Synthesis, Characterization, Quantum-Chemical Calculations and Cytotoxic Activity of 1,8-Naphthalimide Derivatives with Non-Protein Amino Acids

Author(s): Marin N. Marinov, Emilia D. Naydenova*, Georgi T. Momekov, Rumyana Y. Prodanova, Nadezhda V. Markova, Yulian T. Voynikov, Neyko M. Stoyanov

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

Volume 19 , Issue 10 , 2019

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Graphical Abstract:


Background: The 1,8-Naphthalimides constitute an important class of biologically active, DNAbinding compounds. There are no available data on the synthesis of 1,8-naphthalimide derivatives with nonprotein amino acids and their biological activity. The aim of this paper was to determine the synthesis, structural characterization and cytotoxic activity of new 1-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)cycloalkane-1- carboxylic acids with 5-, 6-, 7-, 8- and 12-membered rings as well as 2-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)- yl)adamantane-2-carboxylic acid and 1-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-1,2,3,4-tetrahydronaphthalene- 1-carboxylic acid.

Methods: The target compounds were obtained by an interaction of 1,8-naphthalic anhydride with a series of non-protein amino acids. The optimized geometry and harmonic vibrational frequencies have been calculated by DFT employing B3LYP functional using 6-31G(d,p) basis set. An ab initio (MP2 and Hartee-Fock) and DFT (different functionals) using several basis sets have been applied for NMR calculations. The cytotoxic effects of the synthesized compounds are assessed against two human tumor cell lines, namely K-562 (chronic myeloid leukemia) and HUT-78 (cutaneous T-cell lymphoma) after 72 h exposure, using the MTT-dye reduction assay. The apoptogenic effects and the ability to modulate the NFκB-signaling pathways were determined using commercially available ELISA kits.

Results: All compounds inhibited the growth of malignant cells at micromolar concentrations whereby compound 4b (1-(1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)cyclohexane-1-carboxylic acid) demonstrated superior activity in both cell lines with IC50 values comparable to those of the reference anticancer drug melphalan.

Conclusion: New 1,8-naphthalimide derivatives with non-protein amino acids were successfully synthesized. Quantum-chemical calculations were performed to elucidate the structure of the newly synthesized compounds. There is a proper alignment between theoretical and experimental results. The cytotoxicity of the synthesized products against two human tumor cell lines, namely K-562 and HUT-78 was evaluated. All compounds inhibited the growth of malignant cells at micromolar concentrations. The pharmacodynamics evaluation of compound 4b showed that its cytotoxicity is mediated by induction of apoptosis and inhibition of NFκB-signaling.

Keywords: 1, 8-Naphthalimides, Non-protein amino acids, Synthesis, DFT, GIAO, Cytotoxicity, MTT.

Kamal, A.; Bolla, N.R.; Srikanth, P.S.; Srivastava, A.K. Naphthalimide derivatives with therapeutic characteristics: A patent review. Expert Opin. Ther. Pat., 2013, 23(3), 299-317.
Banerjee, S.; Veale, E.B.; Phelan, C.M.; Murphy, S.A.
Tocci, G.M.; Gillespie, L.J.; Frimannsson, D.O.; Kelly, J.M.; Gunnlaugsson, T. Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents. Chem. Soc. Rev., 2013, 42, 1601-1618.
Wang, K-R.; Qian, F.; Wang, X-M.; Tan, G-H.; Rong, R-X.; Cao, Z-R.; Chen, H.; Zhang, P-Z.; Li, X-L. Cytotoxic activity and DNA binding of naphthalimide derivatives with amino acid and dichloroacetamide functionalizations. Chin. Chem. Lett., 2014, 25(7), 1087-1093.
Braña, M.F.; Ramos, A. Naphthalimides as anticancer agents: synthesis and biological activity. Anticancer. Agents Med. Chem., 2001, 1(3), 237-255.
Braña, M.F.; Sanz, A.M.; Castellano, J.M.; Roldán, C.M.; Roldán, C. Synthesis and cytostatic activity of benz(d.e)isoquinolin-1.3-diones. Structure-activity relationships. Eur. J. Med. Chem., 1981, 16, 207-212.
Braña, M.F.; Berlanga, J.M.C.; Roldan, C.M. 4-acylamino-nphenylbutyramides- useful as pharmaceuticals. DE Patent 2,318, 136, November, 08, 1973.
Braña, M.F.; Castellano, J.M.; Roldán, C.M.; Santos, A.; Vázquez, D.; Jiménez, 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.
Braña, M.F.; Castellano, J.M.; Jiménez, A.; Lombart, A.; Rabadan, F.P.; Roldán, M.; Roldán, C.; Santos, A.; Vázquez, D. Synthesis, cytostatic activity and mode of action of a new series of imide derivatives of 3-nitro-11α naphtalic acid. Curr. Chemother, 1978, 2, 1216-1217.
Waring, M.J.; Gonzalez, A.; Jimenez, A.; Vazquez, D. Intercalative binding to DNA of antitumour drugs derived from 3-nitro-1, 8-naphthalic acid. Nucleic Acids Res., 1979, 7(1), 217-230.
Hsiang, Y.H.; Jiang, J.B.; Liu, L.F. Topoisomerase II-mediated DNA cleavage by amonafide and its structural analogs. Mol. Pharmacol., 1989, 36(3), 371-376.
Wu, A.; Xu, Y.; Qian, X. Novel naphthalimide-amino acid conjugates with flexible leucine moiety as side chain: Design, synthesis and potential antitumor activity. Bioorg. Med. Chem., 2009, 17(2), 592-599.
Yang, Q.; Yang, P.; Qian, X.; Tong, L. Naphthalimide intercalators with chiral amino side chains: Effects of chirality on DNA binding, photodamage and antitumor cytotoxicity. Bioorg. Med. Chem. Lett., 2008, 18(23), 6210-6213.
Ramchander, J. Synthesis of 3 (N(1,3dioxo 1H benzo[de] isoquinolin-2(3H)-yl)alkyl)-2-(4-substituted) phenylthiazolidine-4-carboxylic acid. Der Pharma Chem., 2015, 7(11), 288-293.
Duke, R.M.; Veale, E.B.; Pfeffer, F.M.; Kruger, P.E.; Gunnlaugsson, T. Colorimetric and fluorescent anion sensors: An overview of recent developments in the use of 1,8-naphthalimide-based chemosensors. Chem. Soc. Rev., 2010, 39, 3936-3953.
Gunnlaugsson, T.; Glynn, M.; Tocci, G.M.; Kruger, P.E.; Pfeffer, F.M. Anion recognition and sensing in organic and aqueous media using luminescent and colorimetric sensors. Coord. Chem. Rev., 2006, 250(23-24), 3094-3117.
Li, Y.; Cao, L.; Tian, H. Fluoride ion-triggered dual fluorescence switch based on naphthalimides winged zinc porphyrin. J. Org. Chem., 2006, 71(21), 8279-8282.
Patrick, L.G.F.; Whiting, A. Synthesis and application of some polycondensable fluorescent dyes. Dyes Pigm, 2002, 52(2), 137-143.
Martin, E.; Weigand, R.; Pardo, A. Solvent dependence of the inhibition of intramolecular charge-transfer in N-substituted 1,8-naphthalimide derivatives as dye lasers. J. Lumin., 1996, 68(2-4), 157-164.
Tao, Z-F.; Qian, X. Naphthalimide hydroperoxides as photonucleases: Substituent effects and structural basis. Dyes Pigm., 1999, 43(2), 139-145.
Stewart, W.W. Synthesis of 3,6-disulfonated 4-aminonaphthalimides. J. Am. Chem. Soc., 1981, 103(25), 7615-7620.
Bouché, C-M.; Berdagué, P.; Facoetti, H.; Robin, P.; Barny, P.; Schott, M. Side-chain electroluminescent polymers. Synth. Met., 1996, 81(2-3), 191-195.
Tian, H.; Gan, J.; Chen, K.; He, J.; Song, Q.L.; Hou, X.Y. Positive and negative fluorescent imaging induced by naphthalimide polymers. J. Mater. Chem., 2002, 12, 1262-1267.
Zhu, W.; Hu, M.; Yao, R.; Tian, H. A novel family of twisted molecular luminescent materials containing carbazole unit for single-layer organic electroluminescent devices. Photochem. Photobiol. A: Chem, 2003, 154(2-3), 169-177.
Grabchev, I.; Chovelon, J-M. Synthesis and functional properties of green fluorescent poly(methylmethacrylate) for use in liquid crystal systems. Polym. Adv. Technol., 2003, 14, 601-608.
Cosnard, F.; Wintgens, V. A new fluoroionophore derived from 4-amino-N-methyl-1,8-naphthalimide. Tetrahedron Lett., 1998, 39(18), 2751-2754.
De Souza, M.M.; Corrêa, R.; Cechinel, F.V.; Grabchev, I.; Bojinov, V. 4-Nitro-1,8-naphthalimides exhibit antinociceptive properties. Pharmazie, 2002, 57, 430-431.
Connors, T.A.; Elson, L.A.; Haddow, A.; Ross, W.C.J. The tumor growth inhibitory activity of 1-aminocyclopentanecarboxylic acid and related peptides. Biochem. Pharmacol., 1958, 1, 239-240.
Martel, F.; Berlinguet, L. Impairment of tumor growth by unnatural amino acids. Can. J. Biochem. Physiol., 1959, 37, 433-439.
Benefiel, W.W.; Helsper, J.T.; Sharp, G.S. Apparent control of multiple myeloma by 1-aminocyclopentane-1-carboxylic acid (NSC-1026). Cancer Chemother. Rep., 1960, 9, 21-22.
Goldin, A.; Vendditi, J.M.; Kline, I.; Mantel, N. Evaluation of antileukemic agents employing advanced Leukemia L-1210 in mice IV. Cancer Res., 1961, 21, 27-39.
Ross, R.B.; Noll, C.I.; Ross, W.C.J.; Nadkarni, M.V.; Morrison, B.H.; Bond, H.W. Cycloaliphatic amino acids in cancer chemotherapy. J. Med. Pharm. Chem., 1961, 3, 1-23.
Krant, M.J.; Iszard, D.M.; Abadi, A.; Carey, R.W. Treatment of multiple myeloma by 1-aminocyclopentanecarboxylic acid (NSC-1026). Cancer Chemother. Rep., 1962, 22, 59-64.
Hayes, R.L.; Washburn, L.C.; Wieland, B.W.; Sun, T.T.; Turtle, R.R.; Butler, T.A. Carboxy-labeled 11C-1-aminocyclopentanecarboxylic acid, a potential agent for cancer detection. J. Nucl. Med., 1976, 17, 748-751.
Staykova, S.T.; Wesselinova, D.W.; Vezenkov, L.T.; Naydenova, E.D. Synthesis and in vitro antitumor activity of new octapeptide analogs of somatostatin containing unnatural amino acids. Amino Acids, 2015, 47(5), 1007-1013.
Marinov, M.; Ganchev, D.; Nikolov, A.; Marinova, P.; Krustev, S.; Madzharova, V.; Stoyanov, N. In vitro fungicidal activity of cyclopentanespiro-5-hydantoin and its derivatives towards Blumeria graminis f. sp. tritici. Agric. Sci., 2013, 12, 97-101.
Marinov, M.N.; Ganchev, D.H.; Marinova, P.E.; Nikolov, A.S.; Prodanova, R.Y.; Krustev, S.V.; Zlateva, M.R.; Stoyanov, N.M. In vivo insecticidal activity of cyclopentanespiro-5-hydantoin and its two derivatives towards Oleander aphid (Aphis nerii) and effect on Buddleja davidii. J. Sci. Appl. Res, 2013, 4, 171-177.
Stoyanov, N.; Marinov, M. Two methods for spirothiohydantoin synthesis. Acta Chim. Slov., 2012, 59, 680-685.
Marinov, M.N.; Naydenova, E.D.; Prodanova, R.Y.; Stoyanov, N.M. Synthesis of some non-protein amino acids derived from spirohydantoins. J. Sci. Appl. Res, 2016, 10, 39-46.
Granovsky, A.A. Firefly version 8. gran/firefly/index.html
Schmidt, M.W.; Baldridge, K.K.; Boatz, J.A.; Elbert, S.T.; Gordon, M.S.; Jensen, J.H.; Koseki, S.; Matsunaga, N.; Nguyen, K.A.; Su, S.; Windus, T.L.; Dupuis, M.; Montgomery, Jr, J.A. General atomic and molecular electronic structure system. J. Comput. Chem., 1993, 14(11), 1347-1363.
Gordon, M.S.; Schmidt, M.W. Advances in electronic structure theory: GAMESS a decade later.In: Theory and Applications of Computational Chemistry: The first forty years; Dykstra, C.E.; Frenking, G.; Kim, K.S.; Scuseria, G.E., Eds.; Elsevier, 2005, pp. 1167-1189.
Wolinski, K.; Hinton, J.F.; Pulay, P. Efficient implementation of the gauge-independent atomic orbital method for NMR chemical shift calculations. J. Am. Chem. Soc., 1990, 112, 8251-8260.
Ditchfield, R. Self-consistent perturbation theory of diamagnetism. Mol. Phys., 1974, 27, 789-807.
Tomasi, J.; Mennucci, B.; Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev., 2005, 105(8), 2999-3093.
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.P.; Izmaylov, A.F.; Bloino, J.; Zheng, G.; Sonnenberg, J.L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J.A., Jr; Peralta, J.E.; Ogliaro, F.; Bearpark, M.; Heyd, J.J.; Brothers, E.; Kudin, K.N.; Staroverov, V.N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J.C.; Iyengar, S.S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J.M.; Klene, M.; Knox, J.E.; Cross, J.B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.; Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.; Ochterski, J.W.; Martin, R.L.; Morokuma, K.; Zakrzewski, V.G.; Voth, G.A.; Salvador, P.; Dannenberg, J.J.; Dapprich, S.; Daniels, A.D.; Farkas, Ö.; Foresman, J.B.; Ortiz, J.V.; Cioslowski, J.; Fox, D.J. Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford, CT, 2009.
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.
Konstantinov, S.; Eibl, M.H.; Berger, M.R. BCR-ABL influences the antileukemic efficacy of alkylphosphocholines. Br. J. Haematol., 1999, 107, 365-374.
Bucherer, H.T.; Lieb, V.A. On the formation of substituted hydantoins from aldehydes and ketones. Synthesis of hydantoins. J. Prakt. Chem., 1934, 141(1-2), 5-43.
Naydenova, E.; Pencheva, N.; Popova, J.; Stoyanov, N.; Lazarova, M.; Aleksiev, B. Aminoderivatives of cycloalkanespirohydantoins: Synthesis and biological activity. Farmaco, 2002, 57(3), 189-194.
Marinov, M.; Naydenova, E.; Prodanova, R.; Markova, N.; Marinova, P.; Kostova, I.; Valcheva, I.; Draganova, D.; Naydenov, M.; Penchev, P.; Stoyanov, N. Synthesis, characterization, theoretical calculations and antimicrobial studies of substituted 3-amino-cyclohexanespiro-5-hydantoins. Agric. Sci., 2016, 19, 117-122.
Nagasawa, H.T.; Elberling, J.A.; Shirota, F.N. 2-Aminoadamantane-2-carboxylic acid, a rigid, achiral, tricyclic α-amino acid with transport inhibitory properties. J. Med. Chem., 1973, 16(7), 823-826.
Marinov, M.; Marinova, P.; Stoyanov, N.; Markova, N.; Enchev, V. Synthesis of 3′,4′-dihydro-2H,2‘H,5H-spiro[imidazolidine-4,1’-naphthalene]-2,5-dione and its derivatives. Acta Chim. Slov., 2014, 61, 420-424.
Marinov, M.N.; Bakalova, S.M.; Prodanova, R.Y.; Markova, N.V. Conformational and spectral properties of newly synthesized compounds obtained by reaction of alrestatin with 3-amino-cycloalkanespiro-5-hydantoins. Bulg. Chem. Commun., 2017, 49, 146-152.
Blicharska, B.; Kupka, T. Theoretical DFT and experimental NMR studies on uracil and 5-fluorouracil. J. Mol. Struct., 2002, 613, 153-166.
d’Antuono, P.; Botek, E.; Champagne, B.; Wieme, J.; Reyniers, M-F.; Marin, G.B.; Adriaensens, P.J.; Gelan, J.M. Density functional theory investigation of the stereochemistry effects on 1H and 13C NMR chemical shifts of poly(vinyl chloride) oligomers. Chem. Phys. Lett., 2005, 411(1-3), 207-213.

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Year: 2019
Published on: 23 October, 2019
Page: [1276 - 1284]
Pages: 9
DOI: 10.2174/1871520619666190307115231
Price: $65

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