Naphthoquinones represent the group of plant secondary metabolites with cytotoxic properties based on their ability to generate reactive oxygen species and interfere with the processes of cell respiration. Due to this fact, the possible cytotoxic mechanisms on cellular and subcellular levels are investigated intensively. There are many targets of cytotoxic action on the cellular level; however, DNA is a critical target of many cytotoxic compounds. Due to the cytotoxic properties of naphthoquinones, it is necessary to study the processes of naphthoquinones, DNA interactions (1,4-naphthoquinone, binapthoquinone, juglone, lawsone, plumbagin), especially by using modern analytical techniques. In our work, the Raman spectroscopy was used to determine the possible binding sites of the naphthoquinones on the DNA and to characterize the bond of naphthoquinone to DNA. Experimental data reveals the relationships between the perturbations of structure-sensitive Raman bands and the types of the naphthoquinones involved. The modification of DNA by the studied naphthoquinones leads to the nonspecific interaction, which causes the transition of B-DNA into A-DNA conformation. The change of the B-conformation of DNA for all measured DNA modified by naphthoquinones except plumbagin is obvious.

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 3 612 42 Brno Czech Republic

Department of Chemistry and Biochemistry Faculty of Agronomy Mendel University in Brno Zemedelska 1 613 00 Brno Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 3 612 42 Brno Czech Republic

Institute of Biophysics Academy of Sciences of the Czech Republic Kralovopolska 135 C612 65 Brno Czech Republic

Zentiva k s Development Department U Kabelovny 130 102 37 Praha 10 Czech Republic

See more in PubMed

Sakunphueak A, Panichayupakaranant P. Effects of donor plants and plant growth regulators on naphthoquinone production in root cultures of Impatiens balsamina. Plant Cell, Tissue and Organ Culture. 2010;102(1):9–15.

Babula P, Adam V, Havel L, Kizek R. Noteworthy secondary metabolites naphthoquinones—their occurrence, pharmacological properties and analysis. Current Pharmaceutical Analysis. 2009;5(1):47–68.

Babula P, Huska D, Hanustiak P, et al. Flow injection analysis coupled with carbon electrodes as the tool for analysis of naphthoquinones with respect to their content and functions in biological samples. Sensors. 2006;6(11):1466–1482.

Babula P, Mikelová R, Adam V, et al. Chromatographic analysis of naphthoquinones in plants. Chemicke Listy. 2006;100(4):271–276.

Emadi A, Le A, Harwood CJ, et al. Metabolic and electrochemical mechanisms of dimeric naphthoquinones cytotoxicity in breast cancer cells. Bioorganic and Medicinal Chemistry. 2011;19(23):7057–7062. PubMed PMC

Ross AE, Emadi A, Marchionni L, et al. Dimeric naphthoquinones, a novel class of compounds with prostate cancer cytotoxicity. BJU International. 2011;108(3):447–454. PubMed PMC

Nakagawa K. New developments in research on vitamin K biosynthesis. Journal of Health Science. 2010;56(6):623–631.

Oldenburg J, Marinova M, Müller-Reible C, Watzka M. The vitamin K cycle. Vitamins and Hormones. 2008;78:35–62. PubMed

Stafford DW. The vitamin K cycle. Journal of Thrombosis and Haemostasis. 2005;3(8):1873–1878. PubMed

Babula P, Adam V, Kizek R, Sladký Z, Havel L. Naphthoquinones as allelochemical triggers of programmed cell death. Environmental and Experimental Botany. 2009;65(2-3):330–337.

Aithal BK, Kumar MRS, Rao BN, Udupa N, Rao BSS. Juglone, a naphthoquinone from walnut, exerts cytotoxic and genotoxic effects against cultured melanoma tumor cells. Cell Biology International. 2009;33(10):1039–1049. PubMed

Gong K, Li W. Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: a potential new treatment for hepatocellular carcinoma. Free Radical Biology and Medicine. 2011;51(12):2259–2271. PubMed

Klaus V, Hartmann T, Gambini J, et al. 1,4-Naphthoquinones as inducers of oxidative damage and stress signaling in HaCaT human keratinocytes. Archives of Biochemistry and Biophysics. 2010;496(2):93–100. PubMed

Kitagawa RR, Bonacorsi C, da Fonseca LM, Vilegas W, Raddi MSG. Anti-Helicobacter pylori activity and oxidative burst inhibition by the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin from Paepalanthus latipes. Revista Brasileira de Farmacognosia. 2011;22(1):53–59.

Levin GS, Tremasova Ya. G, Kostova SV. On the mechanism of action of a synthetic 1,4-naphthoquinone derivative on the respiratory chain of liver and heart mitochondria. Biokhimiya. 1989;54(10):1630–1637. PubMed

Medentsev AG, Arinbasarova YA, Akimenko VK. Respiratory activity and naphthoquinone synthesis in the fungus Fusarium decemcellulare exposed to oxidative stress. Mikrobiologiya. 2002;71(2):176–182. PubMed

Medentsev AG, Maslov AN, Akimenko VK. Naphthoquinone metabolites of the fungi Fusarium and Verticillium: the mechanism of phytotoxic effect. Biokhimiya. 1990;55(10):1766–1772.

Beretta GL, Zunino F. Anthracycline Chemistry and Biology II: Mode of Action, Clinical Aspects and New Drugs. Vol. 283. Berlin, Germany: Springer; 2008. Molecular mechanisms of anthracycline activity; pp. 1–19. PubMed

Masarik M, Huska D, Adam V, et al. Doxorubicin and genomic DNA, new insights in drug-nucleic acids interactions. International Journal of Molecular Medicine. 2009;24:S49–S49.

Prusa R, Huska D, Adam V, et al. In vivo and in vitro electrochemical investigation of doxorubicin/ellipticine interaction with DNA. Clinical Chemistry. 2009;55(6):A217–A217.

Trnkova L, Stiborova M, Huska D, et al. Electrochemical biosensor for investigation of anticancer drugs interactions (doxorubicin and ellipticine) with DNA. IEEE Sensors Conference (SENSORS '09); October 2009; New York, NY, USA. pp. 1200–1203.

Hao Z-Y, Liu Q-W, Xu J, Jia L, Li S-B. Synthesis, characterization, antioxidant activities, and DNA-binding studies of (E)-N′-[1-(pyridin-2-yl)ethylidene]isonicotinohydrazide and its Pr(III) and Nd(III) complexes. Chemical and Pharmaceutical Bulletin. 2010;58(10):1306–1312. PubMed

Jovin TM, McIntosh LP, Arndt-Jovin DJ. Left-handed DNA: from synthetic polymers to chromosomes. Journal of Biomolecular Structure and Dynamics. 1983;1(1):21–57. PubMed

Khan N-UH, Pandya N, Kumar M, et al. Influence of chirality using Mn(iii) salen complexes on DNA binding and antioxidant activity. Organic and Biomolecular Chemistry. 2010;8(19):4297–4307. PubMed

Pizarro AM, Habtemariam A, Sadler PJ. Activation mechanisms for organometallic anticancer complexes. Topics in Organometallic Chemistry. 2010;32:21–56.

Sachs EF, Nadler A, Diederichsen U. A DNA and metal binding hybrid based on triostin A. Journal of Peptide Science. 2010;16:86–86.

Tajmirriahi HA, Langlais M, Savoie R. Metal Ions in Biology and Medicine. 1990. A comparative-study of DNA interaction with divalent metal-ions—metal-ion binding-sites and DNA conformational-changes, studied by laser Raman-spectroscopy; pp. 561–563.

Woisard A, Fazakerley GV, Guschlbauer W. Z-DNA is formed by poly(dC-DG) and poly (dm5C-dG) at micro or nanomolar concentrations of some zinc(II) and copper(II) complexes. Journal of Biomolecular Structure and Dynamics. 1985;2(6):1205–1220. PubMed

Zimmer C, Luck G. Conformation and reactivity of DNA. VI. Circular dichroism studies of salt induced conformational changes of DNAs of different base composition. Biochimica et Biophysica Acta. 1974;361(1):11–32. PubMed

Brozovic A, Damrot J, Tsaryk R, et al. Cisplatin sensitivity is related to late DNA damage processing and checkpoint control rather than to the early DNA damage response. Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis. 2009;670(1-2):32–41. PubMed

Vrána O, Mašek V, Dražan V, Brabec V. Raman spectroscopy of DNA modified by intrastrand cross-links of antitumor cisplatin. Journal of Structural Biology. 2007;159(1):1–8. PubMed

Zhang R, Niu Y, Zhou Y. Increase the cisplatin cytotoxicity and cisplatin-induced DNA damage in HepG2 cells by XRCC1 abrogation related mechanisms. Toxicology Letters. 2010;192(2):108–114. PubMed

Brabec V, Vrana O, Boudny V. Superhelical torsion controls DNA interstrand cross-linking by antitumor cisplatin. Progress in Biophysics and Molecular Biology. 1996;65:PB113–PB113. PubMed PMC

Katsuda Y, Yoshikawa Y, Sato T, et al. Cisplatin and its analogues induce a significant change in the higher-order structure of long duplex DNA. Chemical Physics Letters. 2009;473(1–3):155–159.

Wermann H, Stoop H, Gillis AJM, et al. Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. Journal of Pathology. 2010;221(4):433–442. PubMed

Yu JJ, Liang XB, Yan QW, et al. Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy—Molecular Mechanisms and Clinical Applications. Totowa, NJ, USA: Humana Press; 2009. CHK2 and ERCC1 in the DNA adduct repair pathway that mediates acquired cisplatin resistance; pp. 189–194.

da Silva MN, Ferreira VF, De Souza MCBV. An overview of the chemistry and pharmacology of naphthoquinones with emphasis on β-Lapachone and derivatives. Quimica Nova. 2003;26(3):407–416.

Wei C, Jia G, Yuan J, Feng Z, Li C. A spectroscopic study on the interactions of porphyrin with G-quadruplex DNAs. Biochemistry. 2006;45(21):6681–6691. PubMed

Kawiak A, Królicka A, Łojkowska E. In vitro cultures of Drosera aliciae as a source of a cytotoxic naphthoquinone: ramentaceone. Biotechnology Letters. 2011;33(11):2309–2316. PubMed

Kontogiannopoulos KN, Assimopoulou AN, Dimas K, Papageorgiou VP. Shikonin-loaded liposomes as a new drug delivery system: physicochemical characterization and in vitro cytotoxicity. European Journal of Lipid Science and Technology. 2011;113(9):1113–1123.

Kitagawa RR, Vilegas W, Carlos IZ, Raddi MSG. Antitumor and immunomodulatory effects of the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin. Revista Brasileira de Farmacognosia. 2011;21(6):1084–1088.

Plyta ZF, Li T, Papageorgiou VP, et al. Inhibition of topoisomerase I by naphthoquinone derivatives. Bioorganic and Medicinal Chemistry Letters. 1998;8(23):3385–3390. PubMed

Babula P, Vanco J, Krejcova L, et al. Voltammetric characterization of Lawsone-Copper(II) ternary complexes and their interactions with dsDNA. International Journal of Electrochemical Science. 2012;7(8):7349–7366.

Bulovas A, Dirvianskyte N, Talaikyte Z, et al. Electrochemical and structural properties of self-assembled monolayers of 2-methyl-3-(ω-mercaptoalkyl)-1,4-naphthoquinones on gold. Journal of Electroanalytical Chemistry. 2006;591(2):175–188.

Sajan D, Laladhas KP, Hubert Joe I, Jayakumar VS. Vibrational spectra and density functional theoretical calculations on the antitumor drug, plumbagin. Journal of Raman Spectroscopy. 2005;36(10):1001–1011.

Carvalho CEM, Brinn IM, Pinto AV, Pinto MDCFR. Fluorescent symmetric phenazines from naphthoquinones 3. Steady-state spectroscopy and solvent effect of seven phenazine derivatives: structure-photophysics correlations. Journal of Photochemistry and Photobiology A. 2000;136(1-2):25–33.

Carvalho CEM, de Lucas NC, Herrera JOM, Pinto AV, Pinto MCFR, Brinn IM. Fluorescent symmetric phenazines from naphthoquinones 4. Solvent effect on time-resolved fluorescence. Journal of Photochemistry and Photobiology A. 2004;167(1):1–9.

Balakrishnan G, Babaei A, McQuillan AJ, Umapathy S. Resonance Raman and infrared spectral studies on radical anions of model photosynthetic reaction center quinones (naphthoquinone derivatives) Journal of Biomolecular Structure and Dynamics. 1998;16(1):123–131. PubMed

Burie J-R, Boussac A, Boullais C, et al. FTIR spectroscopy of UV-generated quinone radicals: evidence for an intramolecular hydrogen atom transfer in ubiquinone, naphthoquinone, and plastoquinone. Journal of Physical Chemistry. 1995;99(12):4059–4070.

Kažemekaite M, Railaite V, Bulovas A, et al. Synthesis, self-assembling and redox properties of 2-[(ω-sulfanylalkyl)amino]-1,4-naphthoquinones. Collection of Czechoslovak Chemical Communications. 2006;71(9):1383–1391.

Umadevi M, Ramasubbu A, Vanelle P, Ramakrishnan V. Spectral investigations on 2-methyl-1,4-naphthoquinone: solvent effects, host-guest interactions and SERS. Journal of Raman Spectroscopy. 2003;34(2):112–120.

Leopold N, Lendl B. A new method for fast preparation of highly surface-enhanced raman scattering (SERS) active silver colloids at room temperature by reduction of silver nitrate with hydroxylamine hydrochloride. Journal of Physical Chemistry B. 2003;107(24):5723–5727.

Munro CH, Smith WE, Garner M, Clarkson J, White PC. Characterization of the surface of a citrate-reduced colloid optimized for use as a substrate for surface-enhanced resonance raman scattering. Langmuir. 1995;11(10):3712–3720.

Prescott B, Steinmetz W, Thomas GJ., Jr. Characterization of DNA structures by laser Raman spectroscopy. Biopolymers. 1984;23(2):235–256. PubMed

Rodger A. Linear dichroism. Methods in Enzymology. 1993;226:232–258. PubMed

Bugarcic T, Nováková O, Halámiková A, et al. Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes. Journal of Medicinal Chemistry. 2008;51(17):5310–5319. PubMed

Dalla Via L, Gia O, Magno SM, Dolmella A, Marton D, Di Noto V. Synthesis, characterization and biological activity of platinum(II) complexes with l- and d-ornithine ligands. Inorganica Chimica Acta. 2006;359(13):4197–4206.

Giovagnini L, Marzano C, Bettio F, Fregona D. Mixed complexes of Pt(II) and Pd(II) with ethylsarcosinedithiocarbamate and 2-/3-picoline as antitumor agents. Journal of Inorganic Biochemistry. 2005;99(11):2139–2150. PubMed

Žaludová R, Natile G, Brabec V. The effect of antitumor trans-[PtCl2(E-iminoether)2] on B→Z transition in DNA. Anti-Cancer Drug Design. 1997;12(4):295–309. PubMed

Duguid J, Bloomfield VA, Benevides J, Thomas GJ., Jr. Raman spectroscopy of DNA-metal complexes. I. Interactions and conformational effects of the divalent cations: Mg, Ca, Sr, Ba, Mn, Co, Ni, Cu, Pd, and Cd. Biophysical Journal. 1993;65(5):1916–1928. PubMed PMC

Marzilli LG, Saad JS, Kuklenyik Z, Keating KA, Xu Y. Relationship of solution and protein-bound structures of DNA duplexes with the major intrastrand cross-link lesions formed on cisplatin binding to DNA. Journal of the American Chemical Society. 2001;123(12):2764–2770. PubMed

Serban D, Benevides JM, Thomas GJ., Jr. DNA secondary structure and Raman markers of supercoiling in Escherichia coli plasmid pUC19. Biochemistry. 2002;41(3):847–853. PubMed

Benevides JM, Kawakami J, Thomas GJ., Jr. Mechanisms of drug-DNA recognition distinguished by Raman spectroscopy. Journal of Raman Spectroscopy. 2008;39(11):1627–1634.

Benevides JM, Overman SA, Thomas GJ., Jr. Raman, polarized Raman and ultraviolet resonance Raman spectroscopy of nucleic acids and their complexes. Journal of Raman Spectroscopy. 2005;36(4):279–299.

Deng H, Bloomfield VA, Benevides JM, Thomas GJ. Dependence of the raman signature of genomic B-DNA on nucleotide base sequence. Biopolymers. 1999;50(6):656–666. PubMed

Duguid JG, Bloomfield VA, Benevides JM, Thomas GJ., Jr. Raman spectroscopy of DNA-metal complexes. II. The thermal denaturation of DNA in the presence of Sr2+, Ba2+, Mg2+, Ca2+, Mn2+, Co2+, Ni2+, and Cd2+ . Biophysical Journal. 1995;69(6):2623–2641. PubMed PMC

Duguid JG, Bloomfield VA, Benevides JM, Thomas GJ., Jr. DNA melting investigated by differential scanning calorimetry and Raman spectroscopy. Biophysical Journal. 1996;71(6):3350–3360. PubMed PMC

Morari CI, Muntean CM. Numerical simulations of Raman spectra of guanine-cytosine Watson-Crick and protonated Hoogsteen base pairs. Biopolymers. 2003;72(5):339–344. PubMed

Muntean CM, Bratu I. Raman spectroscopic study on the subpicosecond dynamics in calf-thymus DNA, upon lowering the pH and in the presence of Mn2+ ions. Spectroscopy. 2008;22(6):475–489.

Muntean CM, Dostál L, Misselwitz R, Welfle H. DNA structure at low pH values, in the presence of Mn2+ ions: a Raman study. Journal of Raman Spectroscopy. 2005;36(11):1047–1051.

Muntean CM, Segers-Nolten GMJ. Raman microspectroscopic study of effects of Na(I) and Mg(II) ions on low pH induced DNA structural changes. Biopolymers. 2003;72(4):225–229. PubMed

Peticolas WL, Dai Z, Thomas GA. The use of Raman spectroscopy to characterize double B/Z conformational junctions in DNA. Journal of Molecular Structure. 1991;242:135–141.

Rajani C, Kincaid JR, Petering DH. The presence of two modes of binding to calf thymus DNA by metal-free bleomycin: a low frequency Raman study. Biopolymers. 1999;52(3):129–146. PubMed

Schmitt M, Popp J. Raman spectroscopy at the beginning of the twenty-first century. Journal of Raman Spectroscopy. 2006;37(1–3):20–28.

Evertsz EM, Thomas GA, Peticolas WL. Raman spectroscopic studies of the DNA Crobinding site conformation, free and bound to cro protein. Biochemistry. 1991;30(4):1149–1155. PubMed

Dadarlat VM, Saxena VK. Stability of triple-helical poly(dT)-poly(dA)-poly(dT) DNA with counterions. Biophysical Journal. 1998;75(1):70–91. PubMed PMC

Gróf P, Aslanian D, Rontó G. Changes of phage T7 nucleoprotein structure at low ionic strength. A Raman spectroscopic study. Biochimica et Biophysica Acta. 1996;1289(1):95–104. PubMed

Muntean CM, Puppels GJ, Greve J, Segers-Nolten GMJ, Cinta-Pinzaru S. Raman microspectroscopic study on low-pH-induced DNA structural transitions in the presence of magnesium ions. Journal of Raman Spectroscopy. 2002;33(10):784–788.

Aubrey KL, Casjens SR, Thomas GJ., Jr. Secondary structure and interactions of the packaged dsDNA genome of bacteriophage P22 investigated by Raman difference spectroscopy. Biochemistry. 1992;31(47):11835–11842. PubMed

Muntean CM, Bratu I. Molecular relaxation processes in calf-thymus DNA, in the presence of Mn2+ and Na+ ions: a Raman spectroscopic study. Spectroscopy. 2008;22(5):345–359.

Stangret J, Savoie R. Vibrational spectroscopic study of the interaction of metal ions with diethyl phosphate, a model for biological systems. Canadian Journal of Chemistry. 1992;70(12):2875–2883.

Mukherjee S, Bhattacharyya D. Effect of phosphorothioate chirality on the grooves of DNA double helices: a molecular dynamics study. Biopolymers. 2004;73(2):269–282. PubMed

Shanmugasundaram M, Puranik M. Computational prediction of vibrational spectra of normal and modified DNA nucleobases. Journal of Raman Spectroscopy. 2009;40(12):1726–1748.

Qi J, Liu B, Li Y, Wu D, Tang W. Raman spectroscopic study on Hela cells irradiated by X rays of different doses. Chinese Optics Letters. 2009;7(8):734–737.

Lin D, Lin J, Wu Y, et al. Investigation on the interactions of lymphoma cells with paclitaxel by Raman spectroscopy. Spectroscopy. 2011;25(1):23–32.

Gfrorer A, Schnetter ME, Wolfrum J, Greulich KO. Double and triple helices of nucleic-acid polymers, studied by Uv-resonance Raman-spectroscopy. Berichte der Bunsengesellschaft für Physikalische Chemie. 1993;97(2):155–162.

Krafft C, Hinrichs W, Orth P, Saenger W, Welfle H. Interaction of Tet repressor with operator DNA and with tetracycline studied by infrared and Raman spectroscopy. Biophysical Journal. 1998;74(1):63–71. PubMed PMC

Movileanu L, Benevides JM, Thomas GJ., Jr. Temperature dependence of the Raman spectrum of DNA. Part I—Raman signatures of premelting and melting transitions of Poly(dA-dT) · poly(dA-dT) Journal of Raman Spectroscopy. 1999;30(8):637–649. PubMed

Muntean CM, Bratu I. Molecular dynamics in calf-thymus DNA, at neutral and low pH, in the presence of Na+, Ca2+ and Mg2+ ions: a Raman microspectroscopic study. Spectroscopy. 2007;21(4):193–204.

Muntean CM, Nalpantidis K, Feldmann I, Deckert V. Zn2+-DNA interactions in aqueous systems: a Raman spectroscopic study. Spectroscopy. 2009;23(3-4):155–163.

Toyama A, Matsubuchi A, Fujimoto N, Takeuchi H. Isotope-edited UV Raman spectroscopy of protein-DNA interactions: binding modes of cyclic AMP receptor protein to a natural DNA recognition site. Journal of Raman Spectroscopy. 2005;36(4):300–306.

Clement RM, Sturm J, Daune MP. Interaction of metallic cations with DNA. VI. Specific binding of Mg++ and Mn++ . Biopolymers. 1973;12(2):405–421.

Iyandurai N, Sarojini R. Selenomethionine induced changes on the binding of spermine with DNA: a study by Fourier transform Raman and Fourier Transform infra red spectroscopy. International Journal of Pharmacology. 2009;5(2):126–136.

Notingher I, Verrier S, Romanska H, Bishop AE, Polak JM, Hench LL. In situ characterisation of living cells by Raman spectroscopy. Spectroscopy. 2002;16(2):43–51.

Yao H, Tao Z, Ai M, et al. Raman spectroscopic analysis of apoptosis of single human gastric cancer cells. Vibrational Spectroscopy. 2009;50(2):193–197.