41598-017-08062-2] [PMID: 28801675]
[32]
Goldstein, L.J.; Galski, H.; Fojo, A.; Willingham, M.; Lai, S.L.; Gazdar, A.; Pirker, R.; Green, A.; Crist, W.; Brodeur, G.M.; Lieber, M. Expression of a multidrug resistance gene in human cancers. J. Natl. Cancer Inst., 1989, 81(2), 116-124.
[http://dx.doi.org/10.1093/jnci/81.2.116] [PMID: 2562856]
[33]
Sharom, F.J. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics, 2008, 9, 105-127.
[http://dx.doi.org/10.2217/14622416.9.1.105]
[34]
Binkhathlan, Z.; Lavasanifar, A. P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives. Curr. Cancer Drug Targets, 2013, 13(3), 326-346.
[http://dx.doi.org/10.2174/15680096113139990076] [PMID: 23369096]
[35]
Palmeira, A.; Sousa, E.; Vasconcelos, M.H.; Pinto, M.M. Three decades of P-gp inhibitors: Skimming through several generations and scaffolds. Curr. Med. Chem., 2012, 19(13), 1946-2025.
[http://dx.doi.org/10.2174/092986712800167392] [PMID: 22257057]
[36]
Zhang, C.G.; Zhu, W.J.; Liu, Y.; Yuan, Z.Q.; Yang, S.D.; Chen, W.L.; Li, J.Z.; Zhou, X.F.; Liu, C.; Zhang, X.N. Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy. Sci. Rep., 2016, 6, 23859.
[http://dx.doi.org/10.1038/srep23859] [PMID: 27030638]
[37]
Dash, R.P.; Jayachandra Babu, R.; Srinivas, N.R. Therapeutic potential and utility of elacridar with respect to P-glycoprotein inhibition: An insight from the published in vitro, preclinical and clinical studies. Eur. J. Drug Metab. Pharmacokinet., 2017, 42(6), 915-933.
[http://dx.doi.org/10.1007/s13318-017-0411-4] [PMID: 28374336]
[38]
Ma, W.; Feng, S.; Yao, X.; Yuan, Z.; Liu, L.; Xie, Y. Nobiletin enhances the efficacy of chemotherapeutic agents in ABCB1 overexpression cancer cells. Sci. Rep., 2015, 5, 18789.
[http://dx.doi.org/10.1038/srep18789] [PMID: 26689156]
[39]
Klepsch, F.; Chiba, P.; Ecker, G.F. Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein. PLOS Comput. Biol., 2011, 7(5) e1002036
[http://dx.doi.org/10.1371/journal.pcbi.1002036]] [PMID: 21589945]
[40]
Schwarz, T.; Montanari, F.; Cseke, A.; Wlcek, K.; Visvader, L.; Palme, S.; Chiba, P.; Kuchler, K.; Urban, E.; Ecker, G.F. Subtle structural differences trigger inhibitory activity of propafenone analogues at the two polyspecific ABC transporters: P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). ChemMedChem, 2016, 11(12), 1380-1394.
[http://dx.doi.org/10.1002/cmdc.201500592] [PMID: 26970257]
[41]
Zamora, J.M.; Pearce, H.L.; Beck, W.T. Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol. Pharmacol., 1988, 33(4), 454-462.
[PMID: 3162758]
[42]
Pearce, H.L.; Safa, A.R.; Bach, N.J.; Winter, M.A.; Cirtain, M.C.; Beck, W.T. Essential features of the P-glycoprotein pharmacophore as defined by a series of reserpine analogs that modulate multidrug resistance. Proc. Natl. Acad. Sci. USA, 1989, 86(13), 5128-5132.
[http://dx.doi.org/10.1073/pnas.86.13.5128] [PMID: 2567994]
[43]
Pace, C.N.; Horn, G.; Hebert, E.J.; Bechert, J.; Shaw, K.; Urbanikova, L.; Scholtz, J.M.; Sevcik, J. Tyrosine hydrogen bonds make a large contribution to protein stability. J. Mol. Biol., 2001, 312(2), 393-404.
[http://dx.doi.org/10.1006/jmbi.2001.4956] [PMID: 11554795]
[44]
Seelig, A. A general pattern for substrate recognition by P-glycoprotein. Eur. J. Biochem., 1998, 251(1-2), 252-261.
[http://dx.doi.org/10.1046/j.1432-1327.1998.2510252.x] [PMID: 9492291]

Rights & Permissions Print Cite
Article Metrics
15
© 2024 Bentham Science Publishers | Privacy Policy