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

[ Vol. 19 , Issue. 10 ]

Author(s):

Marin N. Marinov, Emilia D. Naydenova*, Georgi T. Momekov, Rumyana Y. Prodanova, Nadezhda V. Markova, Yulian T. Voynikov and Neyko M. Stoyanov   Pages 1276 - 1284 ( 9 )

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.

Affiliation:

Department of General Chemistry, Faculty of Plant Protection and Agroecology, Agricultural University – Plovdiv, Plovdiv 4000, Department of Organic Chemistry, University of Chemical Technology and Metallurgy, Sofia 1756, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Department of General Chemistry, Faculty of Plant Protection and Agroecology, Agricultural University – Plovdiv, Plovdiv 4000, Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia 1113, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Department of Chemistry and Chemical Technologies, “Angel Kanchev” University of Ruse, Razgrad Branch, Razgrad 7200



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