Azacyanines as Novel Topoisomerase II Alpha Inhibitors

Author(s): Sercan Guloglu, Fahriye Nur Kirmaci, Özgül Persil Çetinkol*, Mehrdad Forough, Aybuke Gulkaya.

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 5 , 2020

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Abstract:

Introduction: Topoisomerase II alpha (Topo IIα) has become one of the extensively exploited targets in chemotherapy due to its role in regulating the topological constraints of DNA during replication and transcription. Small molecules targeting Topo IIα’s activity such as etoposide (VP-16) and doxorubicin are extensively used in the treatment of many different types of cancer.

Objective: Here, the effects of three small molecules, named as azacyanines, on Topo IIα have been assessed.

Methods: In-vitro Topoisomerase IIα drug screening kit and agarose gel imaging were used for the assessment of Topo IIα’s activity.

Results: Our results revealed that all the azacyanines investigated decreased the catalytic activity of Topo IIα dramatically. More importantly, the decrease in the catalytic activity of Topo IIα in the presence of azacyanines was higher than the presence of VP-16, which is a commercially available chemotherapy drug. Upon further investigation, it has been observed that Azamethyl’s catalytic inhibition of Topo IIα was concentration dependent and the catalytic activity of Topo IIα was almost completely abolished in the presence of 100.0 μM of Azamethyl.

Conclusion: These findings reveal the potential of azacyanines as effective Topo IIα inhibitors and chemotherapeutic agents.

Keywords: Azacyanines, catalytic inhibition, small molecules, azamethyl, topoisomerase IIα, DNA.

[1]
Nitiss, J.L. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer, 2009, 9(5), 327-337. [http://dx.doi.org/10.1038/nrc2608]. [PMID: 19377505].
[2]
Vos, S.M.; Tretter, E.M.; Schmidt, B.H.; Berger, J.M. All tangled up: How cells direct, manage and exploit topoisomerase function. Nat. Rev. Mol. Cell Biol., 2011, 12(12), 827-841. [http://dx.doi.org/10.1038/nrm3228]. [PMID: 22108601].
[3]
Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70, 369-413. [http://dx.doi.org/10.1146/annurev.biochem.70.1.369]. [PMID: 11395412].
[4]
Wang, J.C. Moving one DNA double helix through another by a type II DNA topoisomerase: The story of a simple molecular machine. Q. Rev. Biophys., 1998, 31(2), 107-144. [http://dx.doi.org/10.1017/S0033583598003424]. [PMID: 9794033].
[5]
Kathiravan, M.K.; Khilare, M.M.; Nikoomanesh, K.; Chothe, A.S.; Jain, K.S. Topoisomerase as target for antibacterial and anticancer drug discovery. J. Enzyme Inhib. Med. Chem., 2013, 28(3), 419-435. [http://dx.doi.org/10.3109/14756366.2012.658785]. [PMID: 22380774].
[6]
Winkler, D. Modelling topoisomerase I inhibition by minor groove binders. Bioorg. Med. Chem., 2011, 19(4), 1450-1457. [http://dx.doi.org/10.1016/j.bmc.2011.01.003]. [PMID: 21273082].
[7]
Liu, L.F. DNA topoisomerase poisons as antitumor drugs. Annu. Rev. Biochem., 1989, 58, 351-375. [http://dx.doi.org/10.1146/annurev.bi.58.070189.002031]. [PMID: 2549853].
[8]
Oviatt, A.A.; Kuriappan, J.A.; Minniti, E.; Vann, K.R.; Onuorah, P.; Minarini, A.; De Vivo, M.; Osheroff, N. Polyamine-containing etoposide derivatives as poisons of human type II topoisomerases: Differential effects on topoisomerase IIα and IIβ. Bioorg. Med. Chem. Lett., 2018, 28(17), 2961-2968. [http://dx.doi.org/10.1016/j.bmcl.2018.07.010]. [PMID: 30006062].
[9]
Zuma, A.A.; Cavalcanti, D.P.; Maia, M.C.P.; de Souza, W.; Motta, M.C.M. Effect of topoisomerase inhibitors and DNA-binding drugs on the cell proliferation and ultrastructure of Trypanosoma cruzi. Int. J. Antimicrob. Agents, 2011, 37(5), 449-456. [http://dx.doi.org/10.1016/j.ijantimicag.2010.11.031]. [PMID: 21292448].
[10]
Classen, S.; Olland, S.; Berger, J.M. Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187. Proc. Natl. Acad. Sci. USA, 2003, 100(19), 10629-10634. [http://dx.doi.org/10.1073/pnas.1832879100]. [PMID: 12963818].
[11]
Li, H.; Xie, N.; Gleave, M.E.; Dong, X. Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression. Oncotarget, 2015, 6(24), 20474-20484. [http://dx.doi.org/10.18632/oncotarget.4105]. [PMID: 26009876].
[12]
Ghosh, S.; Mukhopadhyay, S.; Sarkar, M.; Mandal, A.; Das, V.; Kumar, A.; Giri, B. Biological evaluation of a halogenated triterpenoid, 2α-bromo-dihydrobelulonic acid as inhibitor of human topoisomerase IIα and HeLa cell proliferation. Chem. Biol. Interact., 2017, 268, 68-76. [http://dx.doi.org/10.1016/j.cbi.2017.02.015]. [PMID: 28254521].
[13]
Bau, J.T.; Kang, Z.; Austin, C.A.; Kurz, E.U. Salicylate, a catalytic inhibitor of topoisomerase II, inhibits DNA cleavage and is selective for the α isoform. Mol. Pharmacol., 2014, 85(2), 198-207. [http://dx.doi.org/10.1124/mol.113.088963]. [PMID: 24220011].
[14]
Chène, P.; Rudloff, J.; Schoepfer, J.; Furet, P.; Meier, P.; Qian, Z.; Schlaeppi, J.M.; Schmitz, R.; Radimerski, T. Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue. BMC Chem. Biol., 2009, 9(1), 1-16. [http://dx.doi.org/10.1186/1472-6769-9-1]. [PMID: 19128485].
[15]
Seiter, K. Toxicity of the topoisomerase II inhibitors. Expert Opin. Drug Saf., 2005, 4(2), 219-234. [http://dx.doi.org/10.1517/14740338.4.2.219]. [PMID: 15794715].
[16]
Haddadin, M.J.; Kurth, M.J.; Olmstead, M.M. One-step synthesis of new heterocyclic azacyanines. Tetrahedron Lett., 2000, 41(30), 5613-5616. [http://dx.doi.org/10.1016/S0040-4039(00)00908-4].
[17]
Tutuncu, S.; Guloglu, S.; Kuçukakdag, A.; Cetinkol, O.P. selective high binding affinity of azacyanines to polyd(a).polyd(t).polyd(t) triplex: The effect of chain length and branching on stabilization, selectivity and affinity. Chem Select, 2018, 45(3), 12878-12887. [http://dx.doi.org/10.1002/slct.201802802].
[18]
Çetinkol, Ö.P.; Hud, N.V. Molecular recognition of poly(A) by small ligands: an alternative method of analysis reveals nanomolar, cooperative and shape-selective binding. Nucleic Acids Res., 2009, 37(2), 611-621. [http://dx.doi.org/10.1093/nar/gkn977]. [PMID: 19073699].
[19]
Çetinkol, Ö.P.; Engelhart, A.E.; Nanjunda, R.K.; Wilson, W.D.; Hud, N.V. Submicromolar, selective G-quadruplex ligands from one pot: Thermodynamic and structural studies of human telomeric DNA binding by azacyanines. ChemBioChem, 2008, 9(12), 1889-1892. [PMID: 18600816].
[20]
Hyun, Min Genome instability induced by triplex forming mirror repeats in S.cerevisiae, PhD thesis. Georgia Institute of Technology (USA), 2009.
[21]
WHO Model List of Essential Medicines - 19th List. Essential Medicines, (April), 2015, 1.45
[22]
Lee, P.Y.; Costumbrado, J.; Hsu, C.Y.; Kim, Y.H. Agarose gel electrophoresis for the separation of DNA fragments. J. Vis. Exp., 2012, (62), 1-5. [http://dx.doi.org/10.3791/3923]. [PMID: 22546956].


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Article Details

VOLUME: 17
ISSUE: 5
Year: 2020
Page: [666 - 671]
Pages: 6
DOI: 10.2174/1570180816666190628161945
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