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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

General Research Article

Anticancer Activity and Topoisomerase II Inhibition of Naphthalimides with ω-Hydroxylalkylamine Side-Chains of Different Lengths

Author(s): Mateusz D. Tomczyk, Anna Byczek-Wyrostek, Klaudia Strama, Martyna Wawszków, Przemysław Kasprzycki and Krzysztof Z. Walczak*

Volume 15, Issue 5, 2019

Page: [550 - 560] Pages: 11

DOI: 10.2174/1573406414666180912105851

Price: $65


Background: The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA.

Objective: To investigate the influence of type of substituents and substitution positions in 1,8- naphthalimde skeleton on the inhibition of Topoisomerase II activity.

Methods: The starting 1,8-naphthalimide were prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituents were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- positions using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines.

Results: Antiproliferative activity of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 µM to 7 µM) against model cancer cell lines. It was demonstrated that upon treatment with concentration of 200 µM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide.

Conclusion: The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activity. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.

Keywords: Naphthalimide, amonafide, mitonafide, anticancer, topoisomerase II, DNA intercalator.

Graphical Abstract
Hsiang, Y.H.; Jiang, J.B.; Liu, L.F. Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs. Mol. Pharmacol., 1989, 36, 371-376.
Kaina, B. DNA damage-triggered apoptosis: Critical role of DNA repair, double-strand breaks, cell proliferation and signaling. Biochem. Pharmacol., 2003, 66(8), 1547-1554.
Hsiang, Y.H.; Jiang, J.B.; Liu, L.F. Naphthalimides induce G2 arrest through the ATM-activated Chk2-executed pathway in HCT116 cells. Neoplasia, 2009, 11(11), 1226-1234.
Rosell, R.; Carles, J.; Abad, A.; Ribelle, N.; Barnadas, A.; Benavides, A.; Miguel, M. Phase study of mitonafide in 120 hour continuous. Invest. New Drugs, 1992, 10(3), 171-175.
Díaz-Rubio, E.; Martín, M.; López-Vega, J.M.; Casado, A.; Benavides, A. Phase I study of mitonafide with a 3-day administration schedule: Early interruption due to severe central nervous system toxicity. Invest. New Drugs, 1994, 12(4), 277-281.
Miller, A.A.; Case, D.; Harmon, M.; Savage, P.; Lesser, G.; Hurd, D.; Melin, S.A.J. Phase I study of lenalidomide in solid tumors. J. Thorac. Oncol., 2007, 2(5), 445-449.
Felder, T.B.; McLean, M.A.; Vestal, M.L.; Lu, K.; Farquhar, D.; Legha, S.S.; Shah, R.; Newman, R.A. Pharmacokinetics and metabolism of the antitumor drug amonafide (NCS308847) in humans. Drug Metab. Dispos., 1987, 15(6), 773-778.
Taningher, M.; Malacarne, D.; Izzotti, A.; Ugolini, D.; Parodi, S. Drug metabolism polymorphisms as modulators of cancer susceptibility. Mutat. Res., 1999, 436(3), 227-261.
Innocenti, F.; Iyer, L.; Ratain, M.J. Pharmacogenetics of anticancer agents: Lessons from amonafide and irinotecan. Drug Metab. Dispos., 2001, 29(4), 596-600.
Ratain, M.J.; Mick, R.; Berezin, F.; Janisch, L.; Schilsky, R.L.; Vogelzang, N.J.; Lane, L.B. Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res., 1993, 53(10), 2304-2308.
Norton, J.T.; Witschi, M.A.; Luong, L.; Kawamura, A.; Ghosh, S.; Stack, M.S.; Sim, E.; Avram, M.J.; Appella, D.H.; Huang, S. Synthesis and anticancer activities of 6-amino amonafide derivatives. Anticancer Drugs, 2008, 19(1), 23-36.
Braña, M.F.; Castellano, J.M.; Jimenez, A.; Llombart, A.; Rabadan, F.P.; Roldan, M.; Roldan, C.; Santos, A.; Vazquez, D. Synthesis, cytostatic activity and mode of action of a new series of imide derivatives of 3-nitro-1,8-naphthalic acid. Curr. Chemother., 1978, 2, 1216-1217.
Braña, M.F.; Castellano, J.M.; Roldán, C.M.; Santos, A.; Vazquez, D.; Jimenez, A. Synthesis and mode(s) of action of a new series of imide derivatives of 3-nitro-1,8-naphthalic acid. Cancer Chemother. Pharmacol., 1980, 4(1), 61-66.
Wang, K.; An, H.; Wang, Y.; Yan, X.; Li, R.; Chen, H.; Zhang, P.; Li, J.; Li, X.; Zhang, J. Synthesis, DNA binding properties and bioactivity of Naphthalimide Polyethylene Imine conjugates. Chinese J. Org. Chem., 2012, 32(4), 696-702.
Chen, Z.; Liang, X.; Zhang, H.; Xie, H.; Liu, J.; Xu, Y.; Zhu, W.; Wang, Y.; Wang, X.; Tan, S.; Kuang, D.; Qian, X. A new class of naphthalimide-based antitumor agents that inhibit topoisomerase II and induce lysosomal membrane permeabilization and apoptosis. J. Med. Chem., 2010, 53(6), 2589-2600.
Li, S.; Xu, S.; Tang, Y.; Ding, S.; Zhang, J.; Wang, S.; Zhou, G.; Zhou, C.; Li, X. Synthesis, anticancer activity and DNA-binding properties of novel 4-pyrazolyl-1,8-naphthalimide derivatives. Bioorg. Med. Chem. Lett., 2014, 24(2), 586-590.
Kokosza, K.; Andrei, G.; Schols, D.; Snoeck, R.; Piotrowska, D.G. Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues. Bioorg. Med. Chem., 2015, 23(13), 3135-3146.
Wang, K.; Wang, Y.; Yan, X.; Chen, H.; Ma, G.; Zhang, P.; Li, J.; Li, X.; Zhang, J. DNA binding and anticancer activity of naphthalimides with 4-hydroxyl-alkylamine side chains at different lengths. Bioorg. Med. Chem. Lett., 2012, 22(2), 937-941.
Zee-Cheng, R.K.; Cheng, C.C.N. -(Aminoalkyl)imide antineoplastic agents. Synthesis and biological activity. J. Med. Chem., 1985, 28(9), 1216-1222.
Khosravi, A.; Moradian, S.; Gharanjig, K.; Taromi, F.A. Synthesis and spectroscopic studies of some naphthalimide based disperse azo dyestuffs for the dyeing of polyester fibres. Dyes Pigments, 2006, 69(1-2), 79-92.
Qin, J.C.; Yan, J.; Wang, B.D.; Yang, Z.Y. Rhodamine-naphthalene conjugate as a novel ratiometric fluorescent probe for recognition of Al3+. Tetrahedron Lett., 2016, 57(17), 1935-1939.
Wells, C.H.J.; Wilson, J.A. Studies on nitroaromatic compounds. Part II. An electron spin resonance study of the radical anions of some nitronaphthalic anhydrides. J. Chem. Soc. B, 1971, 1588-1592.
Yuan, D.; Brown, R.G.; Hepworth, J.D.; Alexiou, M.S.; Tyman, J.H.P. The synthesis and fluorescence of novel N-substituted-1,8-naphthylimides. J. Heterocycl. Chem., 2008, 45(2), 397-404.
Berridge, M.V.; Tan, A.S.; McCoy, K.D.; Wang, R. The biochemical and cellular basis of cell proliferation assays that use tetrazolium salts. Biochemica, 1996, 4(1), 15-19.
Lombardo, T.; Anaya, L.; Kornblihtt, L.; Blanco, G. In:Flow Cytometry - Recent Perspectives; Schmid, I., Ed.; Intech Open Science, 2012. Chapter 20, 393-420.
Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.; Ribaucour, F.; Simon, G.; Sauvage, S.; Gaussin, J.F.; Tuti, J.; El Yazidi, M.; Van Vynckt, F.; Mijatovic, T.; Lefranc, F.; Darro, F.; Kiss, R. 2,2,2-Trichloro-N-(2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-ylcarbamoyl)acet-amide (UNBS3157), a novel nonhematotoxic naphthalimide deriv-ative with potent antitumor activity. J. Med. Chem., 2007, 50(17), 4122-4134.
Wang, K.R.; Qian, F.; Sun, Q.; Ma, C.L.; Rong, R.X.; Cao, Z.R.; Wang, X.M.; Li, X.L. Substituent effects on cytotoxic activity, spectroscopic property, and DNA binding property of naphthalimide derivatives. Chem. Biol. Drug Des., 2016, 87(5), 664-672.
Sharma, M.C.; Sharma, S.; Sharma, P.; Kumar, A. Comparative QSAR and pharmacophore modeling of substituted 2-[2′-(dimethylamino) ethyl]-1, 2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones derivatives as anti-tumor activity. Med. Chem. Res., 2013, 22(12), 5772-5788.
Quintana-Espinoza, P.; Martín-Acosta, P.; Amesty, Á.; Martín-Rodríguez, P.; Lorenzo-Castrillejo, I.; Fernández-Pérez, L.; Machín, F.; Estévez-Braun, A. 5-Ethynylarylnaphthalimides as antitumor agents: Synthesis and biological evaluation. Bioorg. Med. Chem., 2017, 25(6), 19760-1983.
Johnson, C.A.; Hudson, G.A.; Hardebeck, L.K.E.; Jolley, E.A.; Ren, Y.; Lewis, M.; Znosko, B.M. Effect of intercalator substituent and nucleotide sequence on the stability of DNA- and RNA-naphthalimide complexes. Bioorg. Med. Chem., 2015, 23(13), 3586-3591.
Wang, K.R.; Qian, F.; Yang, Z.B.; An, H.W.; Han, D.; Chen, H.; Zhang, P.Z. Li., X.L. Anticancer activity and DNA binding of 4-alkylenediamines modified naphthalimide derivatives. Lett. Drug Des. Discov., 2014, 11(6), 742-748.
Pourpak, A.; Landowski, T.H.; Dorr, R.T. Ethonafide-induced cytotoxicity is mediated by topoisomerase II inhibition in prostate cancer cells. J. Pharmacol. Exp. Ther., 2007, 321(3), 1109-1117.

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