Structurally Diverse Bufadienolides from the Skins of Bufo Bufo Gargarizans and Their Cytotoxicity

Overview

Journal Sci Rep

Specialty Science

Date 2024 Nov 9

PMID 39521925

Authors

Lingjie Meng

Qian Cao

Xinyi Du

Huijing Lv

Chengjin Li

Xiaoke Zhang

Nian Jiang

Yi Xiao

Affiliations

Soon will be listed here.

Abstract

Natural products, with their extensive chemical diversity, distinctive biological activities, and vast reservoirs, provide a robust foundation for advancing cancer therapeutics. A comprehensive phytochemical investigation of the skins from Bufo bufo gargarizans afforded two new bufadienolide derivatives identified as bufalactamides A and B (1-2), along with six known compounds: argentinogenin (3), desacetylcinobufagin (4), desacetylcinobufaginol (5), cinobufaginol (6), bufalin (7) and gamabufalin (8). The structural elucidation of these compounds was meticulously carried out by analyses of spectroscopic data (1D and 2D NMR, HR-ESIMS), and comparison with the literature data. Plausible biosynthetic pathways for the new compounds were also discussed. Moreover, the cytotoxicity of the compounds was investigated using various cancer cell lines, including lung cancer (A549), colon cancer (HCT-116), liver cancer (SK-Hep-1), and ovarian cancer (SKOV3). Our research findings indicated that compounds 3, and 6-8 exhibit potent cytotoxic activity (IC < 2.5 µM). In contrast, compounds 4 and 5 display moderate cytotoxic activity (IC < 50 µM) while compounds 1 and 2 show no cytotoxic activity (IC > 100 µM). From this data, we conducted a comprehensive analysis of the structure-activity relationships among these compounds.

References

Zhao J, Xu L, Li L, Ren G, Shao Y, Liu Q . Traditional Chinese medicine bufalin inhibits infectious hematopoietic necrosis virus infection and . Microbiol Spectr. 2024; 12(3):e0501622. PMC: 10913368. DOI: 10.1128/spectrum.05016-22. View

Ruan L, Song Z, Jiang R . 3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation. Nat Prod Bioprospect. 2024; 14(1):19. PMC: 10912398. DOI: 10.1007/s13659-024-00442-2. View

Li B, Tian H, Zhang D, Lei Y, Wang L, Jiang R . Bufadienolides with cytotoxic activity from the skins of Bufo bufo gargarizans. Fitoterapia. 2015; 105:7-15. DOI: 10.1016/j.fitote.2015.05.013. View

Jiang N, Li S, Meng L, Zhang Y, Yu C, Xiao Y . Gamabufotalin inhibits colitis-associated colorectal cancer by suppressing transcription factor STAT3. Eur J Pharmacol. 2024; 966:176372. DOI: 10.1016/j.ejphar.2024.176372. View

Xiang C, Fu Y, Hao T, Wei L, Liu Y, Fan Z . Podophyllotoxin-loaded PEGylated E-selectin peptide conjugate targeted cancer site to enhance tumor inhibition and reduce side effect. Eur J Med Chem. 2023; 260:115780. DOI: 10.1016/j.ejmech.2023.115780. View

Liu J, Deng L, Tian H, Ruan Z, Cao H, Ye W . Anti-tumor effects and 3D-quantitative structure-activity relationship analysis of bufadienolides from toad venom. Fitoterapia. 2019; 134:362-371. DOI: 10.1016/j.fitote.2019.03.006. View

De Wang X, Sun Y, Qu F, Su G, Zhao Y . 4-XL-PPD, a novel ginsenoside derivative, as potential therapeutic agents for gastric cancer shows anti-cancer activity via inducing cell apoptosis medicated generation of reactive oxygen species and inhibiting migratory and invasive. Biomed Pharmacother. 2019; 118:108589. DOI: 10.1016/j.biopha.2019.01.050. View

Meng L, Li S, Kong Q, Wang M, Zhang X, Zhu X . Two new 19-hydroxy bufadienolides with cytotoxic activity from the skins of . Nat Prod Res. 2020; 35(23):4894-4900. DOI: 10.1080/14786419.2020.1741582. View

Gao X, Zhu Y, Lv T, Luo M, Jiang Y, Sun L . Resveratrol restrains colorectal cancer metastasis by regulating miR-125b-5p/TRAF6 signaling axis. Am J Cancer Res. 2024; 14(5):2390-2407. PMC: 11162648. DOI: 10.62347/ZBVG9125. View

10.

Kamalakkannan V, Salim A, Capon R . Microbiome-Mediated Biotransformation of Cane Toad Bufagenins. J Nat Prod. 2017; 80(7):2012-2017. DOI: 10.1021/acs.jnatprod.7b00134. View

11.

Liu F, Chen X, Yang J, Zhao Z, Wang Q, Li P . Revealing active components and action mechanism of Fritillariae Bulbus against non-small cell lung cancer through spectrum-effect relationship and proteomics. Phytomedicine. 2023; 110:154635. DOI: 10.1016/j.phymed.2022.154635. View

12.

Park K, Lee H, Kim S, Yun H . Paeoniflorigenone regulates apoptosis, autophagy, and necroptosis to induce anti-cancer bioactivities in human head and neck squamous cell carcinomas. J Ethnopharmacol. 2022; 288:115000. DOI: 10.1016/j.jep.2022.115000. View

13.

Wang Y, Zhang A, Li Q, Liu C . Modulating pancreatic cancer microenvironment: The efficacy of Huachansu in mouse models via TGF-β/Smad pathway. J Ethnopharmacol. 2024; 326:117872. DOI: 10.1016/j.jep.2024.117872. View

14.

Wei G, Wang Y, Yang G, Wang Y, Ju R . Recent progress in nanomedicine for enhanced cancer chemotherapy. Theranostics. 2021; 11(13):6370-6392. PMC: 8120226. DOI: 10.7150/thno.57828. View

15.

Atanasov A, Zotchev S, Dirsch V, Supuran C . Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021; 20(3):200-216. PMC: 7841765. DOI: 10.1038/s41573-020-00114-z. View

16.

Li M, Feng Z, Han R, Hu B, Zhang R, Wang H . Paclitaxel promotes mTOR signaling-mediated apoptosis in esophageal cancer cells by targeting MUC20. Thorac Cancer. 2023; 14(31):3089-3096. PMC: 10626250. DOI: 10.1111/1759-7714.15091. View

17.

Song L, Chen X, Mi L, Liu C, Zhu S, Yang T . Icariin-induced inhibition of SIRT6/NF-κB triggers redox mediated apoptosis and enhances anti-tumor immunity in triple-negative breast cancer. Cancer Sci. 2020; 111(11):4242-4256. PMC: 7648025. DOI: 10.1111/cas.14648. View

18.

Wang M, Hu S, Yang J, Yuan L, Han L, Liang F . Arenobufagin inhibits lung metastasis of colorectal cancer by targeting c-MYC/Nrf2 axis. Phytomedicine. 2024; 127:155391. DOI: 10.1016/j.phymed.2024.155391. View

19.

Wang X, Zhuang Y, Wang Y, Jiang M, Yao L . The recent developments of camptothecin and its derivatives as potential anti-tumor agents. Eur J Med Chem. 2023; 260:115710. DOI: 10.1016/j.ejmech.2023.115710. View

20.

Meng L, Kong Q, Xie J, Pan F, Lu K, Li S . Bufogarlides A-C, three new bufadienolides with double bond from the skins of . Nat Prod Res. 2022; 38(3):470-476. DOI: 10.1080/14786419.2022.2127709. View