THE CRUCIALITY OF THE 1, 2, 4-TRIOXANE RING IN THE BIOLOGICAL ACTIVITIES OF ANTICANCER ARTEMISININS: AN EXPERIMENT FOR CHEMICAL EDUCATION AT DIFFERENT LEVELS
DOI:
https://doi.org/10.36557/2674-9432.2026v5n3p319-342Palavras-chave:
Artemisinins; 1,2,4-trioxane ring; Molecular electrostatic potential; Molecular orbital; Ligand-receptor interaction.Resumo
In the proposed experiment, artemisinin and its derivatives (artemisinins), with and without the endoperoxide bridge, (R-O-O-R’), are investigated through molecular electrostatic potential (MEP), molecular orbitals (MOs), and their interactions with the biological receptors transferrin and heme, aiming to understand aspects of the interaction with the two biological receptors and to clarify the importance of the 1,2,4-trioxane ring in the antitumor activities of this class of compounds in HepG2 cells. The pattern of MEP maps obtained with the theoretical method B3LYP/6-31G** basis set indicates that artemisinins carrying the 1,2,4-trioxane ring are active against HepG2 liver cancer and may undergo electrophilic attacks by transferrin and heme receptors in the endoperoxide bridge region (C3-O2-O1-C12a). The positioning of MOs on artemisinin atoms supports the anchoring of transferrin and heme receptors in the ligand-receptor interaction process. Investigation of ligand-receptor, molecular docking, showed that artemisinins interacting with transferrin and heme exhibit d(O1Fe2+) < d(O2Fe2+), and these distances increase with biological activity (IC50). Comparison of d(O1Fe2+) and d(O2Fe2+) for transferrin and heme shows greater distances in the interaction with transferrin. Finally, investigation with MEP, MOs, and ligand-receptor interaction indicates the relevance of the 1,2,4-trioxane ring in the anticancer activity of artemisinins.
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Referências
Allen, F. H. (2002). The Cambridge Structural Database: a quarter of a million crystal structures and rising. Acta Crystallography B58, 380-388. https://doi.org/ 10.1107/s0108768102003890
Andrews, N. C. (2000). Iron homeostasis: Insights from genetics and animal models. Nature Review 1, 208–217. https://doi.org/10.1038/35042073
Araújo, J. J. O., Miranda, R. M., Castro, J. S. O., de Figueiredo, A. F., Pinheiro, A. C. B., Morais, S. S. S., dos Santos, M. A. B., Pinheiro, A. L. R., Gil, F. S., Bitencourt, H. R., Alves, G. H. R., & Pinheiro, J. C. (2022). Designing Artemisinins with Antimalarial Potential, Combining Molecular Electrostatic Potential, Ligand-heme Interaction and Multivariate Models. Computational Chemistry, 11(1), 1-23. utational Chemistry, 2023, 11, 1-23 https://www.scirp.org/journal/cc
Avery, M. A., Muraleedharan, K. M., Desai, P. V., Bandyopadhyaya, A. K., Furtado, M. M., & Tekwan, B. L. (2003). Structure-Activity Relationships of the Antimalarial Agent Artemisinin. 8. Design, Synthesis, and CoMFA Studies toward the Development of Artemisinin-Based Drugs against Leishmaniasis and Malaria. Journal of Medicinal Chemistry 46 (20), 4244-4258. https://doi.org/10.1021/jm030181q
Barbosa, P. J., Ferreira, J. E. V., de Figueiredo, A. F., de Almeida, R. C. O., Silva, O. P. P. S., Carvalho, R. J. C., Cristino, M. G. G., Ciríaco-Pinheiro, J., Vieira, J. L. F., & Serra, R. T. A. (2011). Molecular modeling and chemometric study of anticancer derivatives of artemisinin. Journal of Serbian Chemica Society, 76(9), 1263–1282. https://doi.org/ 10.2298/JSC111227111B
Becke, A. D. (1993). Density-functional thermochemistry. III. The role of exact exchange. Journal of Chemical Physics, 98(7), 5648-5652. https://doi.org/10.1063/1.464913
Blinder, S. M. (1965). Basic Concepts of Self-Consistent-Field Theory. American Journal of Physics, 33(6), 431-443. https://doi.org/10.1119/1.1971665
Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, J. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74, 229–263. https:// doi.org/ 10.3322/caac.21834
Cardoso, F. J. B., de Figueiredo, A. F., Lobato, M. S., de Miranda, R. M., de Almeida, R. C. O., & Pinheiro, J. C. (2008). A study on antimalarial artemisinin derivatives using MEP maps and multivariate QSAR, Journal of Molecular Modeling 14 (1), 39–48. https://doi.org/10.1007/s00894-007-0249-9
Castro, J. S. O., Pinheiro, J. C., Morais, S. S. S., Bitencourt, H. R., de Figueiredo, A. F., dos Santos, M. A. B., Gil, F. S., & Pinheiro, A. C. B. (2023). Design of N-11-Azaartemisinins Potentially Active against Plasmodium falciparum by Combined Molecular Electrostatic Potential, LigandReceptor Interaction and Models Built with Supervised Machine Learning Methods. Journal of Biophysical Chemistry, 14(1), 1-29. https://www.scirp.org/journal/jbpc
Chen, H. H., Zhou, H. J., & Fang, X. (2003). Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacological Research 48 (3), 231-236. https://doi.org/10.1016/S1043-6618(03)00107-5
Costa, M. S., Kiralj, R., & Ferreira, M. M. C. (2007). Estudo Teórico da Interação Existente Entre a Artemisinina e o Heme Químca Nova, 30 (1), 25-31.
Dan-Dan, W., Li, H., Ming-Hui, Q., Hong-Yang, Z., Ai-Xi, Y., & Shi-Wen, H. (2025). Mitochondria-targeting artesunate-rhein conjugates: Linker-modulated cell-permeability, heme-affinity and anticancer activity. European Journal of Medicinal Chemistry 282 117100. https://doi.org/10.1016/j.ejmech.2024.117100
Dewar, M. J. S., & Kelemen, J. (1971). LCAO MO Theory Illustrated by Its Application to H2. Journal of Chemical Education, 48(8), 499-501. https://doi.org/10.1021/ed048p494
Dewar, M. J. S., Zoebisch, E. G., Healy, E. F., & Stewart, J. J. P. (1985) Development and use of quantum mechanical molecular models. 76. AMI: a new general purpose quantum mechanical molecular model. Journal of the American Chemical Society, 107(13), 3902-3909. https://doi.org/10.1021/ja00299a024
Efferth, T., Dunstan, H., Sauerbrey, A., Miyachi, H., & Chitambar, C. R. (2001). The anti-malarial artesunate is also active against cancer. International Journal of Oncology 18 (4), 767-73. https://doi.org/10.3892/ijo.18.4.767
Efferth, T., Rauh, R., Kahl, S., Tomicic, M., Böchzelt, H., Tome, M. E., Briehl, M. M., Bauer, R., & Kaina, B. (2005). Molecular modes of action of cantharidin in tumor cells. Biochemical Pharmacology, 69 (5), 811-188. https://doi.org/doi: 10.1016/j.bcp.2004.12.003
Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Montgomery, J. A., Vreven, T., Kudin, K. N., Burant, J. C., Millam, J. M., Iyengar, S. S., Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G. A., Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M., Li, X., Knox, J. E., Hratchian, H. P., 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., Ayala, P. Y., Morokuma, K., Voth, G. A., Salvador, P., Dannenberg, J. J., Zakrzewski, V. G., Dapprich, S., Daniels, A. D., Strain, M. C., Farkas, O., Malick, D. K., Rabuck, A. D., Raghavachari, K., Foresman, J. B., Ortiz, J. V., Cui, O., Baboul, A. G., Clifford, S., Cioslowski, J., Stefanov, B. B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R. L., Fox, D. J., Keith, T., Al-laham, M. A., Peng, C. Y., Nanayakkara, A., Challacombe, M., Gill, P. M. W., Johnson, B., Chen, W., Wong, M. W., Gonzalez, C., & Pople, J. A. (1998). Gaussian 98, Revision A.6. Gaussian, Inc., Pittsburgh.
Flukiger, P., Luthi, H. P., Portmann, S., & Weber. J. (2000-2001). Molekel. Swiss Center for Scientific Computing: Mano, Switzerland.
Guo, W., Wang, W., Lei, F., Zheng, R., Zhao, X., Gu, Y., Yang, M., Tong, Y., & Wang, Y. (2024). Identifying the Main Components and Mechanisms of Action of Artemisia annua L. in the Treatment of Endometrial Cancer Using Network Pharmacology. ACS Omega 9, 8055-8066. https://doi.org/10.1021/acsomega.3c08320
Goodsell, D. S., Morris, G. M., & Olson, A. J. (1996). Automated Docking of Flexible Ligands: Applications of AutoDock. Journal of Molecular Recognition, 9(1), 1-5. https://doi.org/10.1002/(sici)1099-1352(199601)9:1<1::aid-jmr241>3.0.co;2-6
Haber, D. A., & Fearon, E. R. (1998). The promise of cancer genetics. The Lancet, 351, SII1-SII8. https://doi.org/10.1016/s0140-6736(98)90326-9
Haynes, R. K., & Vonwiller, S. C. (1996) The behaviour of qinghaosu (artemisinin) in the presence of heme iron (II) and (III). Tetrahedron Letters, 37 (2), 253-256. https://doi.org/10.1016/0040-4039(95)02141-8
Hehre, W. J., Radom, L., Schleyer, P.v. R., & Pople, J. A. (1986). Ab Initio Molecular Theory. Wiley, New York.
HyperChem, Inc. (2008) ChemPlus: Modular Extension to HyperChem Realease 8.06. Molecular Modeling for Windows. Gainesville.
Jana, S., Iram, S., Thomas, J., Liekens, S., & Dehaen, W. (2017). Synthesis and anticancer activity of novel aza-artemisinin derivatives. Bioorganic & Medicinal Chemistry 3671–3676. http://dx.doi.org/10.1016/j.bmc.2017.04.04
Khanal, P. (2021). Antimalarial and anticancer properties of artesunate and other artemisinins: current development. Monatshefte für Chemie - Chemical Monthly 152, 387–400. https://doi.org/10.1007/s00706-021-02759-x
Lai, H. C., Sasaki, T., & Singh, N. P. (2004). Covalent conjugates between artemisinin related endoperoxides and iron-carrying proteins and methods of use. Patent Application Publication, Pub. No.: US200/0067875A1
Leban, I., Golic, L., & Japelj, M. (1988). Crystal and molecular structure of Qinghaosu: a redetermination, Acta Pharmaeutica Jugoslavica 38, 71-77
Lee, C., Yang, W., & Parr, R. G. (1988). Development of the colic-salvetti correlation-energy formula into a functional of the electron density. Physical Review B, 37(2), 785-789. https://doi.org/10.1103/PhysRevB.37.785
Lisgarten, J. N., Potter, B. S., Bantuzerko, C., & Palmer, R. A. (1988). Structure, absolute configuration, and conformation of the antimalarial compound: Artemisinin. Jounal of Chemical Crystallography, 28, 539-543. https://doi.org/10.1023/A:1023244122450
Liu, Y., Wong, V. K.-W., Ko, B. C.-B., Wong, M.-K., & Che, C.-M. (2005). Synthesis and Cytotoxicity Studies of Artemisinin Derivatives Containing Lipophilic Alkyl Carbon Chains. Organic Letters 7 (8), 1561-1564. https://doi.org/10.1021/ol050230o
Ma, Z., Woon, C. Y.-N., Liu, C.-G., Cheng, J.-T., You, M., Sethi, G., Wong, A. L.-A., Ho, P. C.-L., Zhang, D., Ong, P., Wang, L., & Goh, B.-C. (2021). Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge? Frontiers in Pharmacology 12, 828856. https://doi.org/10.3389/fphar.2021.828856
MacGillivray, R. T. A., Moore, A. S., Chen, J., Anderson, B. F., Baker, H., Luo, Y., Bewley, M., Smith, C. A., Murphy, M. E. P., Wang, Y., Mason, A. B., Woodworth, R. C., Brayer, G. D., & Baker,| E. M. (1988). Two High-Resolution Crystal Structures of the Recombinant N-Lobe of Human Transferrin Reveal a Structural Change Implicated in Iron Release. Biochemistry, 37, 7919-7928. https://doi.org/10.1021/bi980355j
Meng, E. C., Goddard, T. D., Pettersen, E. F., Couch, G. S., Pearson, Z. J., Morris, J. H., & Ferrin, T. E. (2023). UCSF ChimeraX: Tools for structure building and analysis. Protein Science 32 (11), e4792. https://doi.org/10.1002/pro.4792
O’Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., & Hutchison, G. R. (2011) Open Babel: an open chemical toolbox. Journal of Cheminformatics, 3(33), 1-14. https://doi.org/10.1186/1758-2946-3-33
Oliveira , L. F. S., Cordeiro, H. C., Brito, H. G., Pinheiro, A. C. B., dos Santos, M. A. B., Bitencourt, H. R., de Figueiredo, A. F., Araújo, J. J. O., Gil, F. S., Farias, M. S., Barbosa, J. P., & Pinheiro, J. C. (2021). Molecular electrostatic potential and pattern recognition models to design potentially active pentamidine derivatives against Trypanosoma brucei rhodesiense. Research Society and Development, 10(12), e261101220207. https://doi.org/10.33448/rsd-v10i12.20207
O’Neill, P. M., Barton, V. E., & Ward, S. A. (2010). The Molecular Mechanism of Action of Artemisinin—The Debate Continues. Molecules, 15,1705 – 1721. https://doi.org/ 10.3390/molecules15031705
Opsenica, D. M., & Solaja, B. A. (2009). Antimalarial peroxides. Journal Serbian Chemical Society 74, 1155-1193. https://doi.org/doi: 10.2298/JSC0911155О
Pizon, M. D. G., Farias, M. S., de Figueiredo, A. F., Gil, F. S., Pinheiro, A. C. B., Pinheiro, A. L. R., dos Santos, M. A. B., & Pinheiro, J. C. (2024). Relevance of the 1,2,4-trioxane ring in the leishmanicidal activity of artemisinin and derivatives: a computational study. African Journal of Chemical Education, 14(3), 141–158. https://www.ajol.info/index.php/ajce/article/view/276637
Politzer, P., Laurence, P., & Jayasuriya, K. (1985). Molecular Electrostatic Potentials: An Effective Tool for the Elucidation of Biochemical Phenomena. Environmental Health Perspectives, 61, 191-202. https://doi.or/10.1289/ehp.8561191
Politzer, P., Murray, J. (2021). The Neglected Nuclei. Molecules, 26(10) 2982. https://doi.org/10.3390/molecules26102982
Politzer, P., & Truhlar G (1981). Chemical Applications of Atomic and Molecular Electrostatic Potentials. Plenum Press: New York.
Pople, J. A., & Beveride, D. L. (1970). Approximate Molecular Orbital Theory. McGraw-HilL, New York.
Price, R., Luxemburger, C., van Vugt, M., Nosten, F., Kham, A., Simpson J., Looareesuwan, S., Chongsuphajaisiddhi, T., & White, N. J. (1998). Artesunate and mefloquine in the treatment of uncomplicated multidrug-resistant hyperparasitaemic falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 92 (2), 207-211. https://doi.org/10.1016/S0035-9203(98)90750-7
Protein Data Bank. The Rutgers State University. Piscataway, New Jersey. http:www.resb.org/pdb/
Rinner, B., Siegl, V., Pürstner, P., Efferth, T., Brem, B., Greger, H., & Pfragner, R. (2004). Activity of Novel Plant Extracts Against Medullary Thyroid Carcinoma Cells. Anticancer Research, 24, 495-500.
Roothaan, C. C. J. (1951). New Developments in Molecular Orbital Theory. Reviews of Modern Physics 23(2), 69-89. https://doi.org/10.1103/RevModPhys.23.69
Rosenberg, A. S. (2001). Progress in human tumour immunology and immunotherapy. Nature, 411, 380–384. https://doi.org/10.1038/35077246
Sasaki, T., Lai, H. C.-Y., Singh, N. P., & Oh, S. J (2007) University of Washington. US2007//0231300A1.
Schaftenaar, G., & Noordik, J. H. (2000) Molden: a pre-and post processing program for molecular and electronic structures. Journal of Comput-Aided Molecular Design, 14, 123-134. https://doi.org/10.1023/A:1008193805436
Stanzione, F., Giangreco, I., & Cole, J. C. (2021). Use of molecular docking computational tools in drug discovery. In: Witty DR, Cox B, Eds, Progress in Medicinal Chemistry. Elsevier: New York.
Thomsen, R. (2003). Flexible ligand docking using evolutionary algorithms: investigating the effects of variation operators and local search hybrids. Biosystems, 72 (1-2), 57-73. https://doi.org/10.1016/S0303-2647(03)00135-7
Vojtechovský, J., Chu, K., Berendzen, J., Sweet, R. M., & Schlichting, I. (1999). Crystal Structures of Myoglobin-Ligand Complexes at Near-Atomic Resolution. Biophysical Journal, 77, 2153-2174. https://doi.org/10.1016/S0006-3495(99)77056-6
Wall, M. E., & Wani, M. C. (1996). Camptothecin and taxol: from discovery to clinic. Journal of Ethnopharmacology 51 (1-3), 239-254. https://doi.org/doi: 10.1016/0378-8741(95)01367-9
Wani, K. I., Choudhary, S., Zehra, A., Naeem, M., Weathers, P., & Aftab, T. (2021). Enhancing artemisinin content in and delivery from Artemisia annua: a review of alternative, classical, and transgenic approaches. Planta 254, 29. https://doi.org/10.1007/s00425-021-03676-3
Wen, L., Chan, B., C.-L., Qiu, M.-H., Leung, P.-C., & Wong, C.-K. (2024). Artemisinin and Its Derivatives as Potential Anticancer Agents. Molecules 29, 3886. https:// doi.org/10.3390/molecules29163886
Wu, X., Thiel, W., Pezeshki, S., & Lin, H. (2013). Specific Reaction Path Hamiltonian for Proton Transfer in Water: Reparameterized Semiempirical Models. Journal of Chemical Theory and Computation, 9(6), 2672-2686. https://doi.org/10.1021/ct400224n
Xu, C., Zhang, H., Um, L., & Yang, X. (2020). Artemisinins as Anticancer Drugs: Novel Therapeutic Approaches, Molecular Mechanisms, and Clinical Trials. Frontiers in Pharmacology 11, 529881. https://doi.org/10.3389/fphar.2020.529881
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