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Dimerization enhances cytotoxicity and tumor/non-tumor cell selectivity of juglone

Gregor C. Mittag, Isabell Wiengarn, Niels V. Heise, Sophie Hoenke, Hans-Peter Deigner, René Csuk

Abstract


The study investigates the biological activity of spaced juglone dimers derived from the reaction of juglone with dicarboxylic acid dichlorides of varying chain lengths. It builds upon the observation that dimeric structures can exhibit enhanced biological activity compared to their monomeric counterparts. The cytotoxic effects of the synthesized compounds were assessed against a range of human cancer cell lines and non-malignant fibroblasts. Results indicate that the cytotoxicity varied depending on the length of the spacer, with specific dimers showing significantly improved activity. Furthermore, these compounds demonstrated a higher selectivity towards cancer cell lines than non-malignant fibroblasts, suggesting potential for targeted anticancer therapy. 

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- I. Kocacaliskan, T. AkgüL, S. Erisen, Effect of Juglone on Seed Germination and Seedling Growth of Four Common Vegetables, Intern.

J. Life Sci. Biotechnol., 2019, 2(1), 43-49.

- C. Hartwich, Ueber die Fruchtschale von Juclans regia L, Arch. Pharm., 1887, 225, 325-335.

- A. Bernthsen, A. Semper, Uber die Constitution des Juglons und seine Synthese aus Naphthalin, Ber. Deutsch. Chem. Ges., 1887, 20(1), 934-941.

- T. Ahmad, Y.J. Suzuki, Juglone in oxidative stress and cell signaling, Antioxidants, 2019, 8(4), 91.

- S. Azam, R. Pandey, Anshuman, R. Kumar, D. Raj, Vaibhav, A. Kumar, A review on naphthoquinone derivatives as potential antimicrobial agents, Indo Am. J. Pharm. Sci., 2023, 10(6), 16-21.

- J.T. Carrillo, D. Borthakur, Do uncommon plant phenolic compounds have uncommon properties A mini review on novel flavonoids, J. Bioresour. Bioprod., 2021, 6(4), 279-291.

- E. Catanzaro, G. Greco, L. Potenza, C. Calcabrini, C. Fimognari, Natural products to fight cancer: a focus on Juglans regia, Toxins, 2018, 10(11), 469.

- M. Furqan, A. Fayyaz, F. Firdous, H. Raza, A. Bilal, R.S.Z. Saleem, S. Shahzad-ul-Hussan, D. Wang, F.S. Youssef, N.M. Al Musayeib, M.L. Ashour, H. Hussain, A. Faisal, Identification and Characterization of Natural and Semisynthetic Quinones as Aurora Kinase Inhibitors, J. Nat. Prod., 2022, 85(6), 1503-1513.

- L.O. Klotz, X. Hou, C. Jacob, 1,4-naphthoquinones: from oxidative damage to cellular and inter-cellular signaling, Molecules, 2014, 19(9), 14902.

- K. Krohn, N. Boker, Product class 5: anthra-9,10-quinones, anthra-1,2-quinones, anthra-1,4-quinones, anthra-2,9-quinones, and their higher fused analogues, Sci. Synth., 2006, 28, 367-506.

- F. Li, Y. Li, Z.p. Deng, X.j. Zhu, Z.g. Zhang, X.d. Zhang, J.l. Tian, W. Li, P. Zhao, Traditional uses, phytochemistry, pharmacology and clinical applications of Cortex Juglandis Mandshuricae: A comprehensive review, J. Ethnopharmacol., 2022, 285, 114887.

- J.J. Lu, J.L. Bao, G.S. Wu, W.S. Xu, M.Q. Huang, X.P. Chen, Y.T. Wang, Quinones derived from plant secondary metabolites as anticancer agents, Anticancer Agents Med. Chem., 2013, 13(3), 456-463.

- F.A. Macias, A.G. Duran, J.M.G. Molinillo, Allelopathy: The Chemical Language of Plants, Prog. Chem. Org. Nat. Prod., 2020, 112, 1-84.

- R. Rani, K. Sethi, S. Kumar, R.S. Varma, R. Kumar, Natural naphthoquinones and their derivatives as potential drug molecules against trypanosome parasites, Chem. Biol. Drug Des., 2022, 100(6), 786-817.

- C.d.S. Moreira, T.B. Santos, R.H.C.N. Freitas, P.A.F. Pacheco, D.R. da Rocha, Juglone: A Versatile Natural Platform for Obtaining New Bioactive Compounds, Curr. Top. Med. Chem. (Sharjah, United Arab Emirates), 2021, 21(22), 2018-2045.

- C.J. Soderquist, Juglone and allelopathy, J. Chem. Educ., 1973, 50(11), 782-783.

- Y.T. Tang, Y. Li, P. Chu, X.D. Ma, Z.Y. Tang, Z.L. Sun, Molecular biological mechanism of action in cancer therapies: Juglone and its derivatives, the future of development, Biomed. Pharmacother., 2022, 148, 112785.

- A. Thakur, Juglone: a therapeutic phytochemical from Juglans regia L, J. Med. Plants Res., 2011, 5(22), 5324-5330.

- Y.B. Ji, Z.Y. Qu, X. Zou, Juglone-induced apoptosis in human gastric cancer SGC-7901 cells via the mitochondrial pathway, Experimental and Toxicologic Pathology, 2011, 63(1), 69-78.

- Y.B. Ji, G.S. Xin, Z.Y. Qu, X. Zou, M. Yu, Mechanism of juglone-induced apoptosis in MCF-7 cells by the mitochondreial pathway, Genet. Mol. Res. 2016, 15(3), 15038785.

- E. Avci, H. Arikoglu, D. Erkoc, Kaya, Investigation of juglone effects on metastasis and angiogenesis in pancreatic cancer cells, Gene 2016, 588(1), 74-78.

- N. Karki, S. Aggarwal, R.A. Laine, F. Greenway, J.N. Losso, Cytotoxicity of juglone and thymoquinone against pancreatic cancer cells, Chemico-Biol. Interact., 2020, 327, 109142.

- F. Fang, Y. Qin, L. Qi, Q. Fang, L. Zhao, S. Chen, Q. Li, D. Zhang, L. Wang, Juglone exerts antitumor effect in ovarian cancer cells, Iran J. Basic Med. Sci., 2015, 18, 544-548.

- X.B. Zhang, C.L. Zou, Y.X. Duan, F. Wu, G. Li, Activity guided isolation and modification of juglone from Juglans regia as potent cytotoxic agent against lung cancer cell lines, BMC Compl. Altern. Med., 2015, 15(1), 396.

- R. Kanaoka, A. Kushiyama, Y. Seno, Y. Nakatsu, Y. Matsunaga, T. Fukushima, Y. Tsuchiya, H. Sakoda, M. Fujishiro, T. Yamamotoya,

H. Kamata, A. Matsubara, T. Asano, Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines, PLOS ONE, 2015, 10(6), e0127467.

- H. Xu, X. Yu, S. Qu, D. Sui, Juglone, isolated from Juglans mandshurica Maxim, induces apoptosis via down-regulation of AR expression in human prostate cancer LNCaP cells, Bioorg. Med. Chem. Lett., 2013, 23(12), 3631-3634.

- R.C. Montenegro, A.J. Araújo, M.T. Molina, J.D.B.M. Filho, D.D. Rocha, E. Lopéz-Montero, M.O.F. Goulart, E.S. Bento, A.P.N.N. Alves,

C. Pessoa, M.O. de Moraes, L.V. Costa-Lotufo, Cytotoxic activity of naphthoquinones with special emphasis on juglone and its 5-O-methyl derivative, Chemico-Biol. Interact., 2010, 184(3), 439-448.

- D. Bayram, M. Özgöcmen, I. Armagan, M. Sevimli, G.Y. Türel, N. Senol, Investigation of apoptotic effect of juglone on CCL-228-SW 480 colon cancer cell line, J. Cancer Res. Therap., 2019, 15(1), 68-74.

- W. Zhang, A. Liu, Y. Li, X. Zhao, S. Lv, W. Zhu, Y. Jin, Anticancer activity and mechanism of juglone on human cervical carcinoma HeLa cells, Canad. J. Physiol. Pharmacol., 90(11), 1553-1558.

- X. Zhao, W. Zhu, R. Zhang, M. Zhang, J. Zhao, J. Hou, W. Zhang, Targeted juglone blocks the invasion and metastasis of HPV-positive cervical cancer cells, J. Pharmacol. Sci., 2019, 140(3), 211-217.

- S. Fiorito, S. Genovese, V.A. Taddeo, V. Mathieu, R. Kiss, F. Epifano, Novel juglone and plumbagin 5-O derivatives and their in vitro growth inhibitory activity against apoptosis-resistant cancer cells, Bioorg. Med. Chem. Lett., 2016, 26(2), 334-337.

- E. Mehdipour, S. Hasanvandi, P. Shafieyoon, Synthesis, characterization and cytotoxicity investigation of juglone palladium complex; theoretical and biological properties of juglone as an employed ligand, J. Iran. Chem. Soc., 2022, 19(8), 3387-3395.

- S. Kamo, K. Kuramochi, K. Tsubaki, Recent topics in total syntheses of natural dimeric naphthoquinone derivatives, Tetrahedron Lett., 2018, 59(3), 224-230.

- G. Berube, Natural and synthetic biologically active dimeric molecules: Anticancer agents, anti-HIV agents, steroid derivatives and opioid antagonists, Curr. Med. Chem., 2006, 13(2), 131-154.

- G. Berube, D. Rabouin, V. Perron, B. N'Zemba, R.-C. Gaudreault, S. Parent, E. Asselin, Synthesis of unique 17β-estradiol homo-dimers, estrogen receptors binding affinity evaluation and cytocidal activity on breast, intestinal and skin cancer cell lines, Steroids, 2006, 71(10), 911-921.

- C. Ito, T. Matsui, M. Takano, T.-S. Wu, M. Itoigawa, Anti-cell proliferation effect of naphthoquinone dimers isolated from Plumbago zeylanica, Nat. Prod. Res., 2018, 32(18), 2127-2132.

- A. Paquin, Y. Oufqir, I.F. Sevrioukova, C. Reyes-Moreno, G. Berube, Innovative C2-symmetric testosterone and androstenedione dimers: Design, synthesis, biological evaluation on prostate cancer cell lines and binding study to recombinant CYP3A4, Eur. J. Med. Chem., 2021, 220, 113496.

- A. Paquin, C. Reyes-Moreno, G. Berube, Recent advances in the use of the dimerization strategy as a means to increase the biological potential of natural or synthetic molecules, Molecules, 2021, 26(8), 2340.

- M.K. Hadden, B.S. Blagg, Dimeric approaches to anticancer chemotherapeutics, Anticancer Agents Med. Chem., 2008, 8, 807-816.

- N. Heise, F. Lehmann, R. Csuk, T. Mueller, Targeted theranostics: Near-infrared triterpenoic acid-rhodamine conjugates as prerequisites for precise cancer diagnosis and therapy, Eur. J. Med. Chem., 2023, 259, 115663.

- O. Kraft, S. Hoenke, R. Csuk, A tormentic acid-homopiperazine-rhodamine B conjugate of single-digit nanomolar cytotoxicity and high selectivity for several human tumor cell lines, Eur. J. Med. Chem. Rep., 2022, 5, 100043.

- S. Hoenke, I. Serbian, H.P. Deigner, R. Csuk, Mitocanic Di- and triterpenoid rhodamine B conjugates, Molecules, 2022, 25(22), 5443.

- S. Sommerwerk, L. Heller, C. Kerzig, A.E. Kramell, R. Csuk, Rhodamine B conjugates of triterpenoic acids are cytotoxic mitocans even at nanomolar concentrations, Eur. J. Med. Chem., 2017, 127, 1-9.

- S. Hoenke, I. Wiengarn, I. Serbian, A. Al-Harrasi, R. Csuk, Synthesis of amide-spacered dimers of ursolic and oleanolic acid, Mediterr. J. Chem., 2019, 9(1), 24-36.




DOI: http://dx.doi.org/10.13171/mjc02405131779csuk

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