Abstract
Background: Inhibition of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), may increase the efficacy of cancer drugs that cause damage to tumor cell DNA. Among the known TDP1 inhibitors, there are compounds containing moieties of natural substances, e.g., monoterpenoids. In this work, we synthesized several compounds containing aromatic/ heteroaromatic amines and monoterpenoid groups and assessed their TDP1 inhibition potential.
Methods: Structures of all the synthesized compounds were confirmed by 1H and 13C NMR as well as HRMS. The TDP1 inhibitory activity of the amines was determined by real-time fluorescence oligonucleotide biosensor.
Results: The synthesized secondary amines had TDP1 inhibitory activity IC50 in the range of 0.79-9.2 µM. The highest activity was found for (–)-myrtenal derivatives containing p-bromoaniline or m-(trifluoromethyl)aniline residue.
Conclusion: We synthesized 22 secondary amines; of these, 17 amines are novel chemical structures. Many of the amines inhibit TDP1 activity in the low micromolar range. Therefore, these compounds are promising for further study of their antiproliferative activity in conjunction with DNA damaging drugs.
Keywords: Anilines, secondary amines, myrtenal, perillyl aldehyde, terpenes, cancer, molecular modeling, chemical space.
Graphical Abstract
[1]
Champoux, J.J. DNA topoisomerases: Structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70, 369-413.
[2]
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.
[3]
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, 12009-12014.
[4]
Povirk, L.F. Processing of Damaged DNA Ends for Double-Strand Break Repair in Mammalian Cells. ISRN Mol. Biol., 2012, 2012, 1-16.
[5]
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.
[6]
Murai, J.; Huang, S.N.; Das, B.B.; Dexheimer, T.S.; Takeda, S.; Pommier, Y. 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(16), 12848-12857.
[7]
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.
[8]
Dexheimer, T.; Antony, S.; Marchand, C.; Pommier, Y. Tyrosyl- DNA Phosphodiesterase as a Target for Anticancer Therapy. Anticancer. Agents Med. Chem., 2008, 8(4), 381-389.
[9]
Beretta, G.; Cossa, G.; Gatti, L.; Zunino, F.; Perego, P. Tyrosyl-DNA phosphodiesterase 1 targeting for modulation of camptothecin- based treatment. Curr. Med. Chem., 2010, 17(15), 1500-1508.
[10]
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., 2002, 324(5), 917-932.
[11]
Davies, D.R.; Interthal, H.; Champoux, J.J.; Hol, W.G. The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1. Structure, 2002, 10(2), 237-248.
[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]
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.
[14]
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.
[15]
Zakharenko, A.L.; Ponomarev, K.U.; 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.
[16]
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.
[17]
Khomenko, T.; Zakharenko, A.; Odarchenko, T.; Arabshahi, H.J.; Sannikova, V.; Zakharova, O.; Korchagina, D.; Reynisson, J.; Volcho, K.; Salakhutdinov, N.; Lavrik, O.I. New inhibitors of tyrosyl- DNA phosphodiesterase I (Tdp 1) combining 7- hydroxycoumarin and monoterpenoid moieties. Bioorg. Med. Chem., 2016, 24(21), 5573-5581.
[18]
Zakharenko, A.; Khomenko, T.; Zhukova, S.; Koval, O.; Zakharova, O.; Anarbaev, R.; Lebedeva, N.; Korchagina, D.; Komarova, N.; Vasiliev, V.; Reynisson, J.; Volcho, K.; Salakhutdinov, N.; Lavrik, O. Synthesis and biological evaluation of novel tyrosyl- DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety. Bioorg. Med. Chem., 2015, 23(9), 2044-2052.
[19]
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(11), 2961-2967.
[20]
Zakharova, O.; Luzina, O.; Zakharenko, A.; Sokolov, D.; Filimonov, A.; Dyrkheeva, N.; Chepanova, A.; Ilina, E.; Ilyina, A.; Klabenkova, K. Synthesis and Evaluation of Aryliden- and Hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 Inhibitors. Bioorg. Med. Chem. 2018.
[http://dx.doi.org/ 10.1016/j.bmc. 2018.07.039..]
[http://dx.doi.org/ 10.1016/j.bmc. 2018.07.039..]
[21]
Zakharenko, A.L.; Luzina, O.A.; Sokolov, D.N.; Zakharova, O.D.; Rakhmanova, M.E.; Chepanova, A.A.; Dyrkheeva, N.S.; Lavrik, O.I.; Salakhutdinov, N.F. Usnic acid derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1. Russ. J. Bioorganic Chem., 2017, 43(1), 84-90.
[22]
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. Adv. Life Sci. R&D., 2017, 22(9), 1093-1105.
[23]
Gushchina, I.V.; Nilov, D.K.; Zakharenko, A.L.; Lavrik, O.I.; Švedas, V.K. Structure modeling of human tyrosyl-DNA phosphodiesterase 1 and screening for its inhibitors. Acta Nat., 2017, 9(2), 59-66.
[24]
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.
[25]
Salomatina, O.; Popadyuk, I.; Zakharenko, A.; Zakharova, O.; Fadeev, D.; Komarova, N.; Reynisson, J.; Arabshahi, H.; Chand, R.; Volcho, K. Novel semisynthetic derivatives of bile acids as effective tyrosyl-DNA phosphodiesterase 1 inhibitors. Molecules, 2018, 23(3), 679.
[26]
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.A. Synthesis, in silico, in vitro and in vivo study of thieno[2,3-b]pyridine anticancer analogues. MedChemComm, 2015, 6(11), 1987-1997.
[27]
Demidova, Y.S.; Simakova, I.L.; Estrada, M.; Beloshapkin, S.; Suslov, E.V.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F.; Simakov, A.V.; Murzin, D.Y. One-Pot myrtenol amination over au nanoparticles supported on different metal oxides. Appl. Catal. A Gen., 2013, 464, 348-356.
[28]
Demidova, Y.S.; Suslov, E.V.; Simakova, I.L.; Mozhajcev, E.S.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F.; Simakov, A.; Murzin, D.Y. One-pot monoterpene alcohol amination over Au/ZrO2 catalyst: Effect of the substrate structure. J. Catal., 2018, 360, 127-134.
[29]
Demidova, Y.S.; Suslov, E.V.; Simakova, I.L.; Mozhajcev, E.S.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F.; Simakov, A.; Murzin, D.Y. Selectivity control in one-pot myrtenol amination over Au/ZrO2 by molecular hydrogen addition. J. Mol. Catal. Chem., 2017, 426, 60-67.
[30]
Simakova, I.L.; Demidova, Y.S.; Estrada, M.; Beloshapkin, S.; Suslov, E.V.; Volcho, K.P.; Salakhutdinov, N.F.; Murzin, D.Y.; Simakov, A. Gold catalyzed one-pot myrtenol amination: Effect of catalyst redox activation. Catal. Today, 2017, 279, 63-70.
[31]
Demidova, Y.S.; Suslov, E.V.; Simakova, I.L.; Volcho, K.P.; Smolentseva, E.; Salakhutdinov, N.F.; Simakov, A.; Murzin, D.Y. Promoting effect of alcohols and formic acid on au-catalyzed one-pot myrtenol amination. Mol. Catal., 2017, 433, 414-419.
[32]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
[33]
Berman, H.; Henrick, K.; Nakamura, H. Announcing the worldwide protein data bank. Nat. Struct. Mol. Biol., 2003, 10(12), 980-980.
[35]
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.
[36]
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.
[37]
Eldridge, M.D.; Murray, C.W.; Auton, T.R.; Paolini, G.V.; Mee, R.P. 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.
[38]
Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved protein-ligand docking using GOLD. Proteins Struct. Funct. Bioinforma., 2003, 52(4), 609-623.
[39]
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.
[40]
Mooij, W.T.M.; Verdonk, M.L. General and targeted statistical potentials for protein-ligand interactions. Proteins Struct. Funct. Bioinforma., 2005, 61(2), 272-287.
[42]
Ioakimidis, L.; Thoukydidis, L.; Mirza, A.; Naeem, S.; Reynisson, J. Benchmarking the reliability of QikProp. Correlation between experimental and predicted values. QSAR Comb. Sci., 2008, 27(4), 445-456.
[43]
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.
[44]
Ponomarev, K.; Pavlova, A.; Suslov, E.; Ardashov, O.; Korchagina, D.; Nefedov, A.; Tolstikova, T.; Volcho, K.; Salakhutdinov, N. Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties. Med. Chem. Res., 2015, 24(12), 4146-4156.
[45]
Lu, T-J.; Liu, S-W. Asymmetric reduction using lithium aluminum hydride modified with chiral ligands prepared from (1R)-(-)-β-Pinene. J. Chinese. Chem. Soc., 1994, 41(4), 467-471.
[46]
Wijtmans, M.; Verzijl, D.; Bergmans, S.; Lai, M.; Bosch, L.; Smit, M.J.; de Esch, I.J.P.; Leurs, R. CXCR3 Antagonists: Quaternary ammonium salts equipped with biphenyl- and Polycycloaliphatic- Anchors. Bioorg. Med. Chem., 2011, 19(11), 3384-3393.
[47]
Rösler, S.; Ertl, M.; Irrgang, T.; Kempe, R. Cobalt-catalyzed alkylation of aromatic amines by alcohols. Angew. Chemie. Int. Ed., 2015, 54(50), 15046-15050.
[48]
Midland, M.M.; Kazubski, A. A new class of enantioselective organoboron reducing agents. Borane complexes with chiral terpenic 1,2-Azaboracyclohexanes. J. Org. Chem., 1992, 57(10), 2953-2956.
[49]
Maya, R.J.; Poulose, S.; John, J.; Luxmi, V.R. Direct reductive amination of aldehydes via environmentally benign bentonite- gold nanohybrid catalysis. Adv. Synth. Catal., 2017, 359(7), 1177-1184.
[50]
Lee, O-Y.; Law, K-L.; Yang, D. Secondary amine formation from reductive amination of carbonyl compounds promoted by lewis acid using the InCl3/Et3SiH system. Org. Lett., 2009, 11(15), 3302-3305.
[51]
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 DNABiosensor. Biosens. Bioelectron., 2013, 48, 230-237.
[52]
Huang, S.N.; Pommier, Y.; Marchand, C. Tyrosyl-DNA phosphodiesterase 1 (Tdp1) inhibitors. Expert Opin. Ther. Pat., 2011, 21(9), 1285-1292.
[53]
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, J.A. Synthesis, in silico, in vitro and in vivo study of thieno[2,3- b]pyridine anticancer analogues. MedChemComm, 2015, 6(11), 1987-1997.
[54]
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.
[55]
Eurtivong, C.; Reynisson, J. The development of a weighted index to optimize compound libraries for high throughput screening. Mol. Inform., 2018.
[http://dx.doi.org/10.1002/minf.201800068]
[http://dx.doi.org/10.1002/minf.201800068]
Article Metrics
42
4
1
1