Progress in the structural modification and pharmacological activity of isosteviol

Tao Wang , Bowen Pan , Lijuan Liu , Zhangchao Dong , Wenhui Zhang , Xiongwei Liu , Ying Zhou , Yang Shi

Acta Materia Medica ›› 2025, Vol. 4 ›› Issue (1) : 174 -185.

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Acta Materia Medica ›› 2025, Vol. 4 ›› Issue (1) :174 -185. DOI: 10.15212/AMM-2024-0051
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Progress in the structural modification and pharmacological activity of isosteviol
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Abstract

Isosteviol and its derivatives, diterpene compounds with a wide range of biological activities, play important antiviral, antibacterial, antioxidant, antitumor, analgesic, anti-inflammatory, antipyretic, antifungal, and anticardiovascular disease roles. Because of its unique diterpene skeleton, isosteviol is frequently used as an active framework in drug synthesis, thus helping medicinal chemists design highly selective, potentially active, and multifunctional isosteviol analogs for the treatment of various diseases. In recent years, rapid developments in the design and synthesis of isosteviol derivatives have proven effective and important in the field of medicinal chemistry research. This article briefly reviews the novel derivatives obtained through structural modification of isosteviol, including their pharmacological activities, to provide a reference for the development of new synthetic strategies and the construction of new isosteviol derivatives, and to guide preclinical studies and development of new drugs with greater pharmacological efficacy.

Keywords

Isosteviol / Diterpene / Skeleton construction / Structural modification / Pharmacological activity

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Tao Wang, Bowen Pan, Lijuan Liu, Zhangchao Dong, Wenhui Zhang, Xiongwei Liu, Ying Zhou, Yang Shi. Progress in the structural modification and pharmacological activity of isosteviol. Acta Materia Medica, 2025, 4 (1) : 174-185 DOI:10.15212/AMM-2024-0051

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References

[1]

Zhao JH, Wang YW, Yang J, Tong ZJ, Wu JZ, Wang YB, et al.: Natural Products as Potential Lead Compounds to Develop New Antiviral Drugs Over the Past Decade. European Journal of Medicinal Chemistry 2023, 260: 115726.

[2]

Huang B, Zhang Y: Teaching an Old Dog New Tricks: Drug Discovery by Repositioning Natural Products and their Derivatives. Drug Discovery Today 2022, 27: 1936-1944.

[3]

Buchanan WW, Rainsford KD, Kean CA, Kean WF: Narcotic Analgesics. Inflammopharmacology 2024, 32: 23-28.

[4]

Christianson DW: Structural and Chemical Biology of Terpenoid Cyclases. Chemical Reviews 2017, 117: 11570-11648.

[5]

Badshah SL, Ullah A, Ahmad N, Almarhoon ZM, Mabkhot Y: Increasing the Strength and Production of Artemisinin and Its Derivatives. Molecules 2018, 23: 100.

[6]

Sun F, Dang S, Zheng D, Zhang H, Wang Y, Li Y, et al.: Advances in Paclitaxel Biosynthesis and Transcriptional Regulation Mechanisms. Chinese Journal of Biotechnology [Sheng Wu Gong Cheng Xue Bao] 2024, 40: 1380-1405.

[7]

Wintachai P, Kaur P, Lee RC, Ramphan S, Kuadkitkan A, Wikan N, et al.: Activity of Andrographolide Against Chikungunya Virus Infection. Scientific Reports 2015, 5: 14179.

[8]

Khan A, Jayanthi M, Gantasala NP, Bhooshan N, Rao U: A Rapid and Efficient Protocol for In Vitro Multiplication of Genetically Uniform Stevia Rebaudiana (Bertoni). Indian Journal of Experimental Biology 2016, 54: 477-481.

[9]

Raspe DT, Da Silva C, Cláudio Da Costa S: Compounds from Stevia Rebaudiana Bertoni Leaves: An Overview of Nonconventional Extraction Methods and Challenges . Food Bioscience 2022, 46: 101593.

[10]

Salehi B, López MD, Martínez-López S, Victoriano M, Sharifi-Rad J, Martorell M, et al.: Stevia Rebaudiana Bertoni Bioactive Effects: From In Vivo to Clinical Trials Towards Future Therapeutic Approaches. Phytotherapy Research 2019, 33: 2904-2917.

[11]

Holth TAD, Walters MA, Hutt OE, Georg GI: Diversity-oriented Library Synthesis from Steviol and Isosteviol-Derived Scaffolds. ACS Combinatorial Science 2020, 22: 150-155.

[12]

Kataev VE, Khaybullin RN, Garifullin BF, Sharipova RR: New Targets for Growth Inhibition of Mycobacterium Tuberculosis: Why Do Natural Terpenoids Exhibit Antitubercular Activity? Russian Journal of Bioorganic Chemistry 2018, 44: 438-452.

[13]

Mizushina Y, Akihisa T, Ukiya M, Hamasaki Y, Murakami-Nakai C, Kuriyama I, et al.: Structural Analysis of Isosteviol and Related Compounds as DNA Polymerase and DNA Topoisomerase Inhibitors. Life Sciences 2005, 77: 2127-2140.

[14]

Gu W, Rebsdorf A, Hermansen K, Gregersen S, Jeppesen PB: The Dynamic Effects of Isosteviol on Insulin Secretion and Its Inability to Counteract the Impaired β-Cell Function during Gluco-, Lipo-, and Aminoacidotoxicity: Studies In Vitro. Nutrients 2018, 10: 127.

[15]

Xu D, Du W, Zhao L, Davey AK, Wang J: The Neuroprotective Effects of Isosteviol Against Focal Cerebral Ischemia Injury Induced by Middle Cerebral Artery Occlusion in Rats. Planta Medica 2008, 74: 816-821.

[16]

Zhang L, Gao B: Effect of Isosteviol on Wheat Seed Germination and Seedling Growth Under Cadmium Stress. Plants (Basel) 2021, 10: 1779.

[17]

Liu F, Song L, Lu Z, Sun T, Lun J, Zhou C, et al.: Isosteviol Improves Cardiac Function and Promotes Angiogenesis after Myocardial Infarction in Rats. Cell and Tissue Research 2022, 387: 275-285.

[18]

Zhang H, Zhong K, Lu M, Mei Y, Tan E, Sun X, et al.: Neuroprotective Effects of Isosteviol Sodium Through Increasing CYLD by the Downregulation of miRNA-181b. Brain Research Bulletin 2018, 140: 392-401.

[19]

Tang SG, Liu XY, Ye JM, Hu TT, Yang YY, Han T, et al.: Isosteviol Ameliorates Diabetic Cardiomyopathy in Rats by Inhibiting ERK and NF-κB Signaling Pathways. Journal of Endocrinology 2018, 238: 47-60.

[20]

Yao L, Chen X, Shen M, Zhao Y, Cao Q: Isosteviol Attenuates DSS-induced Colitis by Maintaining Intestinal Barrier Function Through PDK1/AKT/NF-κB Signaling Pathway. International Immunopharmacology 2023, 114: 109532.

[21]

Fingleton B: Matrix Metalloproteinases as Regulators of Inflammatory Processes. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research 2017, 1864: 2036-2042.

[22]

Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, et al.: Arginase-1-Expressing Macrophages Suppress Th2 Cytokine-driven Inflammation and Fibrosis. PLoS Pathogens 2009, 5: e1000371.

[23]

Qiao G, Ji W, Sun Z, Wang X, Li P, Jia H, et al.: Isosteviol Reduces the Acute Inflammatory Response after Burns by Upregulating MMP9 in Macrophages Leading to M2 Polarization. International Immunopharmacology 2022, 106: 108609.

[24]

Harreiter J, Roden M: Diabetes Mellitus: Definition, Classification, Diagnosis, Screening and Prevention (Update 2023). Wiener Klinische Wochenschrift 2023, 135: 7-17.

[25]

Ma J, Ma Z, Wang J, Milne RW, Xu D, Davey AK, et al.: Isosteviol Reduces Plasma Glucose Levels in the Intravenous Glucose Tolerance Test in Zucker Diabetic Fatty Rats. Diabetes Obesity and Metabolism 2007, 9: 597-599.

[26]

Henseleit KD, Nelson SB, Kuhlbrodt K, Hennings JC, Ericson J, Sander M: NKX6 Transcription Factor Activity is Required for Alpha- and Beta-Cell Development in the Pancreas. Development 2005, 132: 3139-3149.

[27]

Aigha II, Abdelalim EM: NKX6.1 Transcription Factor: A Crucial Regulator of Pancreatic β Cell Development, Identity, and Proliferation. Stem Cell Research & Therapy 2020, 11: 459.

[28]

Nordentoft I, Jeppesen PB, Hong J, Abudula R, Hermansen K: Isosteviol Increases Insulin Sensitivity and Changes Gene Expression of Key Insulin Regulatory Genes and Transcription Factors in Islets of the Diabetic KKAy Mouse. Diabetes, Obesity and Metabolism 2008, 10: 939-949.

[29]

Xu D, Xu M, Lin L, Rao S, Wang J, Davey AK: The Effect of Isosteviol on Hyperglycemia and Dyslipidemia induced by Lipotoxicity in Rats Fed with High-fat Emulsion. Life Sciences 2012, 90: 30-38.

[30]

Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al.: Estimating the Global Cancer Incidence and Mortality in 2018: GLOBOCAN Sources and Methods. International Journal of Cancer 2019, 144: 1941-1953.

[31]

Sui XC: Evaluation of Cytotoxicity and Biological Activities in Steviol Glycosides Compounds . Wuxi: State Key Laboratory of Food Science and Technology; 2015: 99.

[32]

Denner TC, Heise NV, Csuk R: Isosteviol - A New Scaffold for the Synthesis of Carbonic Anhydrase II Inhibitors. Results in Chemistry 2024, 7: 101426.

[33]

Chen Z, Li Z, Xu R, Xie Y, Li D, Zhao Y: Design, Synthesis, and In Vivo Evaluation of Isosteviol Derivatives as New SIRT3 Activators with Highly Potent Cardioprotective Effects. Journal of Medicinal Chemistry 2024, 67: 6749-6768.

[34]

Voloshina AD, Sapunova AS, Kulik NV, Belenok MG, Strobykina IY, Lyubina AP, et al.: Antimicrobial and Cytotoxic Effects of Ammonium Derivatives of Diterpenoids Steviol and Isosteviol. Bioorganic & Medicinal Chemistry 2021, 32: 115974.

[35]

Korochkina MG, Babaev VM, Strobykina IY, Voloshina AD, Kulik NV, Kataev VE: Synthesis and Antimicrobial Activity of Several Bis-quaternized Ammonium Derivatives of the Diterpenoid Isosteviol. Chemistry of Natural Compounds 2012, 47: 914-917.

[36]

Garifullin BF, Strobykina IY, Khabibulina LR, Sapunova AS, Voloshina AD, Sharipova RR, et al.: Synthesis and Cytotoxicity of the Conjugates of Diterpenoid Isosteviol and N-Acetyl-D-Glucosamine . Natural Product Research 2021, 35: 1372-1378.

[37]

Murillo JA, Echeverri F, Quinones W, Torres F, Isaza L, Robledo SM, et al.: Synthesis, Cytotoxicity, and Leishmanicidal Evaluation of Ent-beyerene and Ent-kaurene Derivatives . European Journal of Organic Chemistry 2021, 2021: 3386-3397.

[38]

Andreeva OV, Garifullin BF, Sharipova RR, Strobykina IY, Sapunova AS, Voloshina AD, et al.: Glycosides and Glycoconjugates of the Diterpenoid Isosteviol with a 1,2,3-Triazolyl Moiety: Synthesis and Cytotoxicity Evaluation. Journal of Natural Products 2020, 83: 2367-2380.

[39]

Sharipova RR, Belenok MG, Garifullin BF, Sapunova AS, Voloshina AD, Andreeva OV, et al.: Synthesis and Anti-Cancer Activities of Glycosides and Glycoconjugates of Diterpenoid Isosteviol. MedChemComm 2019, 10: 1488-1498.

[40]

Sharipova RR, Andreeva OV, Garifullin BF, Strobykina IY, Strobykina AS, Voloshina AD, et al.: Synthesis and Antimicrobial and Antituberculosis Activity of the First Conjugates of the Diterpenoid Isosteviol and D-Arabinofuranose. Chemistry of Natural Compounds 2018, 54: 92-97.

[41]

Liu CJ, Zhang T, Yu SL, Dai XJ, Wu Y, Tao JC: Synthesis, Cytotoxic Activity, and 2D- and 3D-QSAR Studies of 19-Carboxyl-Modified Novel Isosteviol Derivatives as Potential Anticancer Agents. Chemical Biology & Drug Design 2017, 89: 870-887.

[42]

Huang TJ, Yang CL, Kuo YC, Chang YC, Yang LM, Chou BH, et al.: Synthesis and Anti-Hepatitis B Virus Activity of C4 Amide-Substituted Isosteviol Derivatives. Bioorganic & Medicinal Chemistry 2015, 23: 720-728.

[43]

Wang TT, Liu Y, Chen L: Synthesis and Cytotoxic Activity of Nitric Oxide-releasing Isosteviol Derivatives. Bioorganic & Medicinal Chemistry Letters 2014, 24: 2202-2205.

[44]

Khaybullin RN, Zhang M, Fu J, Liang X, Li T, Katritzky AR, et al.: Design and Synthesis of Isosteviol Triazole Conjugates for Cancer Therapy. Molecules 2014, 19: 18676-18689.

[45]

Ukiya M, Sawada S, Kikuchi T, Kushi Y, Fukatsu M, Akihisa T: Cytotoxic and Apoptosis-inducing Activities of Steviol and Isosteviol Derivatives Against Human Cancer Cell Lines. Chemistry & Biodiversity 2013, 10: 177-188.

[46]

Lin LH, Lee LW, Sheu SY, Lin PY: Study on the Stevioside Analogues of Steviolbioside, Steviol, and Isosteviol 19-Alkyl Amide Dimers: Synthesis and Cytotoxic and Antibacterial Activity. Chemical and Pharmaceutical Bulletin 2004, 52: 1117-1122.

[47]

Qi XX, Wang PP, Cui LT, Jin M, Zhao LX, Li G: Synthesis, Characterization and In Vitro Antiproliferative Effects of Isosteviol Derivatives. Journal of Asian Natural Products Research 2024, 26: 812-823.

[48]

Ozsvár D, Bózsity N, Zupkó I, Szakonyi Z: Synthesis and Study of the Structure-activity Relationship of Antiproliferative N-Substituted Isosteviol-based 1,3-Aminoalcohols . Pharmaceuticals 2024, 17: 262.

[49]

Li N, Li X, Deng M, Zhu F, Wang Z, Sheng R, et al.: Isosteviol Derivatives as Protein Tyrosine Phosphatase-1B Inhibitors: Synthesis, Biological Evaluation and Molecular Docking. Bioorganic & Medicinal Chemistry 2023, 83: 117240.

[50]

Chen Z, Xu R, Jia Q, Xu X, Li D, Li Z, et al.: Discovery of New D-Ring Modified Isosteviol Derivatives as Potent Cardioprotective Agents against Oxidative Stress-trigged Damage. Chemistry & Biodiversity 2023, 20: e202300085.

[51]

Zhang H, Liu B, Xu G, Xu C, Ou E, Liu J, et al.: Synthesis and In Vivo Screening of Isosteviol Derivatives as New Cardioprotective Agents. European Journal of Medicinal Chemistry 2021, 219: 113396.

[52]

Lin Z, Guo Y, Gao Y, Wang S, Wang X, Xie Z, et al.: Ent-Kaurane Diterpenoids from Chinese Liverworts and their Antitumor Activities Through Michael Addition as Detected In Situ by a Fluorescence Probe. Journal of Medicinal Chemistry 2015, 58: 3944-3956.

[53]

Xu H, Tang H, Feng H, Li Y: Design, Synthesis and Structure-activity Relationships Studies on the D Ring of the Natural Product Triptolide. ChemMedChem, 2014, 9: 290-295.

[54]

Engel J, Richters A, Getlik M, Tomassi S, Keul M, Termathe M, et al.: Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-based Design Approach. Journal of Medicinal Chemistry 2015, 58: 6844-6863.

[55]

Liu J, Li L, Li X, Wang X, Zhao X, Qiao Y, et al.: Discovery of Lysosome-targeted Covalent Anticancer Agents Based on Isosteviol Skeleton. European Journal of Medicinal Chemistry 2021, 209: 112896.

[56]

Shi Y, Pan BW, Li WC, Wang Q, Wu Q, Pan M, et al.: Synthesis and Biological Evaluation of Isosteviol Derivatives as FXa Inhibitors. Bioorganic & Medicinal Chemistry Letters 2020, 30: 126585.

[57]

Chen P, Zhang D, Li M, Wu Q, Lam YPY, Guo Y, et al.: Discovery of Novel, Potent, Isosteviol-based Antithrombotic Agents. European Journal of Medicinal Chemistry 2019, 183: 111722.

[58]

Jayachandra R, Zhao H, Cheng Z, Luo L, Sun T, Tan W: Synthesis of Isosteviol Analogues as Potential Protective Agents Against Doxorubicin-induced Cardiomyopathy in Zebrafish Embryos. Bioorganic & Medicinal Chemistry Letters 2019, 29: 1705-1709.

[59]

Liu CJ, Liu YP, Yu SL, Dai XJ, Zhang T, Tao JC: Syntheses, Cytotoxic Activity Evaluation and HQSAR Study of 1,2,3-Triazole-Linked Isosteviol Derivatives as Potential Anticancer Agents. Bioorganic & Medicinal Chemistry Letters 2016, 26: 5455-5461.

[60]

Liu CJ, Yu SL, Liu YP, Dai XJ, Wu Y, Li RJ, et al.: Synthesis, Cytotoxic Activity Evaluation and HQSAR Study of Novel Isosteviol Derivatives as Potential Anticancer Agents. European Journal of Medicinal Chemistry 2016, 115: 26-40.

[61]

Garifullin BF, Strobykina IY, Sharipova RR, Kravchenko MA, Andreeva OV, Bazanova OB, et al.: Synthesis and Antituberculosis Activity of the First Macrocyclic Glycoterpenoids Comprising Glucosamine and Diterpenoid Isosteviol. Carbohydrate Research 2016, 431: 15-24.

[62]

Zhu SL, Wu Y, Liu CJ, Wei CY, Tao JC, Liu HM: Synthesis and In Vitro Cytotoxic Activity Evaluation of Novel Heterocycle Bridged Carbothioamide Type Isosteviol Derivatives as Antitumor Agents. Bioorganic & Medicinal Chemistry Letters 2013, 23: 1343-1346.

[63]

Zhu SL, Wu Y, Liu CJ, Wei CY, Tao JC, Liu HM: Design and Stereoselective Synthesis of Novel Isosteviol-fused Pyrazolines and Pyrazoles as Potential Anticancer Agents. European Journal of Medicinal Chemistry 2013, 65: 70-82.

[64]

Zhang T, Lu LH, Liu H, Wang JW, Wang RX, Zhang YX, et al.: D-ring Modified Novel Isosteviol Derivatives: Design, Synthesis and Cytotoxic Activity Evaluation. Bioorganic & Medicinal Chemistry Letters 2012, 22: 5827-5832.

[65]

Wu Y, Dai GF, Yang JH, Zhang YX, Zhu Y, Tao JC: Stereoselective Synthesis of 15-and 16-Substituted Isosteviol Derivatives and their Cytotoxic Activities. Bioorganic & Medicinal Chemistry Letters 2009, 19: 1818-1821.

[66]

Wu Y, Yang JH, Dai GF, Liu CJ, Tian GQ, Ma WY, et al.: Stereoselective Synthesis of Bioactive Isosteviol Derivatives as Alpha-glucosidase Inhibitors. Bioorganic & Medicinal Chemistry 2009, 17: 1464-1473.

[67]

Ma ZW, Liu XF, Liu JT, Tao JC: Highly Enantioselective Michael Addition Catalyzed by New Primary Amine-squaramide Organocatalysts. Chinese Journal of Organic Chemistry 2018, 38: 183-189.

[68]

Song ZT, Zhang T, Du HL, Ma ZW, Zhang CH, Tao JC: Highly Enantioselective Michael Addition Promoted by a New Diterpene-derived Bifunctional Thiourea Catalyst: A Doubly Stereocontrolled Approach to Chiral Succinimide Derivatives. Chirality 2014, 26: 121-127.

[69]

Ma ZW, Liu YX, Zhang WJ, Tao Y, Zhu Y, Tao JC, et al.: Highly Enantioselective Michael Additions of Isobutyraldehyde to Nitroalkenes Promoted by Amphiphilic Bifunctional Primary Amine-thioureas in Organic or Aqueous Medium. European Journal of Organic Chemistry 2011, 2011: 6747-6754.

[70]

Ma ZW, Liu XF, Sun B, Huang XH, Tao JC: Chiral Primary Amine-squaramide Catalyzed Highly Enantioselective Michael Addition of Isobutyraldehyde to Nitroolefins. Synthesis 2017, 49: 1307-1314.

[71]

Ma Z, Wang C, Liu X, Chen X, Tao J, Lv Q: Enantioselective Synthesis of Coumarins Catalyzed by an Isosteviol-derived Tertiary Amine-squaramide Catalyst. Chirality 2022, 34: 325-332.

[72]

An YJ, Zhang YX, Wu Y, Liu ZM, Pi C, Tao JC: Simple Amphiphilic Isosteviol-Proline Conjugates as Chiral Catalysts for the Direct Asymmetric Aldol Reaction in the Presence of Water. Tetrahedron: Asymmetry 2010, 21: 688-694.

[73]

Yang YF, Zhao LJ, Wang TS, Zheng XK, Wu Y: Biological Activity and Structural Modification of Isosteviol Over the Past 15 Years. Bioorganic Chemistry 2024, 143: 107074.

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