Cytotoxic isoflavones from the stem bark of Protea gaguedi
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Diriba Borena Hunde
Abstract
Protea gaguedi is widely used in Ethiopia for the treatments of diarrhea, tumor, urological diseases, and menorrhagia. Despite its extensive use by traditional healers, the pharmacological properties and chemical composition of this medicinal plant remain largely unexplored. Anticipated by these claims, the chromatographic separation of CH2Cl2/CH3OH (1:1) stem bark extract of P. gaguedi led to the isolation of a new isoflavone (1) together with five known compounds: jamaicin (2), 5-methoxydurmillone (3), dipteryxine (4), 4′-O-geranylisoliquiritigenin (5), and stigmasterol (6), whose structures were determined using IR, UV, MS, and NMR and comparison with literature data. The cytotoxic effects of the isolated compounds were evaluated using human cervical carcinoma cell line, KB-3-1. Compounds 1, 2, and 3 demonstrated remarkable cytotoxicity with IC50 values of 24.6 nM, 3.09 µM, and 21.70 µM, respectively, while the other compounds demonstrated negligible or no inhibitory activities against the tested strain. Following the high cytotoxicity of compound 1 against KB-3-1, its activity against the multidrug-resistant subclone KB-V1 was also evaluated and revealing an IC50 of 17.5 nM. In silico molecular docking analyses were performed for these active compounds and revealed relative binding energies (−10.0, −9.4, −9.5 kJ/mol for compounds 1, 2 and 3, respectively) against the ternary target protein complex HPV16 E6/E6AP/p53 (PDB ID: 4XR8). ADME analysis also revealed good cytotoxicity candidacy of these compounds, provided that in vivo activities have been performed for further confirmation.
Funding source: Wollega University
Acknowledgments
The authors are grateful to Professor Sileshi Nemomissa of Addis Ababa University for his support in identifying the plant specimen. Hunde, D.B. acknowledges Wollega University, Ethiopia, for their financial support towards his PhD studies. Abdissa, N. greatly acknowledges the Alexander von Humboldt foundation for experienced researcher re-invitation at the Bielefeld University, Germany.
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Research ethics: IRB is not applicable. This research study is in compliance with research and publishing ethics.
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Informed consent: Not applicable.
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Author contributions: The author has accepted responsibility for the entire content of this manuscript and approved its submission.
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Use of Large Language Models, AI and Machine Learning Tools: None declared.
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Conflict of interest: The author states no conflict of interest.
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Research funding: Part of the work was funded by Wollega University through postgraduate program.
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Data availability: All data generated or analyzed during this study are included in this published article and supporting information.
References
1. Weiss, FE. Sketches of vegetation at home and abroad II. Some aspects of the vegetation of South Africa. New Phytol 1906;5:1–9. https://doi.org/10.1111/j.1469-8137.1906.tb05943.x.Search in Google Scholar
2. Ruth, L, Manani Solomon, D. Ethnobotanical survey and propagation of some endangered medicinal plants from south Nandi district of Kenya. J Animal Plant Sci 2010;8:1016–43.Search in Google Scholar
3. Abebaw, AF, Van Damme, PA. Diversity and role of woody non-timber forest products in Doba district, eastern Ethiopia. Nusantara Bioscience 2023;15. https://doi.org/10.13057/nusbiosci/n150105.Search in Google Scholar
4. Feyisa, K, Feyisa, W, Girma, T, Kemal, T. Traditional medicinal plants used for the treatment of urological and urogenital diseases in Ethiopia: a review. Pharmacogn J 2022;14. https://doi.org/10.5530/pj.2022.14.92.Search in Google Scholar
5. Sammet, B, Bogner, T, Nahrwold, M, Weiss, C, Sewald, N. Approaches for the synthesis of functionalized cryptophycins. J Org Chem 2010;75:6953–60. https://doi.org/10.1021/jo101563s.Search in Google Scholar PubMed
6. Martinez-Zapien, D, Ruiz, FX, Poirson, J, Mitschler, A, Ramirez, J, Forster, A, et al.. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 2016;529:541–5. https://doi.org/10.1038/nature16481.Search in Google Scholar PubMed PubMed Central
7. Lipinski, CA, Lombardo, F, Dominy, BW, Feeney, PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2012;64:4–17. https://doi.org/10.1016/j.addr.2012.09.019.Search in Google Scholar
8. Jia, CY, Li, JY, Hao, GF, Yang, GF. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discov Today 2020;25:248–58. https://doi.org/10.1016/j.drudis.2019.10.014.Search in Google Scholar PubMed
9. Banerjee, P, Eckert, AO, Schrey, AK, Preissner, R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 2018;46:W257–63. https://doi.org/10.1093/nar/gky318.Search in Google Scholar PubMed PubMed Central
10. Peleyeju, GB. Extraction, isolation and characterisation of flavonoids from African Erythrina species and evaluation of some biological activities. South Africa: University of Johannesburg; 2018.Search in Google Scholar
11. Endale, M, Eribo, B, Alemayehu, I, Kibret, B, Mammo, F. Phytochemical analysis of roots of Aloe gilbertii and Millettia ferruginea. J Sci Dev 2016;4:23–9.Search in Google Scholar
12. Na, CS, Hong, SS, Choi, YH, Lee, YH, Hong, SH, Lim, JY, et al.. Neuroprotective effects of constituents of Eragrostis ferruginea against Aβ-induced toxicity in PC12 cells. Arch Pharm Res 2010;33:999–1003. https://doi.org/10.1007/s12272-010-0704-5.Search in Google Scholar PubMed
13. Dagne, E, Bekele, A, Noguchi, H, Shibuya, M, Sankawa, U. O-Geranylated and O-prenylated flavonoids from Millettia ferruginea. Phytochemistry 1990;29:2671–3. https://doi.org/10.1016/0031-9422(90)85210-7.Search in Google Scholar
14. Uttu, AJ, Sallau, MS, Ibrahim, H, Iyun, OR. Isolation, characterization, and docking studies of campesterol and β-sitosterol from Strychnos innocua (Delile) root bark. J Taibah Univ Med Sci 2023;18:566–78. https://doi.org/10.1016/j.jtumed.2022.12.003.Search in Google Scholar PubMed PubMed Central
15. Diksha, SL, Bhatia, D. Mechanistic interplay of different mediators involved in mediating the anti-depressant effect of isoflavones. Metab Brain Dis 2024;39:199–215. https://doi.org/10.1007/s11011-023-01302-7.Search in Google Scholar PubMed
16. Buyinza, D, Chalo, DM, Derese, S, Ndakala, A, Yenesew, A. Flavonoids and Isoflavonoids of Millettia dura and Millettia ferruginea: phytochemical review and chemotaxonomic values. Biochem Systemat Ecol 2020;91:104053. https://doi.org/10.1016/j.bse.2020.104053.Search in Google Scholar
17. Borena, D, Abdissa, Z, Kenasa, G, Gurmessa, F, Duguma, T, Abebe, D, et al.. In vitro antibacterial activity, molecular docking and ADMET analysis of phytochemicals from the roots of Stephania abyssimica. J Sci Technol Arts Res 2024;13:89–124.Search in Google Scholar
18. Agamah, FE, Mazandu, GK, Hassan, R, Bope, CD, Thomford, NE, Ghansah, A, et al.. Computational/in silico methods in drug target and lead prediction. Briefings Bioinf 2020;21:1663–75. https://doi.org/10.1093/bib/bbz103.Search in Google Scholar PubMed PubMed Central
19. Karamanolis, NN, Kounatidis, D, Vallianou, NG, Dimitriou, K, Tsaroucha, E, Tsioulos, G, et al.. Unraveling the anti-cancer mechanisms of antibiotics: current insights, controversies, and future perspectives. Antibiotics 2024;14:9. https://doi.org/10.3390/antibiotics14010009.Search in Google Scholar PubMed PubMed Central
20. Ferraz, MV, Viana, IF, Coêlho, DF, da Cruz, CH, de Arruda Lima, M, de Luna Aragão, MA, et al.. Association strength of E6 to E6AP/p53 complex correlates with HPV‐mediated oncogenesis risk. Biopolymers 2022;13:e23524. https://doi.org/10.1002/bip.23524.Search in Google Scholar PubMed
21. Asma, ST, Acaroz, U, Imre, K, Morar, A, Shah, SR, Hussain, SZ, et al.. Natural products/bioactive compounds as a source of anticancer drugs. Cancers 2022;14:6203. https://doi.org/10.3390/cancers14246203.Search in Google Scholar PubMed PubMed Central
22. Abel, AC, Mühlethaler, T, Dessin, C, Schachtsiek, T, Sammet, B, Sharpe, T, et al.. Bridging the maytansine and vinca sites: cryptophycins target β-tubulin’s T5-loop. J Biol Chem 2024;300:107363. https://doi.org/10.1016/j.jbc.2024.107363.Search in Google Scholar PubMed PubMed Central
23. Mahmud, S, Paul, GK, Biswas, S, Kazi, T, Mahbub, S, Mita, MA, et al.. Phytochemdb: a platform for virtual screening and computer-aided drug designing. Database 2022;2022:baac002. https://doi.org/10.1093/database/baac002.Search in Google Scholar PubMed PubMed Central
24. Gadaleta, D, Vuković, K, Toma, C, Lavado, GJ, Karmaus, AL, Mansouri, K, et al.. SAR and QSAR modeling of a large collection of LD50 rat acute oral toxicity data. J Cheminf 2019;11:1–6. https://doi.org/10.1186/s13321-019-0383-2.Search in Google Scholar PubMed PubMed Central
Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/znc-2025-0076).
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