Login Register Cart 0
Generic placeholder image

Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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

Insight into Mechanism of Action of Anticancer Benzazoles

Author(s): Ozum Ozturk, Esin Aki-Yalcin*, Ismail Yalcin and Renate Grifitth

Volume 20, Issue 23, 2020

Page: [2056 - 2069] Pages: 14

DOI: 10.2174/1568026620666200819152108

Price: $65

Abstract

Background: Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription, and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome. This ultimately leads to the accumulation of DNA strand breaks and cell death.

Methods: Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell-free system. Their interactions with the enzyme were studied by carrying out molecular docking studies using and comparing two different docking programs.

Results: The results of the docking studies clarified binding modes of these compounds to the topoisomerase II enzyme.

Conclusion: This study also provides guidelines to design novel and more potent antitumor agents functioning as human topoisomerase II enzyme inhibitors.

Keywords: Homology modeling, Anticancer, Topoisomerase II, Molecular docking, Benzazole, Enzyme inhibitors.

« Previous Next »
Graphical Abstract

[1]
Hu, W.; Huang, X.S.; Wu, J.F.; Yang, L.; Zheng, Y.T.; Shen, Y.M.; Li, Z.Y.; Li, X. Discovery of novel topoisomerase ii inhibitors by medicinal chemistry approaches. J. Med. Chem., 2018, 61(20), 8947-8980.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01202] [PMID: 29870668]
[2]
Dong, K.C.; Berger, J.M. Structural basis for gate-dna recognition and bending by type iia topoisomerases. Nature, 2007, 450(7173), 1201-1205.
[http://dx.doi.org/10.1038/nature06396] [PMID: 18097402]
[3]
Pommier, Y. DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem. Rev., 2009, 109(7), 2894-2902.
[http://dx.doi.org/10.1021/cr900097c] [PMID: 19476377]
[4]
Berger, J.M.; Gamblin, S.J.; Harrison, S.C.; Wang, J.C. Structure and mechanism of DNA topoisomerase II. Nature, 1996, 379(6562), 225-232.
[http://dx.doi.org/10.1038/379225a0] [PMID: 8538787]
[5]
Wendorff, T.J.; Schmidt, B.H.; Heslop, P.; Austin, C.A.; Berger, J.M. The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J. Mol. Biol., 2012, 424(3-4), 109-124.
[http://dx.doi.org/10.1016/j.jmb.2012.07.014] [PMID: 22841979]
[6]
Nitiss, J.L.; Targeting, D.N.A. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer, 2009, 9(5), 338-350.
[http://dx.doi.org/10.1038/nrc2607] [PMID: 19377506]
[7]
Pinar, A.; Yurdakul, P.; Yildiz, I.; Temiz-Arpaci, O.; Açan, N.L.; Akı-Şener, E.; Yalçın, I. Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors. Biochem. Biophys. Res. Commun., 2004, 317(2), 670-674.
[http://dx.doi.org/10.1016/j.bbrc.2004.03.093] [PMID: 15063810]
[8]
Kadayat, T.M.; Song, C.; Shin, S.; Magar, T.B.; Bist, G.; Shrestha, A.; Thapa, P.; Na, Y.; Kwon, Y.; Lee, E.S. Synthesis, topoisomerase I and II inhibitory activity, cytotoxicity, and structure-activity relationship study of 2-phenyl- or hydroxylated 2-phenyl-4-aryl-5H-indeno[1,2-b]pyridines. Bioorg. Med. Chem., 2015, 23(13), 3499-3512.
[http://dx.doi.org/10.1016/j.bmc.2015.04.031] [PMID: 26022080]
[9]
Oksuzoglu, E.; Ertan-Bolelli, T.; Can, H.; Tarhan, M.; Ozturk, K.; Yildiz, I. Antitumor activities on HL-60 human leukemia cell line, molecular docking, and quantum-chemical calculations of some sulfonamide-benzoxazoles. Artif. Cells Nanomed. Biotechnol., 2017, 45(7), 1388-1396.
[http://dx.doi.org/10.1080/21691401.2016.1241796] [PMID: 27829297]
[10]
Zilifdar, F.; Foto, E.; Ertan-Bolelli, T.; Aki-Yalcin, E.; Yalcin, I.; Diril, N. Biological evaluation and pharmacophore modeling of some benzoxazoles and their possible metabolites. Arch. Pharm. (Weinheim), 2018, 351(2), 1-10.
[http://dx.doi.org/10.1002/ardp.201700265] [PMID: 29359805]
[11]
Young, D. Computational Drug Design: A Guide For Computational and Medicinal Chemists; John Wiley Sons, INC.: Hoboken, New Jersey , 2009.
[12]
Shoichet, B.K.; McGovern, S.L.; Wei, B.; Irwin, J.J. Lead discovery using molecular docking. Curr. Opin. Chem. Biol., 2002, 6(4), 439-446.
[http://dx.doi.org/10.1016/S1367-5931(02)00339-3] [PMID: 12133718]
[13]
Iacopetta, D.; Rosano, C.; Puoci, F.; Parisi, O.I.; Saturnino, C.; Caruso, A.; Longo, P.; Ceramella, J.; Malzert-Fréon, A.; Dallemagne, P.; Rault, S.; Sinicropi, M.S. Multifaceted properties of 1,4-dimethylcarbazoles: Focus on trimethoxybenzamide and trimethoxyphenylurea derivatives as novel human topoisomerase II inhibitors. Eur. J. Pharm. Sci., 2017, 96, 263-272.
[http://dx.doi.org/10.1016/j.ejps.2016.09.039] [PMID: 27702608]
[14]
Kuskucu, M.; Akyildiz, V.; Kulmány, A.; Ergün, Y.; Zencir, S.; Zupko, I.; Durdagi, S.; Zaka, M.; Sahin, K.; Orhan, H.; Topcu, Z. Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study. Med. Chem. Res., 2020, 29, 189-198.
[http://dx.doi.org/10.1007/s00044-019-02472-9]
[15]
Fiser, A.; Šali, A. Modeller: generation and refinement of homology-based protein structure models, Charles W. Carter, Jr.; Robert, M.S. Eds., In: Methods in enzymology; Academic Press: London, , 2003; 374, pp. 461-491.
[16]
Dassault Systèmes. BIOVIA; Discovery Studio: San Diego. Available from: https://www.3ds.com/products-services/biovia
[17]
Wu, C-C.; Li, T-K.; Farh, L.; Lin, L-Y.; Lin, T-S.; Yu, Y.J.; Yen, T-J.; Chiang, C-W.; Chan, N-L. Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science, 2011, 333(6041), 459-462.
[http://dx.doi.org/10.1126/science.1204117] [PMID: 21778401]
[18]
Wang, Y.R.; Chen, S.F.; Wu, C.C.; Liao, Y.W.; Lin, T-S.; Liu, K.T.; Chen, Y.S.; Li, T.K.; Chien, T.C.; Chan, N.L. Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry. Nucleic Acids Res., 2017, 45(18), 10861-10871.
[http://dx.doi.org/10.1093/nar/gkx742] [PMID: 28977631]
[19]
Sali, A.; Blundell, T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol., 1993, 234(3), 779-815.
[http://dx.doi.org/10.1006/jmbi.1993.1626] [PMID: 8254673]
[20]
Sherman, W.; Day, T.; Jacobson, M.P.; Friesner, R.A.; Farid, R. Novel procedure for modeling ligand/receptor induced fit effects. J. Med. Chem., 2006, 49(2), 534-553.
[http://dx.doi.org/10.1021/jm050540c] [PMID: 16420040]
[21]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol., 1997, 267(3), 727-748.
[http://dx.doi.org/10.1006/jmbi.1996.0897] [PMID: 9126849]
[22]
Schrödinger. Maestro v11.3; Schrödinger, Inc.: Portland, OR, 2017.
[23]
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem., 2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID: 15027865]
[24]
Jacobson, M.P.; Pincus, D.L.; Rapp, C.S.; Day, T.J.F.; Honig, B.; Shaw, D.E.; Friesner, R.A. A hierarchical approach to all-atom protein loop prediction. Proteins, 2004, 55(2), 351-367.
[http://dx.doi.org/10.1002/prot.10613] [PMID: 15048827]
[25]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[26]
Cheng, A.; Merz, K.M., Jr Prediction of aqueous solubility of a diverse set of compounds using quantitative structure-property relationships. J. Med. Chem., 2003, 46(17), 3572-3580.
[http://dx.doi.org/10.1021/jm020266b] [PMID: 12904062]
[27]
Huang, N-L.; Lin, J-H. Recovery of the poisoned topoisomerase II for DNA religation: coordinated motion of the cleavage core revealed with the microsecond atomistic simulation. Nucleic Acids Res., 2015, 43(14), 6772-6786.
[http://dx.doi.org/10.1093/nar/gkv672] [PMID: 26150421]

Rights & Permissions Print Cite
Article Metrics
8
1
© 2024 Bentham Science Publishers | Privacy Policy