Novel Inhibitors of DNA Repair Enzyme TDP1 Combining Monoterpenoid and Adamantane Fragments

Author(s): Evgenii S. Mozhaitsev, Alexandra L. Zakharenko, Evgeniy V. Suslov*, Dina V. Korchagina, Olga D. Zakharova, Inna A. Vasil'eva, Arina A. Chepanova, Ellena Black, Jinal Patel, Raina Chand, Jóhannes Reynisson, Ivanhoe K.H. Leung, Konstantin P. Volcho, Nariman F. Salakhutdinov, Olga I. Lavrik.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 4 , 2019

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Graphical Abstract:


Abstract:

Background and Objective: The DNA repair enzyme tyrosyl-DNA-phosphodiesterase 1 (TDP1) is a current inhibition target to improve the efficacy of cancer chemotherapy. Previous studies showed that compounds combining adamantane and monoterpenoid fragments are active against TDP1 enzyme. This investigation is focused on the synthesis of monoterpenoid derived esters of 1-adamantane carboxylic acid as TDP1 inhibitors.

Methods: New esters were synthesized by the interaction between 1-adamantane carboxylic acid chloride and monoterpenoid alcohols. The esters were tested against TDP1 and its binding to the enzyme was modeling.

Results: 13 Novel ester-based TDP1 inhibitors were synthesized with yields of 21–94%; of these, nine esters had not been previously described. A number of the esters were found to inhibit TDP1, with IC50 values ranging from 0.86–4.08 µM. Molecular modelling against the TDP1 crystal structure showed a good fit of the active esters in the catalytic pocket, explaining their potency. A non-toxic dose of ester, containing a 3,7- dimethyloctanol fragment, was found to enhance the cytotoxic effect of topotecan, a clinically used anti-cancer drug, against the human lung adenocarcinoma cell line A549.

Conclusion: The esters synthesized were found to be active against TDP1 in the lower micromolar concentration range, with these findings being corroborated by molecular modeling. Simultaneous action of the ester synthesized from 3,7-dimethyloctanol-1 and topotecan revealed a synergistic effect.

Keywords: Citronellol, 3, 7-dimethyloctanol, esters, terpene, inhibitors, cytotoxicity, molecular modelling, chemical space.

[1]
Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70, 369-413.
[2]
Pommier, Y. Topoisomerase I inhibitors: Camptothecins and beyond. Nat. Rev. Cancer, 2006, 6, 789-802.
[3]
Comeaux, E.Q.; Van Waardenburg, R.C. Tyrosyl-DNA phosphodiesterase I resolves both naturally and chemically induced DNA adducts and its potential as a therapeutic target. Drug Metab. Rev., 2014, 46(4), 494-507.
[4]
Interthal, H.; Pouliott, J.J.; Champoux, J.J. The tyrosyl-DNA phosphodiesterase TDP1 is a member of the phospholipase D superfamily. Proc. Natl. Acad. Sci. USA, 2001, 98(21), 12009-12014.
[5]
Lebedeva, N.A.; Rechkunova, N.I.; Lavrik, O.I. AP‐site cleavage activity of tyrosyl‐DNA phosphodiesterase 1. FEBS Lett., 2011, 585(4), 683-686.
[6]
Povirk, L.F. Processing of damaged DNA ends for double-strand break repair in mammalian cells. ISRN Mol. Biol., 2012, 2012, 1-16.
[7]
Dexheimer, T.S.; Stephen, A.G.; Fivash, M.J.; Fisher, R.J.; Pommier, Y. The DNA binding and 3′-end preferential activity of human tyrosyl-DNA phosphodiesterase. Nucleic Acids Res., 2010, 38(7), 2444-2452.
[8]
Dexheimer, T.S.; Antony, S.; Marchand, C.; Pommier, Y. Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy. Anticancer. Agents Med. Chem., 2008, 8, 381-389.
[9]
Beretta, G.L.; Cossa, G.; Gatti, L.; Zunino, F.; Perego, P. Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecin-based treatment. Curr. Med. Chem., 2010, 17, 1500-1508.
[10]
Jakobsen, A.K.; Lauridsen, K.L.; Samuel, E.B.; Proszek, J.; Knudsen, B.R.; Hager, H.; Stougaard, M. Correlation between topoisomerase I and tyrosyl-DNA phosphodiesterase 1 activities in non-small cell lung cancer tissue. Exp. Mol. Pathol., 2015, 99(1), 56-64.
[11]
Murai, J.; Huang, S.N.; Das, B.B.; Dexheimer, T.S.; Takeda, S.; Pommier, Y.J. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells. J. Biol. Chem., 2012, 287, 12848-12857.
[12]
Meisenberg, C.; Gilbert, D.C.; Chalmers, A.; Haley, V.; Gollins, S.; Ward, S.E.; El-Khamisy, S.F. Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. Mol. Cancer Ther., 2015, 14(2), 575-585.
[13]
Block, K.I.; Gyllenhaal, C.; Lowe, L.; Amedei, A.; Ruhul Amin, A.R.M.; Amin, A.; Aquilano, K.; Arbiser, J.; Arreola, A.; Arzumanyan, A.; Ashraf, S.S.; Azmi, A.S.; Benencia, F.; Bhakta, D.; Bilsland, A.; Bishayee, A.; Blain, S.W.; Block, P.B.; Boosani, C.S.; Carey, T.E.; Carnero, A.; Carotenuto, M.; Casey, S.C.; Chakrabarti, M.; Chaturvedi, R.; Chen, G.Z.; Chen, H.; Chen, S.; Chen, Y.C.; Choi, B.K.; Ciriolo, M.R.; Coley, H.M.; Collins, A.R.; Connell, M.; Crawford, S.; Curran, C.S.; Dabrosin, C.; Damia, G.; Dasgupta, S.; DeBerardinis, R.J.; Decker, W.K.; Dhawan, P.; Diehl, A.M.E.; Dong, J-T.; Dou, Q.P.; Drew, J.E.; Elkord, E.; El-Rayes, B.; Feitelson, M.A.; Felsher, D.W.; Ferguson, L.R.; Fimognari, C.; Firestone, G.L.; Frezza, C.; Fujii, H.; Fuster, M.M.; Generali, D.; Georgakilas, A.G.; Gieseler, F.; Gilbertson, M.; Green, M.F.; Grue, B.; Guha, G.; Halicka, D.; Helferich, W.G.; Heneberg, P.; Hentosh, P.; Hirschey, M.D.; Hofseth, L.J.; Holcombe, R.F.; Honoki, K.; Hsu, H-Y.; Huang, G.S.; Jensen, L.D.; Jiang, W.G.; Jones, L.W.; Karpowicz, P.A.; Keith, W.N.; Kerkar, S.P.; Khan, G.N.; Khatami, M.; Ko, Y.H.; Kucuk, O.; Kulathinal, R.J.; Kumar, N.B.; Kwon, B.S.; Le, A.; Lea, M.A.; Lee, H-Y.; Lichtor, T.; Lin, L-T.; Locasale, J.W.; Lokeshwar, B.L.; Longo, V.D.; Lyssiotis, C.A.; MacKenzie, K.L.; Malhotra, M.; Marino, M.; Martinez-Chantar, M.L.; Matheu, A.; Maxwell, C.; McDonnell, E.; Meeker, A.K.; Mehrmohamadi, M.; Mehta, K.; Michelotti, G.A.; Mohammad, R.M.; Mohammed, S.I.; Morre, D.J.; Muralidhar, V.; Muqbil, I.; Murphy, M.P.; Nagaraju, G.P.; Nahta, R.; Niccolai, E.; Nowsheen, S.; Panis, C.; Pantano, F.; Parslow, V.R.; Pawelec, G.; Pedersen, P.L.; Poore, B.; Poudyal, D.; Prakash, S.; Prince, M.; Raffaghello, L.; Rathmell, J.C.; Rathmell, W.K.; Ray, S.K.; Reichrath, J.; Rezazadeh, S.; Ribatti, D.; Ricciardiello, L.; Robey, R.B.; Rodier, F.; Rupasinghe, H.P.V.; Russo, G.L.; Ryan, E.P.; Samadi, A.K.; Sanchez-Garcia, I.; Sanders, A.J.; Santini, D.; Sarkar, M.; Sasada, T.; Saxena, N.K.; Shackelford, R.E.; Kumara, H.M.C.S.; Sharma, D.; Shin, D.M.; Sidransky, D.; Siegelin, M.D.; Signori, E.; Singh, N.; Sivanand, S.; Sliva, D.; Smythe, C.; Spagnuolo, C.; Stafforini, D.M.; Stagg, J.; Subbarayan, P.R.; Sundin, T.; Talib, W.H.; Thompson, S.K.; Tran, P.T.; Ungefroren, H.; Vander Heiden, M.G.; Venkateswaran, V.; Vinay, D.S.; Vlachostergios, P.J.; Wang, Z.; Wellen, K.E.; Whelan, R.L.; Yang, E.S.; Yang, H.; Yang, X.; Yaswen, P.; Yedjou, C.; Yin, X.; Zhu, J.; Zollo, M. Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin. Cancer Biol., 2015, 35, S276-S304.
[14]
Davies, D.R.; Interthal, H.; Champoux, J.J.; Hol, W.G.J. Insights into substrate binding and catalytic mechanism of human tyrosyl-DNA phosphodiesterase (TDP1) from vanadate and tungstate-inhibited structures. J. Mol. Biol., 2003, 324, 917-932.
[15]
Davies, D.R.; Interthal, H.; Champoux, J.J.; Hol, W.G.J. The crystal structure of human tyrosyl-DNA phosphodiesterase, TDP1. Structure, 2002, 10(2), 237-248.
[16]
Dexheimer, T.S.; Gediya, L.K.; Stephen, A.G.; Weidlich, I.; Antony, S.; Marchand, C.; Interthal, H.; Nicklaus, M.; Fisher, R.J.; Njar, V.C.; Pommier, Y. 4-Pregnen-21-ol-3,20-dione-21-(4-bromobenzenesufonate) (NSC 88915) and related novel steroid derivatives as tyrosyl-DNA phosphodiesterase (TDP1) inhibitors. J. Med. Chem., 2009, 52(22), 7122-7131.
[17]
Jun, J.H.; Kumar, V.; Dexheimer, T.S.; Wedlich, I.; Nicklaus, M.C.; Pommier, Y.; Malhotra, S.V. Synthesis, anti-cancer screening and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition activity of novel piperidinyl sulfamides. Eur. J. Pharm. Sci., 2018, 111, 337-348.
[18]
Bermingham, A.; Price, E.; Marchand, C.; Chergui, A.; Naumova, A.; Whitson, E.L.; Krumpe, L.R.H.; Goncharova, E.I.; Evans, J.R.; McKee, T.C.; Henrich, C.J.; Pommier, Y.; O’Keefe, B.R. Identification of natural products that inhibit the catalytic function of human tyrosyl-DNA phosphodiesterase (TDP1). SLAS Discov., 2017, 22(9), 1093-1105.
[19]
Nguyen, T.X.; Morrell, A.; Conda-Sheridan, M.; Marchand, C.; Agama, K.; Bermingam, A.; Stephen, A.G.; Chergui, A.; Naumova, A.; Fisher, R.; O’Keefe, B.R.; Pommier, Y.; Cushman, M. Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (TDP1)–topoisomerase I (TOP1) inhibitors. J. Med. Chem., 2012, 55(9), 4457-4478.
[20]
Zakharenko, A.L.; Khomenko, T.M.; Zhukova, S.V.; Koval, O.A.; Zakharova, O.D.; Anarbaev, R.O.; Lebedeva, N.A.; Korchagina, D.V.; Komarova, N.I.; Vasiliev, V.G.; Reynisson, J.; Volcho, K.P.; Salakhutdinov, N.F.; Lavrik, O.I. Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety. Bioorg. Med. Chem., 2015, 23(9), 2044-2052.
[21]
Zakharenko, A.; Luzina, O.; Koval, O.; Nilov, D.; Gushchina, I.; Dyrkheeva, N.; Švedas, V.; Salakhutdinov, N.; Lavrik, O. Tyrosyl-DNA phosphodiesterase 1 inhibitors: Usnic acid enamines enhance the cytotoxic effect of camptothecin. J. Nat. Prod., 2016, 79, 2961-2967.
[22]
Khomenko, T.; Zakharenko, A.; Odarchenko, T.; Arabshahi, H.J.; Sannikova, V.; Zakharova, O.; Korchagina, D.; Reynisson, J.; Volcho, K.; Salakhutdinov, N.; Lavrik, O. New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties. Bioorg. Med. Chem., 2016, 24(21), 5573-5581.
[23]
Antony, S.; Marchand, C.; Stephen, A.G.; Thibaut, L.; Agama, K.K.; Fisher, R.J.; Pommier, Y. Novel high-throughput electrochemiluminescent assay for identification of human tyrosyl-DNA phosphodiesterase (TDP1) inhibitors and characterization of furamidine (NSC 305831) as an inhibitor of TDP1. Nucleic Acids Res., 2007, 35(13), 4474-4484.
[24]
Zhang, X-R.; Wang, H-W.; Tang, W-L.; Zhang, Y.; Yang, H.; Hu, D-X.; Ravji, A.; Marchand, C.; Kiselev, E.; Ofori-Atta, K.; Agama, K.; Pommier, Y.; An, L-K. Discovery, synthesis, and evaluation of oxynitidine derivatives as dual inhibitors of DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), and potential antitumor agents. J. Med. Chem., 2018, 61, 9908-9930.
[25]
Li-Zhulanov, N.S.; Zakharenko, A.L.; Chepanova, A.A.; Patel, J.; Zafar, A.; Volcho, K.P.; Salakhutdinov, N.F.; Reynisson, J.; Leung, I.K.H.; Lavrik, O.I. A novel class of tyrosyl-DNA phosphodiesterase 1 inhibitors that contains the octahydro-2H-chromen-4-ol scaffold. Molecules, 2018, 23(10), 2468.
[26]
Elsayed, M.S.A.; Su, Y.; Wang, P.; Sethi, T.; Agama, K.; Ravji, A.; Redon, C.E.; Kiselev, E.; Horzmann, K.A.; Freeman, J.L.; Pommier, Y.; Cushman, M. Design and synthesis of chlorinated and fluorinated 7-azaindenoisoquinolines as potent cytotoxic anticancer agents that inhibit topoisomerase I. J. Med. Chem., 2017, 60(13), 5364-5376.
[27]
Wang, P.; Elsayed, M.S.A.; Plescia, C.B.; Ravji, A.; Redon, C.E.; Kiselev, E.; Marchand, C.; Zeleznik, O.; Agama, K.; Pommier, Y.; Cushman, M. Synthesis and biological evaluation of the first triple inhibitors of human topoisomerase 1, tyrosyl–DNA phosphodiesterase 1 (Tdp1), and tyrosyl-DNA phosphodiesterase 2 (Tdp2). J. Med. Chem., 2017, 60(8), 3275-3288.
[28]
Zakharenko, A.L.; Ponomarev, K.Y.; Suslov, E.V.; Korchagina, D.V.; Volcho, K.P.; Vasil’eva, I.A.; Salakhutdinov, N.F.; Lavrik, O.I. Inhibitory properties of nitrogen-containing adamantane derivatives with monoterpenoid fragments against tyrosyl-DNA phosphodiesterase 1. Russ. J. Bioorganic Chem., 2015, 41(6), 657-662.
[29]
Ponomarev, K.Y.; Suslov, E.V.; Zakharenko, A.L.; Zakharova, O.D.; Rogachev, A.D.; Korchagina, D.V.; Zafar, A.; Reynisson, J.; Nefedov, A.A.; Volcho, K.P.; Salakhutdinov, N.F.; Lavrik, O.I. Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors. Bioorg. Chem., 2018, 76, 392-399.
[30]
Siramshetty, V.B.; Preissner, R. Drugs as habitable planets in the space of dark chemical matter. Drug Discov. Today, 2018, 23(3), 481-486.
[31]
Ferreira, M.J.P.; Emerenciano, V.P.; Linia, G.A.R.; Romoff, P.; Macari, P.A.T.; Rodrigues, G.V. 13C NMR spectroscopy of monoterpenoids. Prog. Nucl. Magn. Reson. Spectrosc., 1998, 33(3-4), 153-206.
[32]
Scigress ultra v. F.J 2.6 in, Fijitsu Limited, 2008-2016.
[33]
Allinger, N.L. Conformational analysis. 130. MM2. A hydrocarbon force field utilizing V1 and V2 torsional terms. J. Am. Chem. Soc., 1977, 99(25), 8127-8134.
[34]
Jones, G.; Willet, 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.
[35]
Eldridge, M.D.; Murray, C.; Auton, T.R.; Paolini, G.V.; Mee, P.M. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comput. Aided Mol. Des., 1997, 11(5), 425-445.
[36]
Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved protein–ligand docking using GOLD. Proteins, 2003, 52(4), 609-623.
[37]
Korb, O.; Stützle, T.; Exner, T.E. Empirical scoring functions for advanced protein-ligand docking with plants. J. Chem. Inf. Model., 2009, 49(1), 84-96.
[38]
Mooij, W.T.M.; Verdonk, M.L. General and targeted statistical potentials for protein–ligand interactions. Proteins, 2005, 61(2), 272-287.
[39]
QikProp. in. Schrodinger, New York, 2009.
[40]
Ioakimidis, L.; Thoukydidis, L.; Naeem, S.; Mirza, A.; Reynisson, J. Benchmarking the reliability of QikProp. Correlation between experimental and predicted values. QSAR Comb. Sci., 2008, 27(4), 445-456.
[41]
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.
[42]
Dikusar, E.A.; Kozlov, N.G.; Potkin, V.I.; Kovganko, N.V. 1-Adamantanecarboxylic acid esters of certain terpenols, sterols, and plant phenols. Chem. Nat. Compd., 2003, 39(3), 276-279.
[43]
Jensen, P.W.; Falconi, M.; Kristoffersen, E.L.; Simonsen, A.T.; Cifuentes, J.B.; Marcussen, L.B.; Frøhlich, R.; Vagner, J.; Harmsen, C.; Juul, S.; Ho, Y.P.; Withers, M.A.; Lupski, J.R.; Koch, J.; Desideri, A.; Knudsen, B.R.; Stougaard, M. Real-time detection of TDP1 activity using a fluorophore-quencher coupled DNA-biosensor. Biosens. Bioelectron., 2013, 48, 230-237.
[44]
Wang, D.; Margalit, O.; DuBois, R.N. Metronomic topotecan for colorectal cancer: A promising new option. Gut, 2013, 62, 190-191.
[45]
Sehouli, J.; Oskay-Ozcelik, G. Current role and future aspects of topotecan in relapsed ovarian cancer. Curr. Med. Res. Opin., 2009, 25(3), 639-651.
[46]
Huang, S.N.; Pommier, Y.; Marchand, C. Tyrosyl-DNA Phosphodiesterase 1 (TDP1) inhibitors. Expert Opin. Ther. Pat., 2011, 21(9), 1285-1292.
[47]
Arabshahi, H.J.; van Rensburg, M.; Pilkington, L.I.; Jeon, C.Y.; Song, M.; Gridel, L-M.; Leung, E.; Barker, D.; Vuica-Ross, M.; Volcho, K.P.; Zakharenko, A.L.; Lavrik, O.I. Reynisson. A synthesis, in silico, in vitro and in vivo study of thieno[2,3-b]pyridine anticancer analogues. MedChemComm, 2015, 6, 1987-1997.
[48]
Zhu, F.; Logan, G.; Reynisson, J. Wine compounds as a source for HTS screening collections. A feasibility study. Mol. Inform., 2012, 31(11-12), 847-855.


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VOLUME: 19
ISSUE: 4
Year: 2019
Page: [463 - 472]
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DOI: 10.2174/1871520619666181207094243
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