近年来，天然植物是治疗人类疾病的有效药物的最佳来源，在新药研发中引起了药物化学家的极大关注。在1946-2019年的39年里，共批准了1881种药物中，其中有71种(3.8%)为天然产物，356种(18.9%)为天然产物的半合成修饰。在天然产物中，五环三萜类和木脂素类化合物因其结构的多样性、良好的生物活性、副作用小和来源广泛等特点成为具有活力和开发潜力的分子。因此，本文以齐墩果烷型五环三萜类皂皮酸和苯丙素类二苄基丁内酯木脂素类牛蒡子苷元为母核，设计合成了95个化合物，并通过¹H-NMR和¹³C-NMR和HRMS对化合物进行了结构确证。

本文的主要内容分为两个部分：（一）皂皮酸衍生物的合成与抗炎和抗肿瘤活性评价；（二）牛蒡子苷元衍生物的合成与抗炎活性的评价。

第一部分：设计，合成了一系列在C-28位羧基上有取代基团的皂皮酸衍生物，并且对其体外抗肿瘤和抗炎活性进行评价。（1）皂皮酸的抗肿瘤活性研究：对五种人癌细胞系HCT116、MCF -7、SW620、BEL7402和HepG2细胞使用MTT测定目标化合物Z1 ~ Z29的IC₅₀值，可以得出初步的构效关系(SARs)：在提高抗肿瘤活性方面的贡献度，苯环上带吸电子基团的化合物大于带供电子基团的化合物，与其他化合物相比在皂皮酸上引入苯基四氮唑的片段活性最优。化合物Z29（取代基为5-苯基-四唑-1-乙基的化合物）对五种癌细胞具有很强的活性IC₅₀ = 2.46 μM，比皂皮酸强40倍，且具有较好的选择性（SI=4.06）。因此，将Z29对HCT116细胞增殖的作用机制进行探究：Z29浓度依赖性的增加集落形成抑制率，具有显著抑制细胞增殖的作用。流式细胞仪检测结果显示Z29诱导HCT116细胞周期阻滞在G1期。利用不同浓度的Z29（0, 2.5, 5, 10 μM）处理的HCT116细胞显示出显著的凋亡形态变化，总凋亡比率从5.28%上升到14.76％，表明化合物Z29可能诱导细胞凋亡。通过蛋白印迹实验发现：Z29浓度依赖性的抑制了抗凋亡蛋白Bcl-2的表达以及增加了促凋亡蛋白Bax的表达，增加细胞内凋亡蛋白Bax/Bcl-2的比值，可能对诱导细胞凋亡有一定的作用。同时，化合物Z29能下调p-IκB/IκB、p-NF-κB p65/NF-κB p65和p-ERK/ERK、p-JNK/JNK和p-p38/ p38的相对蛋白表达，表明化合物Z29参与调控NF-κB和MAPK信号通路。（2）皂皮酸的抗炎活性研究：利用MTT法对目标化合物体外抗炎活性进行筛选，在30 μM的浓度下，评估了29个目标化合物对RAW264.7的细胞毒性，筛选出21个细胞毒性低的化合物以作为后续抗炎研究。通过Elisa分析法，评价并比较了目标化合物抑制TNF-α和IL-6生成的抗炎活性，以筛选出活性最佳的抗炎分子。化合物Z7和Z24对TNF-α有显著的抑制作用，其中化合物Z24对IL-6有显著的抑制作用。化合物Z24在30 μM的浓度下对TNF-α的抑制率为42.47%，强于皂皮酸的24.99%；对IL-6的抑制率为8.24%。因此选择化合物Z24作为候选化合物。为了进一步评价化合物Z24的抗炎活性，研究了化合物Z24对LPS诱导的TNF-α、IL-6和NO分泌的影响，化合物Z24能有效降低炎症因子TNF-α、IL-6和NO的水平。蛋白印迹实验表明：化合物Z24对炎症通路蛋白iNOS、COX-2、p-NF-kB p65、NF-Kb p65、p-IκB、IκB、p-ERK、ERK、p-JNK、JNK、p-p38和p38的影响，以揭示Z24发挥抗炎的机制。结果显示:化合物Z24能降低iNOS和COX-2表达，并下调p-NF-κB p65/NF-κB p65、p-IκB/IκB、p-ERK/ERK、p-JNK/JNK和p-p38/p38的相对蛋白表达。因此，表明化合物Z24能够通过抑制NF-KB和MAPK信号通路来减少NO、TNF-α和IL-6的产生。

第二部分：设计，合成了一系列在C-22位酚羟基上有苯基三氮唑，苄基三氮唑，三唑酮，香豆素，异噁唑，噁二唑以及其他含氮杂环等基团的牛蒡子苷元衍生物（A1-A11, B1-B11, C1-C9, D1, D2, E1-E9, F1-F5, G1-G11），以及采用曼尼希的方法对牛蒡苷元酚羟基邻位进行结构修饰的一类衍生物（H1-H8）将目标化合物进行体外抗炎筛选，化合物B2（取代基为1-邻氟苄基-1，2，3-三唑-4-亚甲氧基）表现出最强的抑制NO的活性（IC₅₀ = 7.32 μM）， 强于牛蒡子苷元14倍。SARs：在提高抗炎活性方面的贡献度，苯环上带吸电子基团的化合物大于带供电子基团的化合物，苯环上具有邻位的氟原子的化合物的活性可能强于对位的氟原子的化合物。化合物B2能有效降低炎症因子TNF-a、IL-6和NO的水平。蛋白印迹实验表明：化合物B2可以通过NF-κB和MAPK信号通路抑制了iNOS和COX-2的表达，从而发挥抗炎活性。

综上所述，本文通过对天然产物皂皮酸和牛蒡子苷元的结构修饰，共设计合成了95个衍生物。发现1个对癌症治疗有开发潜力的候选化合物Z29以及2个对抗炎治疗有开发潜力的候选化合物（Z24和B2）。为天然产物衍生物在癌症和炎症治疗领域的开发利用提供了一定的借鉴作用。

In recent years, the discovery of natural plants in the development of new drugs has attracted great attention from pharmaceutical chemists and is the best source of effective drugs for the treatment of human diseases. Of the 1881 drugs approved in the 39 years 1946-2019, 71 (3.8 %) were natural products and 356 (18.9 %) were semisynthetic modifications of natural products. Among them, pentacyclic triterpenoids and lignans have become molecules with vitality and development potential due to their structural diversity, good biological activity, small side effects and wide sources. Therefore, in this paper, 95 compounds were designed and synthesized based on oleanane-type pentacyclic triterpenoid Quillaic acid and phenylpropanoid dibenzylbutyrolactone lignan Arctigenin. The structures of the compounds were confirmed by ¹H-NMR, ¹³C-NMR and HRMS.

The main contents of this paper are divided into two parts: (1) Synthesis and anti-inflammatory and anti-tumor activity evaluation of Quillaic acid derivatives; (2) Synthesis and anti-inflammatory activity evaluation of Arctigenin derivatives.

Part I: A series of Quillaic acid derivatives with substituents on the C-28 carboxyl group were designed and synthesized, and their antitumor and anti-inflammatory activities in vitro were evaluated. (1) Study on the anti-tumor activity of Quillaic acid: The IC₅₀ values of target compounds Z1 ~ Z29 were determined by MTT in five human cancer cell lines HCT116, MCF-7, SW620, BEL7402, and HepG2 cells. The preliminary structure-activity relationship (SARs) can be obtained: the contribution of anti-tumor activity: compounds with electron-withdrawing groups on the benzene ring are greater than those with electron-donating groups; compared with other compounds, the fragment activity of introducing phenyltetrazole on Quillaic acid is the best. Compound Z29 (ubstituted 5-phenyl-tetrazol-1-ethyl) has a strong activity against five cancer cells with IC₅₀ = 2.46 μM, which is 40 times stronger than Quillaic acid, and it has good selectivity (SI = 4.06); Therefore, the mechanism of Z29 on the proliferation of HCT116 cells was explored. Z29 concentration-dependently increased colony formation inhibition rate and significantly inhibited cell proliferation. The results of flow cytometry showed that Z29 induced HCT116 cell cycle arrest in G1 phase. HCT116 cells treated with different concentrations of Z29 (0,2.5,5,10 μM) showed significant apoptotic morphological changes, and the total apoptosis rate increased from 5.28 % to 10.00 % and 14.76 %, respectively, indicating that compound Z29 can induce apoptosis. Western blot experiments showed that the effect of compound Z29 on apoptosis-related Bax and Bcl-2. Compared with the control group, Z29 significantly inhibited the expression of anti-apoptotic protein Bcl-2 at a concentration greater than 10 μM. The results showed that Z29 induced apoptosis by increasing the ratio of Bax / Bcl-2. To reveal that Z29 may have some effect on apoptosis. Compound Z29 down-regulated the relative protein expression of p-IκB / IκB, p-NF-κB p65 / NF-κB p65, p-ERK / ERK, p-JNK / JNK and p-p38 / p38. Therefore, compound Z29 concentration-dependently inhibited the expression of anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic protein Bax, and increased the ratio of intracellular apoptotic protein Bax / Bcl-2, which may have anti-apoptotic effects. Compound Z29 may be involved in the regulation of NF-κB and MAPK signaling pathways. (2) Anti-inflammatory activity of Quillaic acid: Screening of anti-inflammatory activity of target compounds in vitro. The cytotoxicity of 29 target compounds to RAW264.7 macrophages was evaluated by MTT assay at a concentration of 30 μM, and 21 compounds with low cytotoxicity were screened for subsequent anti-inflammatory studies. The anti-inflammatory activities of the target compounds in inhibiting the production of TNF-α and IL-6 were evaluated and compared by Elisa analysis to screen out the best anti-inflammatory molecules. Compounds Z7 and Z24 have a significant inhibitory effect on TNF-α, and compound Z24 has a significant inhibitory effect on IL-6. The inhibitory rate of compound Z24 on TNF-α at a concentration of 30 μM is 42.47 %, which is stronger than that of Quillaic acid 24.99 %, the inhibition rate of IL-6 was 8.24 %. Therefore, compound Z24 was selected as a candidate compound. To further evaluate the anti-inflammatory activity of compound Z24, the effects of compound Z24 on LPS-induced secretion of TNF-α, IL-6 and NO were studied. As expected, compound Z24 could effectively reduce the levels of inflammatory factors TNF-α, IL-6 and NO. Western blot experiments showed that compound Z24 had effects on inflammatory pathway proteins iNOS, COX-2, p-NF-kB p65, NF-Kb p65, p-IκB, IκB, p-ERK, ERK, p-JNK, JNK, p-p38 and p38 to reveal the anti-inflammatory mechanism of Z24. The results showed that compound Z24 could decrease the expression of iNOS and COX-2, and down-regulate the relative protein expression of p-NF-κB p65 / NF-κB p65, p-IκB / IκB, p-ERK / ERK, p-JNK / JNK and p-p38 / p38. Therefore, the anti-inflammatory mechanism of compound Z24 may be related to the inhibition of NF-KB and MAPK signaling pathways, thereby reducing the production of NO, TNF-α and IL-6.

Part II: A series of Arctigenin derivatives (A1-A11, B1-B11, C1-C9, D1, D2, E1-E9, F1-F5, G1-G11) containing phenyl triazole, benzyl triazole, triazolone, coumarin, isoxazole, oxadiazole and other nitrogen-containing heterocyclic groups on the phenolic hydroxyl group at C-22 position were designed and synthesized, as well as a class of derivatives (H1-H8) modified by Mannich's method. The target compounds were subjected to anti-inflammatory screening in vitro, and compound B2 (1-o-fluorobenzyl-1,2,3-triazole-4-methoxy) showed the strongest inhibitory activity against NO (IC₅₀ = 7.32 μM), which was 14 times stronger than Arctigenin. SARs: Contribution to increased anti-inflammatory activity: compounds with electron-withdrawing groups on the benzene ring are greater than compounds with electron-donating groups; the activity of compounds with ortho fluorine atoms on the benzene ring may be stronger than that of para fluorine atoms. Compound B2 can effectively reduce the levels of inflammatory factors TNF-a, IL-6 and NO. Western blot experiments showed that compound B2 could inhibit the expression of iNOS and COX-2 through NF-κB and MAPK signaling pathways, thereby exerting anti-inflammatory activity.

In summary, 95 derivatives were designed and synthesized by structural modification of natural products Quillaic acid and Arctigenin in article. One candidate compound Z29 with development potential for cancer treatment and two candidate compounds (Z24 and B2) with development potential for anti-inflammatory treatment were found. It has certain reference significance for the development and utilization of natural products derivatives in the field of cancer and inflammation treatment.

第一章
[1] Alves-Silva J M, Romane A, Efferth T, et al. North African medicinal plants traditionally used in cancer therapy. Front. Pharmacol., 2017, 8: 383/381-383/324.
[2] Tariq A, Pan K, Sun F, et al. A systematic review on ethnomedicines of anti-cancer plants. Phytother. Res., 2017, 31, (2): 202-264.
[3] Singh S, Sharma B, Kanwar S S, et al. Lead Phytochemicals for Anticancer Drug Development. Front Plant Sci, 2016, 7: 1667.
[4] Borkova L, Frydrych I, Jakubcova N, et al. Synthesis and biological evaluation of triterpenoid thiazoles derived from betulonic acid, dihydrobetulonic acid, and ursonic acid. Eur. J. Med. Chem., 2020, 185: 111806.
[5] Kamble S M, Goyal S N, Patil C R. Multifunctional pentacyclic triterpenoids as adjuvants in cancer chemotherapy: a review. RSC Adv., 2014, 4, (63): 33370-33382.
[6] Herrera-Espana A D, Us-Martin J, Hernandez-Ortega S, et al. Synthesis, structure analysis and activity against breast and cervix cancer cells of a triterpenoid thiazole derived from ochraceolide A. J. Mol. Struct., 2020, 1204: 127555.
[7] Han B, Peng Z. Anti-HIV triterpenoid components. J. Chem. Pharm. Res., 2014, 6, (4): 438-443, 436.
[8] Medina-O'Donnell M, Rivas F, Reyes-Zurita F J, et al. Oleanolic Acid Derivatives as Potential Inhibitors of HIV-1 Protease. J. Nat. Prod., 2019, 82, (10): 2886-2896.
[9] Kaur R, Sharma P, Gupta G K, et al. Structure-activity-relationship and mechanistic insights for anti-HIV natural products. Molecules, 2020, 25, (9): 2070.
[10] Bednarczyk-Cwynar B, Zaprutko L, Wachowiak N, et al. Strong and Long-Lasting Antinociceptive and Anti-inflammatory Conjugate of Naturally Occurring Oleanolic Acid and Aspirin. Front Pharmacol, 2016, 7: 202.
[11] Fukumitsu S, Villareal M O, Fujitsuka T, et al. Anti-inflammatory and anti-arthritic effects of pentacyclic triterpenoids maslinic acid through NF-κB inactivation. Mol. Nutr. Food Res., 2016, 60, (2): 399-409.
[12] Prachayasittikul S, Saraban P, Cherdtrakulkiat R, et al. New bioactive triterpenoids and antimalarial activity of Diospyros rubra Lec. EXCLI J, 2010, 9: 1-10.
[13] Wang G W, Deng L Q, Luo Y P, et al. Hepatoprotective triterpenoids and lignans from the stems of Schisandra pubescens. Nat. Prod. Res., 2017, 31, (16): 1855-1860.
[14] Xu G B, Xiao Y H, Zhang Q Y, et al. Hepatoprotective natural triterpenoids. Eur. J. Med. Chem., 2018, 145: 691-716.
[15] Chung P Y. Novel targets of pentacyclic triterpenoids in Staphylococcus aureus: A systematic review. Phytomedicine, 2020, 73: 152933.
[16] Spivak A Y, Khalitova R R, Nedopekina D A, et al. Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation. Steroids, 2020, 154: 108530.
[17] Beinke C, Scherthan H, Port M, et al. Triterpenoid CDDO-Me induces ROS generation and up-regulates cellular levels of antioxidative enzymes without induction of DSBs in human peripheral blood mononuclear cells. Radiat. Environ. Biophys., 2020, 59, (3): 461-472.
[18] Choi C W, Jung H A, Kang S S, et al. Antioxidant constituents and a new triterpenoid glycoside from Flos Lonicerae. Arch. Pharmacal Res., 2007, 30, (1): 1-7.
[19] Yan X J, Gong L H, Zheng F Y, et al. Triterpenoids as reversal agents for anticancer drug resistance treatment. Drug Discov. Today, 2014, 19, (4): 482-488.
[20] Kvasnica M, Urban M, Dickinson N J, et al. Pentacyclic triterpenoids with nitrogen- and sulfur-containing heterocycles: synthesis and medicinal significance. Nat. Prod. Rep., 2015, 32, (9): 1303-1330.
[21] Zhou M, Zhang R H, Wang M, et al. Prodrugs of triterpenoids and their derivatives. Eur. J. Med. Chem., 2017, 131: 222-236.
[22] Rodrigues F C, Anil K N V, Thakur G. Developments in the anticancer activity of structurally modified curcumin: An up-to-date review. Eur. J. Med. Chem., 2019, 177: 76-104.
[23] Khwaza V, Oyedeji O O, Aderibigbe B A. Ursolic acid-based derivatives as potential anti-cancer agents: an update. Int. J. Mol. Sci., 2020, 21, (16): 5920.
[24] Babalola I T, Shode F O. Ubiquitous ursolic acid: a potential pentacyclic triterpene natural product. J. Pharmacogn. Phytochem., 2013, 2, (2): 214-222.
[25] Khwaza V, Oyedeji O O, Aderibigbe B A. Antiviral Activities of Oleanolic Acid and Its Analogues. Molecules, 2018, 23, (9).
[26] Dzubak P, Hajduch M, Vydra D, et al. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat. Prod. Rep., 2006, 23, (3): 394-411.
[27] Xu H, Ji L, Yu C, et al. MiR-423-5p regulates cells apoptosis and extracellular matrix degradation via nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) in interleukin 1 beta (IL-1β)-induced human nucleus pulposus cells. Med. Sci. Monit., 2020, 26: e922497.
[28] Manu K A, Kuttan G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-κB mediated activation of bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol., 2008, 8, (7): 974-981.
[29] Zhang P, Guo T, He H, et al. Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra. Biomed. Pharmacother., 2017, 90: 69-76.
[30] Wang W, Zhao C, Jou D, et al. Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3. Anticancer Res., 2013, 33, (10): 4279-4284.
[31] El Bourakadi K, Mekhzoum M E M, Saby C, et al. Synthesis, characterization and in vitro anticancer activity of thiabendazole-derived 1,2,3-triazole derivatives. New J. Chem., 2020, 44, (28): 12099-12106.
[32] Pokhodylo N, Shyyka O, Matiychuk V. Synthesis and anticancer activity evaluation of new 1,2,3-triazole-4-carboxamide derivatives. Med. Chem. Res., 2014, 23, (5): 2426-2438.
[33] Batra N, Rajendran V, Wadi I, et al. Synthesis, characterization and antiplasmodial efficacy of sulfonamide-appended [1,2,3]-triazoles. J. Heterocycl. Chem., 2020, 57, (4): 1625-1636.
[34] Tan W, Li Q, Wang H, et al. Synthesis, characterization, and antibacterial property of novel starch derivatives with 1,2,3-triazole. Carbohydr. Polym., 2016, 142: 1-7.
[35] Nejadshafiee V, Naeimi H, Zahraei Z. Efficient synthesis and antibacterial evaluation of some substituted β-hydroxy-1,2,3-triazoles. Chem. Data Collect., 2020, 28: 100443.
[36] Dai Z C, Chen Y F, Zhang M, et al. Synthesis and antifungal activity of 1,2,3-triazole phenylhydrazone derivatives. Org. Biomol. Chem., 2015, 13, (2): 477-486.
[37] Cheng C Y, Cheng C Y, Haque A, et al. 1,4-Disubstituted 1H-1,2,3-Triazoles for Renal Diseases: Studies of Viability, Anti-Inflammatory, and Antioxidant Activities. Int. J. Mol. Sci., 2020, 21, (11).
[38] He Y W, Dong C Z, Zhao J Y, et al. 1,2,3-Triazole-containing derivatives of rupestonic acid: Click-chemical synthesis and antiviral activities against influenza viruses. Eur. J. Med. Chem., 2014, 76: 245-255.
[39] Xu Z, Zhao S J, Liu Y. 1,2,3-Triazole-containing hybrids as potential anticancer agents: Current developments, action mechanisms and structure-activity relationships. Eur. J. Med. Chem., 2019, 183: 111700.
[40] Wei G, Luan W, Wang S, et al. A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: Design, synthesis, and biological evaluation. Org. Biomol. Chem., 2015, 13, (5): 1507-1514.
[41] Li F, Liu Y, Wang S, et al. Synthesis and tumor cytotoxicity of novel 1,2,3-triazole-substituted 3-oxo-oleanolic acid derivatives. Chem. Res. Chin. Univ., 2016, 32, (6): 938-942.
[42] Wang S S, Zhang Q L, Chu P, et al. Synthesis and antitumor activity of α,β-unsaturated carbonyl moiety- containing oleanolic acid derivatives targeting PI3K/AKT/mTOR signaling pathway. Bioorg. Chem., 2020, 101: 104036.
[43] Pertino M W, Lopez C, Theoduloz C, et al. 1,2,3-triazole-substituted oleanolic acid derivatives: synthesis and antiproliferative activity. Molecules, 2013, 18: 7661-7674.
[44] Chouaib K, Romdhane A, Delemasure S, et al. Regiospecific synthesis by copper- and ruthenium-catalyzed azide-alkyne 1,3-dipolar cycloaddition, anticancer and anti-inflammatory activities of oleanolic acid triazole derivatives. Arabian J. Chem., 2019, 12, (8): 3732-3742.
[45] Dang Thi T A, Kim Tuyet N T, Pham The C, et al. Synthesis and cytotoxic evaluation of novel ester-triazole-linked triterpenoid-AZT conjugates. Bioorg. Med. Chem. Lett., 2014, 24, (22): 5190-5194.
[46] Chouaib K, Romdhane A, Delemasure S, et al. Regiospecific synthesis, anti-inflammatory and anticancer evaluation of novel 3,5-disubstituted isoxazoles from the natural maslinic and oleanolic acids. Ind. Crops Prod., 2016, 85: 287-299.
[47] Pan S, Hu J, Zheng T, et al. Oleanolic acid derivatives induce apoptosis in human leukemia K562 cell involved in inhibition of both Akt1 translocation and pAkt1 expression. Cytotechnology, 2015, 67, (5): 821-829.
[48] Mallavadhani U V, Vanga N R, Jeengar M K, et al. Synthesis of novel ring-A fused hybrids of oleanolic acid with capabilities to arrest cell cycle and induce apoptosis in breast cancer cells. Eur. J. Med. Chem., 2014, 74: 398-404.
[49] Ng Y P, Chen Y, Hu Y, et al. Olean-12-eno[2,3-c] [1,2,5]oxadiazol-28-oic acid (OEOA) induces G1 cell cycle arrest and differentiation in human leukemia cell lines. PLoS ONE, 2013, 8, (5): e63580.
[50] 孙华, 胡春, 方唯硕. 3-氧代齐墩果酸氨基酸偶联物的合成、水溶性的测定及抗肿瘤活性研究. 中国药物化学杂志, 2008, (01): 11-15.
[51] Khusnutdinova E F, Apryshko G N, Petrova A V, et al. The Synthesis and Selective Cytotoxicity of New Mannich Bases, Derivatives of 19- and 28-Alkynyltriterpenoids. Russ. J. Bioorg. Chem., 2018, 44, (1): 123-127.
[52] Zhang C, Yan W, Li B, et al. A new ligustrazine derivative-selective cytotoxicity by suppression of NF-κB/p65 and COX-2 expression on human hepatoma cells. Part 3. Int. J. Mol. Sci., 2015, 16, (7): 16401-16413.
[53] Wang P, Zhang Y, Xu K, et al. A new ligustrazine derivative - pharmacokinetic evaluation and antitumor activity by suppression of NF-κB/p65 and COX-2 expression in S180 mice. Pharmazie, 2013, 68, (9): 782-789.
[54] Chu F, Xu X, Li G, et al. Amino acid derivatives of ligustrazine-oleanolic acid as new cytotoxic agents. Molecules, 2014, 19, (11): 18215-18231, 18217 pp.
[55] Bi S, Chu F, Wang M, et al. Ligustrazine-oleanolic acid glycine derivative, G-TOA, selectively inhibited the proliferation and induced apoptosis of activated HSC-T6 cells. Molecules, 2016, 21, (11): 1599/1591-1599/1514.
[56] Leal A S, Wang R, Salvador J A R, et al. Synthesis of novel ursolic acid heterocyclic derivatives with improved abilities of antiproliferation and induction of p53, p21waf1 and NOXA in pancreatic cancer cells. Bioorg. Med. Chem., 2012, 20, (19): 5774-5786.
[57] Rashid S, Dar B A, Majeed R, et al. Synthesis and biological evaluation of ursolic acid-triazolyl derivatives as potential anti-cancer agents. Eur. J. Med. Chem., 2013, 66: 238-245.
[58] Popov S A, Semenova M D, Baev D S, et al. Synthesis and cytotoxicity of hybrids of 1,3,4- or 1,2,5-oxadiazoles tethered from ursane and lupane core with 1,2,3-triazole. Steroids, 2020, 162: 108698.
[59] Dar B A, Bhat B A, Qurishi M A. Synthesis and comparative bioevaluation of aliphatic and aromatic triazolyl derivatives of ursolic acid as anticancer agents. J. Appl. Chem. (Lumami, India), 2014, 3, (2): 541-550, 510 pp.
[60] Liu C M, Tian X Y, Su C H, et al. Synthesis and cytotoxicity of pentacyclic triterpenes-aniline nitrogen mustard derivatives. J. Chin. Chem. Soc. (Weinheim, Ger.), 2020, 67, (4): 646-651.
[61] Pattnaik B, Lakshmi J K, Kavitha R, et al. Synthesis, structural studies, and cytotoxic evaluation of novel ursolic acid hybrids with capabilities to arrest breast cancer cells in mitosis. J. Asian Nat. Prod. Res., 2017, 19, (3): 260-271.
[62] Zhang L H, Zhang Z H, Li M Y, et al. Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives. Bioorg. Med. Chem. Lett., 2019, 29, (12): 1440-1445.
[63] Chi K Q, Wei Z Y, Wang K S, et al. Design, synthesis, and evaluation of novel ursolic acid derivatives as HIF-1α inhibitors with anticancer potential. Bioorg. Chem., 2017, 75: 157-169.
[64] Semenova M D, Popov S A, Golubeva T S, et al. Synthesis and Cytotoxicity of Sulfanyl, Sulfinyl and Sulfonyl Group Containing Ursane Conjugates with 1,3,4-Oxadiazoles and 1,2,4-Triazoles. ChemistrySelect, 2021, 6, (25): 6472-6477.
[65] Chen J, Fu H, Wang Z, et al. A New Synthetic Ursolic Acid Derivative IUA with Anti-Tumor Efficacy Against Osteosarcoma Cells via Inhibition of JNK Signaling Pathway. Cell. Physiol. Biochem., 2014, 34, (3): 724-733.
[66] 白锴凯, 陈芬玲, 郭养浩. 熊果酸衍生物的合成及对前列腺癌PC-3细胞的抑制活性. 中国新药杂志, 2012, 21, (22): 2667-2673+2678.
[67] Shao J W, Dai Y C, Xue J P, et al. In vitro and in vivo anticancer activity evaluation of ursolic acid derivatives. Eur. J. Med. Chem., 2011, 46, (7): 2652-2661.
[68] Dang Thi T A, Kim Tuyet N T, Pham The C, et al. Synthesis and cytotoxic evaluation of novel amide-triazole-linked triterpenoid-AZT conjugates. Tetrahedron Lett., 2015, 56, (1): 218-224.
[69] Suman P, Patel A, Solano L, et al. Synthesis and cytotoxicity of Baylis-Hillman template derived betulinic acid-triazole conjugates. Tetrahedron, 2017, 73, (29): 4214-4226.
[70] Khan I, Guru S K, Rath S K, et al. A novel triazole derivative of betulinic acid induces extrinsic and intrinsic apoptosis in human leukemia HL-60 cells. Eur. J. Med. Chem., 2016, 108: 104-116.
[71] Shi W, Tang N, Yan W D. Synthesis and cytotoxicity of triterpenoids derived from betulin and betulinic acid via click chemistry. J. Asian Nat. Prod. Res., 2015, 17, (2): 159-169.
[72] Sidova V, Zoufaly P, Pokorny J, et al. Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives. PLoS ONE, 2017, 12, (2): e0171621.
[73] Majeed R, Sangwan P L, Chinthakindi P K, et al. Synthesis of 3-O-propargylated betulinic acid and its 1,2,3-triazoles as potential apoptotic agents. Eur. J. Med. Chem., 2013, 63: 782-792.
[74] Chakraborty B, Dutta D, Mukherjee S, et al. Synthesis and biological evaluation of a novel betulinic acid derivative as an inducer of apoptosis in human colon carcinoma cells (HT-29). Eur. J. Med. Chem., 2015, 102: 93-105.
[75] Bebenek E, Jastrzebska M, Kadela-Tomanek M, et al. Novel triazole hybrids of betulin: synthesis and biological activity profile. Molecules, 2017, 22, (11): 1876/1871-1876/1816.
[76] Antimonova A N, Petrenko N I, Shakirov M M, et al. Synthesis and Cytotoxic Activity of Lupane Triterpenoids Containing 1,3,4-Oxadiazoles. Chem. Nat. Compd., 2014, 50, (6): 1016-1023.
[77] Luginina J, Linden M, Bazulis M, et al. Electrosynthesis of Stable Betulin-Derived Nitrile Oxides and their Application in Synthesis of Cytostatic Lupane-Type Triterpenoid-Isoxazole Conjugates. Eur. J. Org. Chem., 2021, 2021, (17): 2557-2577.
[78] Liu J H, Zhu Z F, Tang J, et al. Novel NO-releasing derivatives of betulinic acid with antitumor activity. Chin. Chem. Lett., 2015, 26, (6): 759-762.
[79] 朱梓菲, 汤佳, 王婷婷, et al. 白桦酸衍生物的设计合成及抗肿瘤活性. 中国药科大学学报, 2012, 43, (05): 395-400.
[80] Drag-Zalesinska M, Kulbacka J, Saczko J, et al. Esters of betulin and betulinic acid with amino acids have improved water solubility and are selectively cytotoxic toward cancer cells. Bioorg. Med. Chem. Lett., 2009, 19, (16): 4814-4817.
[81] Xu B, Yan W Q, Xu X, et al. Combination of amino acid/dipeptide with ligustrazine-betulinic acid as antitumor agents. Eur. J. Med. Chem., 2017, 130: 26-38.
[82] Manciula D, Roba C, Oprean I, et al. Synthesis of betulinic acid dipeptide derivatives with potential biological activity. Rev. Chim. (Bucharest, Rom.), 2013, 64, (11): 1265-1269.
[83] Rodriguez-Hernandez D, Demuner A J, Barbosa L C A, et al. Novel hederagenin-triazolyl derivatives as potential anti-cancer agents. Eur. J. Med. Chem., 2016, 115: 257-267.
[84] Rodriguez-Hernandez D, Barbosa L C A, Demuner A J, et al. Hederagenin amide derivatives as potential antiproliferative agents. Eur. J. Med. Chem., 2019, 168: 436-446.
[85] Feng Y, Wang W, Zhang Y, et al. Synthesis and biological evaluation of celastrol derivatives as potential anti-glioma agents by activating RIP1/RIP3/MLKL pathway to induce necroptosis. Eur. J. Med. Chem., 2022, 229: 114070.
[86] 张国瑞. 雷公藤红素衍生物的合成及其抗肿瘤活性研究. 延边大学, 2018.
[87] Shang F F, Wang J Y, Xu Q, et al. Design, synthesis of novel celastrol derivatives and study on their antitumor growth through HIF-1α pathway. Eur. J. Med. Chem., 2021, 220: 113474.
[88] Csuk R, Schwarz S, Kluge R, et al. Improvement of the Cytotoxicity and Tumor Selectivity of Glycyrrhetinic Acid by Derivatization with Bifunctional Aminoacids. Arch. Pharm. (Weinheim, Ger.), 2011, 344, (8): 505-513.
[89] Schwarz S, Csuk R. Synthesis and antitumour activity of glycyrrhetinic acid derivatives. Bioorg. Med. Chem., 2010, 18, (21): 7458-7474.
[90] Csuk R, Schwarz S, Kluge R, et al. Synthesis and biological activity of some antitumor active derivatives from glycyrrhetinic acid. Eur. J. Med. Chem., 2010, 45, (12): 5718-5723.
[91] Zhou F, Wu G R, Cai D S, et al. Synthesis and biological activity of glycyrrhetinic acid derivatives as antitumor agents. Eur. J. Med. Chem., 2019, 178: 623-635.
[92] Li Y, Feng L, Song Z F, et al. Synthesis and anticancer activities of glycyrrhetinic acid derivatives. Molecules, 2016, 21, (2): 199/191-199/120.
[93] Pang C, Luo J, Liu C, et al. Synthesis and Biological Evaluation of a Series of Novel Celastrol Derivatives with Amino Acid Chain. Chem Biodivers, 2018, 15, (5): e1800059.
[94] He Y F, Nan M L, Sun J M, et al. Synthesis, characterization and cytotoxicity of new rotundic acid derivatives. Molecules, 2012, 17: 1278-1291.
[95] Safayhi H, Sailer E R. Anti-inflammatory actions of pentacyclic triterpenes. Planta Med., 1997, 63, (6): 487-493.
[96] Suh N, Honda T, Finlay H J, et al. Novel triterpenoids suppress inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in mouse macrophages. Cancer Res., 1998, 58, (4): 717-723.
[97] Bednarczyk-Cwynar B, Zaprutko L, Marciniak J, et al. The analgesic and anti-inflammatory effect of new oleanolic acid acyloxyimino derivative. Eur. J. Pharm. Sci., 2012, 47, (3): 549-555.
[98] Krajka-Kuzniak V, Bednarczyk-Cwynar B, Paluszczak J, et al. Oleanolic acid oxime derivatives and their conjugates with aspirin modulate the NF-κB-mediated transcription in HepG2 hepatoma cells. Bioorg. Chem., 2019, 93: 103326.
[99] Narozna M, Krajka-Kuzniak V, Kleszcz R, et al. Activation of the Nrf2 response by oleanolic acid oxime morpholide (3-hydroxyiminoolean-12-en-28-oic acid morpholide) is associated with its ability to induce apoptosis and inhibit proliferation in HepG2 hepatoma cells. Eur. J. Pharmacol., 2020, 883: 173307.
[100] Krajka-Kuzniak V, Bednarczyk-Cwynar B, Narozna M, et al. Morpholide derivative of the novel oleanolic oxime and succinic acid conjugate diminish the expression and activity of NF-κB and STATs in human hepatocellular carcinoma cells. Chem.-Biol. Interact., 2019, 311: 108786.
[101] Bhandari P, Patel N K, Gangwal R P, et al. Oleanolic acid analogs as NO, TNF-α and IL-1β inhibitors: Synthesis, biological evaluation and docking studies. Bioorg. Med. Chem. Lett., 2014, 24, (17): 4114-4119.
[102] Nkeh-Chungag B N, Oyedeji O O, Oyedeji A O, et al. Anti-Inflammatory and Membrane-Stabilizing Properties of Two Semisynthetic Derivatives of Oleanolic Acid. Inflammation, 2015, 38, (1): 61-69.
[103] Rali S, Oyedeji O O, Aremu O O, et al. Semisynthesis of Derivatives of Oleanolic Acid from Syzygium aromaticum and Their Antinociceptive and Anti-Inflammatory Properties. Mediators Inflamm., 2016, 2016: 8401843.
[104] Jannus F, Medina-O'Donnell M, Neubrand V E, et al. Efficient In Vitro and In Vivo Anti-Inflammatory Activity of a Diamine-PEGylated Oleanolic Acid Derivative. Int. J. Mol. Sci., 2021, 22, (15): 8158.
[105] Honda T, Dinkova-Kostova A T, David E, et al. Synthesis and biological evaluation of 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4-ethynylimidazole. A novel and highly potent anti-inflammatory and cytoprotective agent. Bioorg. Med. Chem. Lett., 2011, 21, (8): 2188-2191.
[106] Onyango E O, Fu L, Cao M, et al. Synthesis and biological evaluation of amino acid methyl ester conjugates of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid against the production of nitric oxide (NO). Bioorg. Med. Chem. Lett., 2014, 24, (2): 532-534.
[107] Zhang T Y, Li C S, Cao L T, et al. New ursolic acid derivatives bearing 1,2,3-triazole moieties: design, synthesis and anti-inflammatory activity in vitro and in vivo. Mol. Diversity, 2022, 26, (2): 1129-1139.
[108] Luan M, Xu Y, Zhang X, et al. Design and synthesis of novel aza-ursolic acid derivatives: in vitro cytotoxicity and nitric oxide release inhibitory activity. Future Med. Chem., 2022, 14, (8): 535-555.
[109] Zhang T Y, Li C S, Li P, et al. Synthesis and evaluation of ursolic acid-based 1,2,4-triazolo[1,5-a]pyrimidines derivatives as anti-inflammatory agents. Mol. Diversity, 2022, 26, (1): 27-38.
[110] 李财虎, 杨聪玲, 张宽, et al. 新型熊果酸苯并咪(噻)唑连苯酯合成及抗炎活性测定. 有机化学, 2012, 32, (01): 133-137.
[111] 杨定菊, 李颖, 尹述凡. 3-O-乙酰基熊果酸3-乙酰基-2-[(未)取代苯基]-2,3-二氢-1,3,4-噁二唑-5-甲酯的合成及其抗炎活性研究. 有机化学, 2008, (06): 1055-1060.
[112] Li C, Chen J, Yuan W, et al. Preventive effect of ursolic acid derivative on particulate matter 2.5-induced chronic obstructive pulmonary disease involves suppression of lung inflammation. IUBMB Life, 2020, 72, (4): 632-640.
[113] Wu J, Ma S, Zhang T-Y, et al. Synthesis and biological evaluation of ursolic acid derivatives containing an aminoguanidine moiety. Med. Chem. Res., 2019, 28, (7): 959-973.
[114] 谭娟, 黄微, 陈善龙, et al. 熊果酸衍生物与查耳酮缀合物的合成及抗炎活性. 药学学报, 2016, 51, (06): 938-946.
[115] Kwon T H, Lee B, Chung S H, et al. Synthesis and NO production inhibitory activities of ursolic acid and oleanolic acid derivatives. Bull. Korean Chem. Soc., 2009, 30, (1): 119-123.
[116] Govdi A I, Sokolova N V, Sorokina I V, et al. Synthesis of new betulinic acid-peptide conjugates and in vivo and in silico studies of the influence of peptide moieties on the triterpenoid core activity. MedChemComm, 2015, 6, (1): 230-238.
[117] Honda T, Liby K T, Su X, et al. Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A. Bioorg. Med. Chem. Lett., 2006, 16, (24): 6306-6309.
[118] Gundoju N, Bokam R, Yalavarthi N R, et al. Betulinic acid derivatives: a new class of α-glucosidase inhibitors and LPS-stimulated nitric oxide production inhibition on mouse macrophage RAW 264.7 cells. Nat. Prod. Res., 2019, 33, (18): 2618-2622.
[119] Spivak A Y, Khalitova R R, Bel'skii Y P, et al. Synthesis of conjugates of lupane triterpenoids with chromane antioxidants and in vitro study of their influence on the production of nitrogen monoxide and on the arginase activity in activated macrophages. Russ. Chem. Bull., 2010, 59, (12): 2219-2229.
[120] Khlebnicova T S, Piven Y A, Lakhvich F A, et al. Betulinic Acid-Azaprostanoid Hybrids: Synthesis and Pharmacological Evaluation as Anti-inflammatory Agents. Anti-Inflammatory Anti-Allergy Agents Med. Chem., 2020, 19, (3): 254-267.
[121] Meira C S, Fernandes do Espirito Santo R, Barbosa dos Santos T, et al. Betulinic acid derivative BA5, a dual NF-kB/calcineurin inhibitor, alleviates experimental shock and delayed hypersensitivity. Eur. J. Pharmacol., 2017, 815: 156-165.
[122] Meira C S, De Souza Santos E, Santo R F D E, et al. Betulinic acid derivative BA5, attenuates inflammation and fibrosis in experimental chronic chagas disease cardiomyopathy by inducing IL-10 and M2 polarization. Front. Immunol., 2019, 10: 1257.
[123] Chen S, Bai Y, Li Z, et al. A betulinic acid derivative SH479 inhibits collagen-induced arthritis by modulating T cell differentiation and cytokine balance. Biochem. Pharmacol. (Amsterdam, Neth.), 2017, 126: 69-78.
[124] Prados M E, Garcia-Martin A, Unciti-Broceta J D, et al. Betulinic acid hydroxamate prevents colonic inflammation and fibrosis in murine models of inflammatory bowel disease. Acta Pharmacol. Sin., 2021, 42, (7): 1124-1138.
[125] Luo Z, He H, Tang T, et al. Synthesis and biological evaluations of betulinic acid derivatives with inhibitory activity on hyaluronidase and anti-inflammatory effects against hyaluronic acid fragment induced inflammation. Front. Chem. (Lausanne, Switz.), 2022, 10: 892554.
[126] 汤立达, 王建武, 张士俊, et al. 新型含异噁唑的甘草次酸酰胺类衍生物的合成研究. 中草药, 2006, (03): 332-337.
[127] 汤立达, 王建武, 雍建平, et al. 新型11-脱氧甘草次酸-30-酰胺衍生物的研究. 中草药, 2006, (01): 20-25.
[128] Li B, Cai S, Yang Y A, et al. Novel unsaturated glycyrrhetic acids derivatives: Design, synthesis and anti-inflammatory activity. Eur. J. Med. Chem., 2017, 139: 337-348.
[129] Zhang Q, Wang Y, Wang Z, et al. Synthesis and anti-inflammatory activities of glycyrrhetinic acid derivatives containing disulfide bond. Bioorg. Chem., 2022, 119: 105542.
[130] Petrenko N I, Dolgikh M P, Petukhova V Z, et al. Synthesis and antiinflammatory and antiulcer properties of glycyrrhetic acid derivatives containing fragments of amino acids or their methyl ethers. Pharm. Chem. J., 2000, 34, (5): 250-253.
[131] Tu B, Liang J, Ou Y, et al. Novel 18β-glycyrrhetinic acid derivatives as a Two-in-One agent with potent antimicrobial and anti-inflammatory activity. Bioorg. Chem., 2022, 122: 105714.
[132] Yang Y, Zhu Q, Zhong Y, et al. Synthesis, anti-microbial and anti-inflammatory activities of 18β-glycyrrhetinic acid derivatives. Bioorg. Chem., 2020, 101: 103985.
[133] Salomatina O V, Markov A V, Logashenko E B, et al. Synthesis of novel 2-cyano substituted glycyrrhetinic acid derivatives as inhibitors of cancer cells growth and NO production in LPS-activated J-774 cells. Bioorg. Med. Chem., 2014, 22, (1): 585-593.
[134] You R, Long W, Lai Z, et al. Discovery of a Potential Anti-Inflammatory Agent: 3-Oxo-29-noroleana-1,9(11),12-trien-2,20-dicarbonitrile. J. Med. Chem., 2013, 56, (5): 1984-1995.
[135] Tsukahara M, Nishino T, Furuhashi I, et al. Synthesis and inhibitory effect of novel glycyrrhetinic acid derivatives on IL-1β-induced prostaglandin E2 production in normal human dermal fibroblasts. Chem. Pharm. Bull., 2005, 53, (9): 1103-1110.
[136] Radwan M O, Ismail M A H, El-Mekkawy S, et al. Synthesis and biological activity of new 18β-glycyrrhetinic acid derivatives. Arabian J. Chem., 2016, 9, (3): 390-399.
[137] Markov A V, Sen'kova A V, Popadyuk I I, et al. Novel 3'-substituted-1',2',4'-oxadiazole derivatives of 18βH-glycyrrhetinic acid and their O-acylated amidoximes: synthesis and evaluation of antitumor and anti-inflammatory potential in vitro and in vivo. Int. J. Mol. Sci., 2020, 21, (10): 3511.
[138] Maitraie D, Hung C F, Tu H Y, et al. Synthesis, anti-inflammatory, and antioxidant activities of 18β-glycyrrhetinic acid derivatives as chemical mediators and xanthine oxidase inhibitors. Bioorg. Med. Chem., 2009, 17, (7): 2785-2792.
[139] Suthar S K, Lee H B, Sharma M. The synthesis of non-steroidal anti-inflammatory drug (NSAID)-lantadene prodrugs as novel lung adenocarcinoma inhibitors via the inhibition of cyclooxygenase-2 (COX-2), cyclin D1 and TNF-α-induced NF-κB activation. RSC Adv., 2014, 4, (37): 19283-19293.
[140] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin., 2018, 68, (6): 394-424.
[141] Gao Q, Deng S,Jiang T Recent developments in the identification and biosynthesis of antitumor drugs derived from microorganisms. Engineering Microbiology.2022, 2.
[142] Nayak S, Gaonkar S L, Musad E A, et al. 1,3,4-Oxadiazole-containing hybrids as potential anticancer agents: Recent developments, mechanism of action and structure-activity relationships. J. Saudi Chem. Soc., 2021, 25, (8): 101284.
[143] Shen Q K, Deng H, Wang S B, et al. Synthesis, and evaluation of in vitro and in vivo anticancer activity of 14-substituted oridonin analogs: A novel and potent cell cycle arrest and apoptosis inducer through the p53-MDM2 pathway. Eur. J. Med. Chem., 2019, 173: 15-31.
[144] Birudukota N, Mudgal M M, Shanbhag V. Discovery and development of azasteroids as anticancer agents. Steroids, 2019, 152: 108505.
[145] Newman DJ,Cragg GM Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J Nat Prod.2020, 83: 770-803.
[146] Yu F, Wang Q, Zhang Z, et al., Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors. J. Med. Chem.2013, 56: 4300-4319.
[147] Das M C, Mahato S B. Triterpenoids. Phytochemistry, 1983, 22, (5): 1071-1095.
[148] Xu R, Fazio G C, Matsuda S P T. On the origins of triterpenoid skeletal diversity. Phytochemistry (Elsevier), 2004, 65, (3): 261-291.
[149] Yu F, Wang Q, Zhang Z, et al. Development of Oleanane-Type Triterpenes as a New Class of HCV Entry Inhibitors. J. Med. Chem., 2013, 56, (11): 4300-4319.
[150] Wen X, Sun H, Liu J, et al. Naturally Occurring Pentacyclic Triterpenes as Inhibitors of Glycogen Phosphorylase: Synthesis, Structure-Activity Relationships, and X-ray Crystallographic Studies. J. Med. Chem., 2008, 51, (12): 3540-3554.
[151] Moses T, Papadopoulou K K, Osbourn A. Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives. Crit. Rev. Biochem. Mol. Biol., 2014, 49, (6): 439-462.
[152] Guo S, Falk E, Kenne L, et al. Triterpenoid saponins containing an acetylated branched D-fucosyl residue from Quillaja saponaria Molina. Phytochemistry, 2000, 53, (8): 861-868.
[153] Kensil C R, Patel U, Lennick M, et al. Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J. Immunol., 1991, 146, (2): 431-437.
[154] Guzman L, Villalon K, Marchant M J, et al. In vitro evaluation and molecular docking of QS-21 and quillaic acid from Quillaja saponaria Molina as gastric cancer agents. Sci. Rep., 2020, 10, (1): 10534.
[155] Kim Y-J, Wang P, Navarro-Villalobos M, et al. Synthetic Studies of Complex Immunostimulants from Quillaja saponaria: Synthesis of the Potent Clinical Immunoadjuvant QS-21Aapi. J. Am. Chem. Soc., 2006, 128, (36): 11906-11915.
[156] Moses T, Papadopoulou K K, Osbourn A. Metabolic and functional diversity of saponins, biosynthetic intermediates and semi-synthetic derivatives. Crit Rev Biochem Mol Biol, 2014, 49, (6): 439-462.
[157] Wang Y, Deng L, Zhong H, et al. Natural plant extract tubeimoside I promotes apoptosis-mediated cell death in cultured human hepatoma (HepG2) cells. Biol Pharm Bull, 2011, 34, (6): 831-838.
[158] Rochd M, Fons F, Chahlaoui A, et al. How to characterize three caryophyllaceous species by the mean of the ratio of two glucuronide prosaponins? Acta Botanica Gallica, 2004, 151, (3): 285-292.
[159] Lu Y, Van D, Deibert L, et al. Antiproliferative quillaic acid and gypsogenin saponins from Saponaria officinalis L. roots. Phytochemistry, 2015, 113: 108-120.
[160] Arslan I. Quillaic Acid–Containing Saponin-Based Immunoadjuvants Trigger Early Immune Responses. Revista Brasileira de Farmacognosia, 2020, 30, (4): 467-473.
[161] Sun H X, Xie Y, Ye Y P. Advances in saponin-based adjuvants. Vaccine, 2009, 27, (12): 1787-1796.
[162] Sivakumar S M, Safhi M M, Kannadasan M, et al. Vaccine adjuvants – Current status and prospects on controlled release adjuvancity. Saudi Pharmaceutical Journal, 2011, 19, (4): 197-206.
[163] Arrau S, Delporte C, Cartagena C, et al. Antinociceptive activity of Quillaja saponaria Mol. saponin extract, quillaic acid and derivatives in mice. J Ethnopharmacol, 2011, 133, (1): 164-167.
[164] Rodriguez-Diaz M, Delporte C, Cartagena C, et al. Topical anti-inflammatory activity of quillaic acid from Quillaja saponaria Mol. and some derivatives. J Pharm Pharmacol, 2011, 63, (5): 718-724.
[165] Delporte C, Backhouse N, Erazo S, et al. Analgesic-antiinflammatory properties of Proustia pyrifolia. J Ethnopharmacol, 2005, 99, (1): 119-124.
[166] Recio M C, Giner R M, Manez S, et al. Structural requirements for the anti-inflammatory activity of natural triterpenoids. Planta Med, 1995, 61, (2): 182-185.
[167] Ban J O, Oh J H, Kim T M, et al. Anti-inflammatory and arthritic effects of thiacremonone, a novel sulfur compound isolated from garlic via inhibition of NF-kappaB. Arthritis Res Ther, 2009, 11, (5): R145.
[168] Ray A, Huisman M V, Tamsma J T, et al. The role of inflammation on atherosclerosis, intermediate and clinical cardiovascular endpoints in type 2 diabetes mellitus. Eur J Intern Med, 2009, 20, (3): 253-260.
[169] Yasukawa K, Iida T, Fujimoto Y. Relative inhibitory activity of bile acids against 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, and chenodeoxycholic acid inhibition of tumour promotion in mouse skin two-stage carcinogenesis. J Pharm Pharmacol, 2009, 61, (8): 1051-1056.
[170] Medeiros R, Otuki M F, Avellar M C, et al. Mechanisms underlying the inhibitory actions of the pentacyclic triterpene alpha-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate. Eur J Pharmacol, 2007, 559, (2-3): 227-235.
[171] Garg V, Maurya R K, Monga V, et al. An insight into the medicinal perspective of synthetic analogs of indole: A review. Eur. J. Med. Chem., 2019, 180: 562-612.
[172] Kakkar S, Narasimhan B. A comprehensive review on biological activities of oxazole derivatives. BMC Chem, 2019, 13, (1): 16.
[173] Narang R, Narasimhan B, Sharma S. A review on biological activities and chemical synthesis of hydrazide derivatives. Curr. Med. Chem., 2012, 19, (4): 569-612.
[174] Bock V D, Speijer D, Hiemstra H, et al. 1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics. Org. Biomol. Chem., 2007, 5, (6): 971-975.
[175] Qin Y, Xu L, Teng Y, et al. Design, synthesis and antibacterial evaluation of novel 3-O-substituted 15-membered azalides possessing 1,2,3-triazole side chains. Bioorg. Med. Chem. Lett., 2021, 49: 128330.
[176] Balabadra S, Kotni M, Manga V, et al. Synthesis and evaluation of naphthyl bearing 1,2,3-triazole analogs as antiplasmodial agents, cytotoxicity and docking studies. Bioorg. Med. Chem., 2017, 25, (1): 221-232.
[177] Costa M S, Boechat N, Rangel E A, et al. Synthesis, tuberculosis inhibitory activity, and SAR study of N-substituted-phenyl-1,2,3-triazole derivatives. Bioorg. Med. Chem., 2006, 14, (24): 8644-8653.
[178] Bian M, Zhen D, Shen Q K, et al. Structurally modified glycyrrhetinic acid derivatives as anti-inflammatory agents. Bioorg. Chem., 2021, 107: 104598.
[179] Guo H Y, Chen Z A, Shen Q K, et al. Application of triazoles in the structural modification of natural products. J. Enzyme Inhib. Med. Chem., 2021, 36, (1): 1115-1144.
[180] Zhang H B, Shen Q K, Wang H, et al. Synthesis and evaluation of novel arctigenin derivatives as potential anti-Toxoplasma gondii agents. Eur. J. Med. Chem., 2018, 158: 414-427.
[181] Shen Q K, Liu C F, Zhang H J, et al. Design and synthesis of new triazoles linked to xanthotoxin for potent and highly selective anti-gastric cancer agents. Bioorg. Med. Chem. Lett., 2017, 27, (21): 4871-4875.
[182] Chekir S, Debbabi M, Regazzetti A, et al. Design, synthesis and biological evaluation of novel 1,2,3-triazole linked coumarinopyrazole conjugates as potent cholin, anti-5-lipoxygenase, anti-tyrosinase and anti-cancer agents. Bioorg. Chem., 2018, 80: 189-194.
[183] 沈庆坤. 冬凌草甲素和丹参酮ⅡA的结构修饰及抗肿瘤活性研究. 延边大学, 2019.
[184] Pertino M W, Verdugo V, Theoduloz C, et al. Synthesis and antiproliferative activity of some novel triazole derivatives from dehydroabietic acid. Molecules, 2014, 19, (2): 2523-2535, 2513 pp.
[185] Glomb T, Szymankiewicz K, Swiatek P. Anti-cancer activity of derivatives of 1,3,4-oxadiazole. Molecules, 2018, 23, (12): 3361/3361-3361/3316.
[186] Paruch K, Popiolek L, Wujec M. Antimicrobial and antiprotozoal activity of 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines: a review. Med. Chem. Res., 2020, 29, (1): 1-16.
[187] De S S, Khambete M P, Degani M S. Oxadiazole scaffolds in anti-tuberculosis drug discovery. Bioorg. Med. Chem. Lett., 2019, 29, (16): 1999-2007.
[188] Sondhi S M, Kumar S, Kumar N, et al. Synthesis anti-inflammatory and anticancer activity evaluation of some pyrazole and oxadiazole derivatives. Med. Chem. Res., 2012, 21, (10): 3043-3052.
[189] Bhutani R, Pathak D P, Kapoor G, et al. Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis, in silico ADME study, molecular docking and in vivo anti-diabetic assessment. Bioorg. Chem., 2019, 83: 6-19.
[190] Bostroem J, Hogner A, Llinas A, et al. Oxadiazoles in Medicinal Chemistry. J. Med. Chem., 2012, 55, (5): 1817-1830.
[191] Bajaj S, Asati V, Singh J, et al. 1,3,4-Oxadiazoles: An emerging scaffold to target growth factors, enzymes and kinases as anticancer agents. Eur. J. Med. Chem., 2015, 97: 124-141.
[192] Wei Z Y, Chi K Q, Wang K S, et al. Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents. Bioorg. Med. Chem. Lett., 2018, 28, (10): 1797-1803.
[193] Wang S, Chen J, Shi J, et al. Novel Cinnamic Acid Derivatives Containing the 1,3,4-Oxadiazole Moiety: Design, Synthesis, Antibacterial Activities, and Mechanisms. J. Agric. Food Chem., 2021, 69, (40): 11804-11815.
[194] Rajak H, Kharya M D, Mishra P. Synthesis of novel 1,3,4-oxadiazole analogues for their anti-inflammatory activity. Adv. Pharmacol. Toxicol., 2018, 19, (3): 1-8.
[195] Zhao T, Yang Y, Yang J, et al. Harmine-inspired design and synthesis of benzo[d]imidazo[2,1-b]thiazole derivatives bearing 1,3,4-oxadiazole moiety as potential tumor suppressors. Bioorg. Med. Chem., 2021, 46: 116367.
[196] Rashid M, Husain A, Mishra R. Synthesis of benzimidazoles bearing oxadiazole nucleus as anticancer agents. Eur. J. Med. Chem., 2012, 54: 855-866.
[197] Du Q R, Li D D, Pi Y Z, et al. Novel 1,3,4-oxadiazole thioether derivatives targeting thymidylate synthase as dual anticancer/antimicrobial agents. Bioorg. Med. Chem., 2013, 21, (8): 2286-2297.
[198] Subba Rao A V, Vishnu Vardhan M V P S, Subba Reddy N V, et al. Synthesis and biological evaluation of imidazopyridinyl-1,3,4-oxadiazole conjugates as apoptosis inducers and topoisomerase IIα inhibitors. Bioorg. Chem., 2016, 69: 7-19.
[199] Hatti I, Sreenivasulu R, Jadav S S, et al. Synthesis and biological evaluation of 1,3,4-oxadiazole-linked bisindole derivatives as anticancer agents. Monatsh. Chem., 2015, 146, (10): 1699-1705.
[200] Kotla R, Murugulla A C, Ruddarraju R, et al. Synthesis and biological evaluation of 1,3,4-oxadiazole fused tetrazole amide derivatives as anticancer agents. Chem. Data Collect., 2020, 30: 100548.
[201] Balaraju V, Kalyani S, Sridhar G, et al. Design, synthesis and biological assessment of 1,3,4-oxadiazole incorporated oxazole-triazole derivatives as anticancer agents. Chem. Data Collect., 2021, 33: 100695.
[202] Lakshmithendral K, Saravanan K, Elancheran R, et al. Design, synthesis and biological evaluation of 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives as anti-breast cancer agents. Eur. J. Med. Chem., 2019, 168: 1-10.
[203] Cali P, Naerum L, Mukhija S, et al. Isoxazole-3-hydroxamic acid derivatives as peptide deformylase inhibitors and potential antibacterial agents. Bioorg. Med. Chem. Lett., 2004, 14, (24): 5997-6000.
[204] Kamal A, Bharathi E V, Reddy J S, et al. Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents. Eur. J. Med. Chem., 2011, 46, (2): 691-703.
[205] Dadmal T L, Appalanaidu K, Kumbhare R M, et al. Synthesis and biological evaluation of triazole and isoxazole-tagged benzothiazole/benzoxazole derivatives as potent cytotoxic agents. New J. Chem., 2018, 42, (19): 15546-15551.
[206] Eddington N D, Cox D S, Roberts R R, et al. Synthesis and anticonvulsant activity of enaminones. 4. Investigations on isoxazole derivatives. Eur. J. Med. Chem., 2002, 37, (8): 635-648.
[207] Kankala S, Kankala R K, Gundepaka P, et al. Regioselective synthesis of isoxazole-mercaptobenzimidazole hybrids and their in vivo analgesic and anti-inflammatory activity studies. Bioorg. Med. Chem. Lett., 2013, 23, (5): 1306-1309.
[208] Nie J P, Qu Z N, Chen Y, et al. Discovery and anti-diabetic effects of novel isoxazole based flavonoid derivatives. Fitoterapia, 2020, 142: 104499.
[209] Lee Y S, Byeang H K. Heterocyclic nucleoside analogues: design and synthesis of antiviral, modified nucleosides containing isoxazole heterocycles. Bioorg. Med. Chem. Lett., 2002, 12, (10): 1395-1397.
[210] Fox R I, Herrmann M L, Frangou C G, et al. Mechanism of action for leflunomide in rheumatoid arthritis. Clin. Immunol. (Orlando, Fla.), 1999, 93, (3): 198-208.
[211] Batra S, Srinivasan T, Rastogi S K, et al. Combinatorial synthesis and biological evaluation of isoxazole-based libraries as antithrombotic agents. Bioorg. Med. Chem. Lett., 2002, 12, (15): 1905-1908.
[212] Carenzi A, Chiarino D, Napoletano M, et al. New isoxazole derivatives provided with antihypertensive activity. Arzneim.-Forsch., 1989, 39, (6): 642-646.
[213] Kochetkov N K, Sokolov S D. Recent developments in isoxazole chemistry. Advan. Heterocyclic Chem. (A. R. Katritzky, editor, Academic), 1963, 2: 365-422.
[214] Pedada S R, Yarla N S, Tambade P J, et al. Synthesis of new secretory phospholipase A2-inhibitory indole containing isoxazole derivatives as anti-inflammatory and anticancer agents. Eur. J. Med. Chem., 2016, 112: 289-297.
[215] Aktas D A, Akinalp G, Sanli F, et al. Design, synthesis and biological evaluation of 3,5-diaryl isoxazole derivatives as potential anticancer agents. Bioorg. Med. Chem. Lett., 2020, 30, (19): 127427.
[216] Kalin J H, Zhang H, Gaudrel-Grosay S, et al. Chiral Mercaptoacetamides Display Enantioselective Inhibition of Histone Deacetylase 6 and Exhibit Neuroprotection in Cortical Neuron Models of Oxidative Stress. Chemmedchem, 2012, 7, (3): 425-439.
[217] Li L Y, Xiao J, Liu Q, et al. Parecoxib inhibits glioblastoma cell proliferation, migration and invasion by upregulating miRNA-29c. Biol. Open, 2017, 6, (3): 311-316.
[218] Lemos S, Sampaio-Marques B, Ludovico P, et al. Elucidating the mechanisms of action of parecoxib in the MG-63 osteosarcoma cell line. Anti-Cancer Drugs, 2020, 31, (5): 507-517.
[219] Ji Z, Ahmed A A, Albert D H, et al. Isothiazolopyrimidines and isoxazolopyrimidines as novel multi-targeted inhibitors of receptor tyrosine kinases. Bioorg. Med. Chem. Lett., 2006, 16, (16): 4326-4330.
[220] Gaikwad N B, Bansod S, Mara A, et al. Design, synthesis, and biological evaluation of N-(4-substituted)-3-phenylisoxazolo[5,4-d]pyrimidin-4-amine derivatives as apoptosis-inducing cytotoxic agents. Bioorg. Med. Chem. Lett., 2021, 49: 128294.
[221] Sambasiva Rao P, Kurumurthy C, Veeraswamy B, et al. Synthesis of novel 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives and their cytotoxic activity. Bioorg. Med. Chem. Lett., 2014, 24, (5): 1349-1351.
[222] Sheng C, Che X, Wang W, et al. Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism. Eur. J. Med. Chem., 2011, 46, (11): 5276-5282.
[223] Zhang HJ, Zhang GR, Piao HR, et al., Synthesis and characterisation of celastrol derivatives as potential anticancer agents. J. Enzyme Inhib. Med. Chem., 2018, 33, (1), 190-198.
[224] Voynikov Y, Valcheva V, Momekov G, et al. Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents. Bioorg. Med. Chem. Lett., 2014, 24, (14): 3043-3045.
[225] Hicks R P, Abercrombie J J, Wong R K, et al. Antimicrobial peptides containing unnatural amino acid exhibit potent bactericidal activity against ESKAPE pathogens. Bioorg. Med. Chem., 2013, 21, (1): 205-214.
[226] Mc Carthy O K, Schipani A, Buendia A M, et al. Design, synthesis and evaluation of novel uracil amino acid conjugates for the inhibition of Trypanosoma cruzi dUTPase. Bioorg. Med. Chem. Lett., 2006, 16, (14): 3809-3812.
[227] Iwaszkiewicz-Grzes D, Cholewinski G, Kot-Wasik A, et al. Synthesis and biological activity of mycophenolic acid-amino acid derivatives. Eur. J. Med. Chem., 2013, 69: 863-871.
[228] Pomarnacka E, Kozlarska-Kedra I. Synthesis of 1-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)semi-carbazides and their transformation into 4-chloro-2-mercapto-N-(4,5-dihydro-5-oxo-4-phenyl-1H-1,2,4-triazol-3-yl)benzenesulfonamides as potential anticancer and anti-HIV agents. Farmaco, 2003, 58, (6): 423-429.
[229] Han M, Jia X, Cai E, et al. The effects of Arctigenin-Valine ester on chemotherapy-induced myelosuppression in mice. Bioorg. Med. Chem., 2019, 27, (12): 2480-2486.
[230] Guo W, Bo, Zhang H, Yan W, Qiang, et al. Design, synthesis, and biological evaluation of ligustrazine - betulin amino-acid/dipeptide derivatives as anti-tumor agents. Eur. J. Med. Chem., 2020, 185: 111839.
[231] Lo Y L, Ho C T, Tsai F L. Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin. Eur. J. Pharm. Sci., 2008, 35, (1-2): 52-67.
[232] Wu G R, Xu B, Yang Y Q, et al. Synthesis and biological evaluation of podophyllotoxin derivatives as selective antitumor agents. Eur. J. Med. Chem., 2018, 155: 183-196.
[233] Szulczyk D, Dobrowolski M A, Roszkowski P, et al. Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies. Eur. J. Med. Chem., 2018, 156: 631-640.
[234] Gao C, Chang L, Xu Z, et al. Recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents. Eur. J. Med. Chem., 2019, 163: 404-412.
[235] Gonzalez-Lara M F, Sifuentes-Osornio J, Ostrosky-Zeichner L. Drugs in Clinical Development for Fungal Infections. Drugs, 2017, 77, (14): 1505-1518.
[236] Karabanovich G, Nemecek J, Valaskova L, et al. S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents. Eur. J. Med. Chem., 2017, 126: 369-383.
[237] Mohite P B, Bhaskar V H. Potential pharmacological activities of tetrazoles in the new millennium. Int. J. PharmTech Res., 2011, 3, (3): 1557-1566.
[238] Popova E A, Protas A V, Trifonov R E. Tetrazole Derivatives as Promising Anticancer Agents. Anti-Cancer Agents Med. Chem., 2017, 17, (14): 1856-1868.
[239] Subba Rao A V, Swapna K, Shaik S P, et al. Synthesis and biological evaluation of cis-restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers. Bioorg. Med. Chem., 2017, 25, (3): 977-999.
[240] Zhao J W, Guo J W, Huang M J, et al. Design, synthesis and biological evaluation of new steroidal β-triazoly enones as potent antiproliferative agents. Steroids, 2019, 150: 108431.
[241] Luan T, Jin C, Jin C M, et al. Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents. J. Enzyme Inhib. Med. Chem., 2019, 34, (1): 761-772.
[242] Ghosh K, Sarkar A R, Chattopadhyay A P. Anthracene-Labeled 1,2,3-Triazole-Linked Bispyridinium Amide for Selective Sensing of H2PO4- by Fluorescence and Gel Formation. Eur. J. Org. Chem., 2012, 2012, (7): 1311-1317.
[243] Wei Z Y, Cui B R, Cui X, et al. Design, synthesis, and negative inotropic evaluation of 4-phenyl-1H-1,2,4-triazol-5(4H)-one derivatives containing triazole or piperazine moieties. Chem. Biol. Drug Des., 2017, 89, (1): 47-60.
[244] Liu Y X, Cui Z P, Liu B, et al. Design, Synthesis, and Herbicidal Activities of Novel 2-Cyanoacrylates Containing Isoxazole Moieties. J. Agric. Food Chem., 2010, 58, (5): 2685-2689.
[245] Zheng Y G, Pei X, Xia D X, et al. Design, synthesis, and cytotoxic activity of novel 2H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine derivatives. Bioorg. Chem., 2021, 109: 104711.
[246] Hwang S G, Park J, Park J Y, et al. Anti-cancer activity of a novel small molecule compound that simultaneously activates p53 and inhibits NF-κB signaling. PLoS ONE, 2012, 7, (9): e44259.
[247] Yenmis G, Yaprak Sarac E, Besli N, et al. Anti-cancer effect of metformin on the metastasis and invasion of primary breast cancer cells through mediating NF-kB activity. Acta Histochem., 2021, 123, (4): 151709.
[248] Zerbini L F, Wang Y, Czibere A, et al. NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45α and γ is essential for cancer cell survival. Proc. Natl. Acad. Sci. U. S. A., 2004, 101, (37): 13618-13623.
[249] Denlinger C E, Rundall B K, Jones D R. Modulation of antiapoptotic cell signaling pathways in non-small cell lung cancer: the role of NF-kappaB. Semin. Thorac. Cardiovasc. Surg., 2004, 16, (1): 28-39.
[250] Wang Z, Li M Y, Mi C, et al. Mollugin has an anti-cancer therapeutic effect by inhibiting TNF-α-induced NF-κB activation. Int. J. Mol. Sci., 2017, 18, (8): 1619/1611-1619/1613.
[251] Ko J H, Lee J H, Jung S H, et al. 2,5-Dihydroxyacetophenone induces apoptosis of multiple myeloma cells by regulating the MAPK activation pathway. Molecules, 2017, 22, (7): 1157/1151-1157/1115.
[252] Wang H B, Zuo J W, Zha L, et al. Design and synthesis of novel glycyrrhetin ureas as anti-inflammatory agents for the treatment of acute kidney injury. Bioorg. Chem., 2021, 110: 104755.
[253] Ganguly R, Pierce GN, The toxicity of dietary trans fats. Food Chem. Toxicol., 2015, 78, 170-176.
[254] Grivennikov SI, Greten FR, Karin M, Immunity, inflammation, and cancer. Cell (Cambridge, MA, U. S.), 2010, 140, (6), 883-899.
[255] Moodie R, Stuckler D, Monteiro C, et al., Profits and pandemics: prevention of harmful effects of tobacco, alcohol, and ultra-processed food and drink industries. Lancet, 2013, 381, (9867), 670-679.
[256] Miller R G, Mitchell J D, Moore D H. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst. Rev., 2012, (3): CD001447.
[257] Rastogi A, Tiwari M K, Ghangrekar M M. A review on environmental occurrence, toxicity and microbial degradation of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). J. Environ. Manage., 2021, 300: 113694.
[258] Osafo N, Agyare C, Obiri D D, et al.; IntechOpen Ltd., 2017, pp 5-15.
[259] Cashman J N. The mechanisms of action of NSAIDs in analgesia. Drugs, 1996, 52, (Suppl. 5): 13-23.
[260] Vane J R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (London), New Biol., 1971, 231, (25): 232-235.
[261] Ugwu D I, Okoro U C, Ukoha P O, et al. Novel anti-inflammatory and analgesic agents: synthesis, molecular docking and in vivo studies. J. Enzyme Inhib. Med. Chem., 2018, 33, (1): 405-415.
[262] Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst. Rev., 2002, (4): CD002296.
[263] Lee A, Cooper M C, Craig J C, et al. Effects of nonsteroidal anti-inflammatory drugs on post-operative renal function in normal adults. Cochrane Database Syst. Rev., 2001, (2): CD002765.
[264] Caughey G E, Roughead E E, Pratt N, et al. Stroke risk and NSAIDs: an Australian population-based study. Med. J. Aust., 2011, 195, (9): 525-529.
[265] Varas-Lorenzo C, Riera-Guardia N, Calingaert B, et al. Stroke risk and NSAIDs: a systematic review of observational studies. Pharmacoepidemiol. Drug Saf., 2011, 20, (12): 1225-1236.
[266] 卞明. 甘草次酸、补骨脂酚和柠檬苦素衍生物的设计合成及其抗炎活性研究[D]. 延边大学, 2021.
[267] 庞磊. 高乌甲素和人参二醇衍生物的设计合成及其生物活性研究. 延边大学, 2020.
[268] Naaz F, Preeti Pallavi M C, Shafi S, et al. 1,2,3-triazole tethered Indole-3-glyoxamide derivatives as multiple inhibitors of 5-LOX, COX-2 & tubulin: Their anti-proliferative & anti-inflammatory activity. Bioorg. Chem., 2018, 81: 1-20.
[269] Felipe J L, Cassamale T B, Lourenco L D, et al. Anti-inflammatory, ulcerogenic and platelet activation evaluation of novel 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids. Bioorg. Chem., 2022, 119: 105485.
[270] Grover J, Bhatt N, Kumar V, et al. 2,5-Diaryl-1,3,4-oxadiazoles as selective COX-2 inhibitors and anti-inflammatory agents. RSC Adv., 2015, 5, (56): 45535-45544.
[271] Abd-Ellah H S, Abdel-Aziz M, Shoman M E, et al. Novel 1,3,4-oxadiazole/oxime hybrids: Synthesis, docking studies and investigation of anti-inflammatory, ulcerogenic liability and analgesic activities. Bioorg. Chem., 2016, 69: 48-63.
[272] Hamoud M M S, Osman N A, Rezq S, et al. Design and Synthesis of Novel 1,3,4-Oxadiazole and 1,2,4-Triazole Derivatives as Cyclooxygenase-2 Inhibitors with Anti-inflammatory and Antioxidant activity in LPS-stimulated RAW264.7 Macrophages. Bioorg. Chem., 2022, 124: 105808.
[273] Zheng X J, Li C S, Cui M Y, et al. Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents. Bioorg. Med. Chem. Lett., 2020, 30, (13): 127237.
[274] Popov S A, Semenova M D, Baev D S, et al. Lupane-type conjugates with aminoacids, 1,3,4- oxadiazole and 1,2,5-oxadiazole-2-oxide derivatives: Synthesis, anti-inflammatory activity and in silico evaluation of target affinity. Steroids, 2019, 150: 108443.
[275] Saleem M, Yu S M, Rafiq M, et al. Synthesis, Crystal Structure, Anti-inflammatory and Anti-hyperglycemic Activities of Novel 3,4-Disubstituted 1,2,4-Triazol-5(4H)-one Derivatives. Med. Chem. (Sharjah, United Arab Emirates), 2014, 10, (8): 810-823.
[276] Yang G, Gao M, Sun Y, et al. Design, synthesis and anti-inflammatory activity of 3-amino acid derivatives of ocotillol-type sapogenins. Eur. J. Med. Chem., 2020, 202: 112507.
[277] Panda S S, Girgis A S, Thomas S J, et al. Synthesis, pharmacological profile and 2D-QSAR studies of curcumin-amino acid conjugates as potential drug candidates. Eur. J. Med. Chem., 2020, 196: 112293.
[278] Tampio J, Loffler S, Guillon M, et al. Improved L-Type amino acid transporter 1 (LAT1)-mediated delivery of anti-inflammatory drugs into astrocytes and microglia with reduced prostaglandin production. Int. J. Pharm. (Amsterdam, Neth.), 2021, 601: 120565.
[279] Zheng X Y, Mao C Y, Qiao H, et al. Plumbagin suppresses chronic periodontitis in rats via down-regulation of TNF-α, IL-1β and IL-6 expression. Acta Pharmacol. Sin., 2017, 38, (8): 1150-1160.
[280] Lee S B, Lee W S, Shin J S, et al. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int. Immunopharmacol., 2017, 49: 21-29.
[281] Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu. Rev. Immunol., 2009, 27: 693-733.
[282] Fan H Y, Gao Z F, Ji K, et al. The in vitro and in vivo anti-inflammatory effect of osthole, the major natural coumarin from Cnidium monnieri (L.) Cuss, via the blocking of the activation of the NF-κB and MAPK/p38 pathways. Phytomedicine, 2019, 58: 152864.
[283] Guan P, Wang X, Jiang Y, et al. The anti-inflammatory effects of jiangrines from Jiangella alba through inhibition of p38 and NF-κB signaling pathways. Bioorg. Chem., 2020, 95: 103507.
[284] Chen H B, Luo C D, Liang J L, et al. Anti-inflammatory activity of coptisine free base in mice through inhibition of NF-κB and MAPK signaling pathways. Eur. J. Pharmacol., 2017, 811: 222-231.
第二章
[1] Wu S H, Du J H, Abula N B, et al. Research progress of effects of Arctium lappa L. Zhonghua Zhongyiyao Zazhi, 2017, 32, (7): 3093-3095.
[2] Wang Y, Ma W. Research progress on the chemical constituents of Arctium lappa L. and its protective effects on cardiovascular disease. Huaxia Yixue, 2020, 33, (3): 184-187.
[3] Hirose M, Yamaguchi T, Lin C, et al. Effects of arctiin on PhIP-induced mammary, colon and pancreatic carcinogenesis in female Sprague-Dawley rats and MeIQx-induced hepatocarcinogenesis in male F344 rats. Cancer Lett. (Shannon, Irel.), 2000, 155, (1): 79-88.
[4] Moritani S, Nomura M, Takeda Y, et al. Cytotoxic components of Bardanae Fructus (Goboshi). Biol. Pharm. Bull., 1996, 19, (11): 1515-1517.
[5] Jeong J B, Hong S C, Jeong H J, et al. Arctigenin induces cell cycle arrest by blocking the phosphorylation of Rb via the modulation of cell cycle regulatory proteins in human gastric cancer cells. Int. Immunopharmacol., 2011, 11, (10): 1573-1577.
[6] Takasaki M, Konoshima T, Komatsu K, et al. Anti-tumor-promoting activity of lignans from the aerial part of Saussurea medusa. Cancer Lett. (Shannon, Irel.), 2000, 158, (1): 53-59.
[7] Hyam SR, Lee I-A, Gu W, et al. Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages. Eur J Pharmacol 2013; 708 (1-3): 21-29.
[8] Hausott B, Greger H, Marian B. Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells. J. Cancer Res. Clin. Oncol., 2003, 129, (10): 569-576.
[9] Brecht K, Riebel V, Couttet P, et al. Mechanistic insights into selective killing of OXPHOS-dependent cancer cells by arctigenin. Toxicol. In Vitro, 2017, 40: 55-65.
[10] Awale S, Lu J, Kalauni S K, et al. Identification of Arctigenin as an Antitumor Agent Having the Ability to Eliminate the Tolerance of Cancer Cells to Nutrient Starvation. Cancer Res., 2006, 66, (3): 1751-1757.
[11] Yang S, Ma J, Xiao J, et al. Arctigenin Anti-Tumor Activity in Bladder Cancer T24 Cell Line Through Induction of Cell-Cycle Arrest and Apoptosis. Anat. Rec., 2012, 295, (8): 1260-1266.
[12] Lee D Y, Song M C, Yoo K H, et al. Lignans from the fruits of Cornus kousa Burg. and their cytotoxic effects on human cancer cell lines. Arch. Pharmacal Res., 2007, 30, (4): 402-407.
[13] Yao X, Li G, Lu C, et al. Arctigenin promotes degradation of inducible nitric oxide synthase through CHIP-associated proteasome pathway and suppresses its enzyme activity. Int. Immunopharmacol., 2012, 14, (2): 138-144.
[14] Hirano T, Gotoh M, Oka K. Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci., 1994, 55, (13): 1061-1069.
[15] Gao Q, Yang M, Zuo Z. Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L. Acta Pharmacol. Sin., 2018, 39, (5): 787-801.
[16] Cho J Y, Kim A R, Yoo E S, et al. Immunomodulatory effect of arctigenin, a lignan compound, on tumour necrosis factor-alpha and nitric oxide production, and lymphocyte proliferation. J. Pharm. Pharmacol., 1999, 51, (11): 1267-1273.
[17] Kim A R, Kim H S, Lee J M, et al. Arctigenin suppresses receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast differentiation in bone marrow-derived macrophages. Eur. J. Pharmacol., 2012, 682, (1-3): 29-36.
[18] Zhao F, Wang L, Liu K. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway. J. Ethnopharmacol., 2009, 122, (3): 457-462.
[19] Cho M K, Jang Y P, Kim Y C, et al. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits MAP kinases and AP-1 activation via potent MKK inhibition: the role in TNF-α inhibition. Int. Immunopharmacol., 2004, 4, (10-11): 1419-1429.
[20] Kou X, Qi S, Dai W, et al. Arctigenin inhibits lipopolysaccharide-induced iNOS expression in RAW264.7 cells through suppressing JAK-STAT signal pathway. Int. Immunopharmacol., 2011, 11, (8): 1095-1102.
[21] Lee J Y, Cho B J, Park T W, et al. Dibenzylbutyrolactone lignans from Forsythia koreana fruits attenuate lipopolysaccharide-induced inducible nitric oxide synthetase and cyclooxygenase-2 expressions through activation of nuclear factor-κB and mitogen-activated protein kinase in RAW264.7 cells. Biol. Pharm. Bull., 2010, 33, (11): 1847-1853.
[22] Hyam S R, Lee I-A, Gu W, et al. Arctigenin ameliorates inflammation in vitro and in vivo by inhibiting the PI3K/AKT pathway and polarizing M1 macrophages to M2-like macrophages. Eur. J. Pharmacol., 2013, 708, (1-3): 21-29.
[23] Cho M K, Park J W, Jang Y P, et al. Potent inhibition of lipopolysaccharide-inducible nitric oxide synthase expression by dibenzylbutyrolactone lignans through inhibition of IκBα phosphorylation and of p65 nuclear translocation in macrophages. Int. Immunopharmacol., 2002, 2, (1): 105-116.
[24] Shi X B, Sun H Z, Zhou D, et al. Arctigenin Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats. Inflammation, 2015, 38, (2): 623-631.
[25] Zhang W Z, Jiang Z K, He B X, et al. Arctigenin Protects against Lipopolysaccharide-Induced Pulmonary Oxidative Stress and Inflammation in a Mouse Model via Suppression of MAPK, HO-1, and iNOS Signaling. Inflammation, 2015, 38, (4): 1406-1414.
[26] Wu X, Yang Y, Dou Y, et al. Arctigenin but not arctiin acts as the major effective constituent of Arctium lappa L. fruit for attenuating colonic inflammatory response induced by dextran sulfate sodium in mice. Int. Immunopharmacol., 2014, 23, (2): 505-515.
[27] Li X M, Miao Y, Su Q Y, et al. Gastroprotective effects of arctigenin of Arctium lappa L. on a rat model of gastric ulcers. Biomed. Rep., 2016, 5, (5): 589-594.
[28] Vlietinck A J, De Bruyne T, Apers S, et al. Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection. Planta Med., 1998, 64, (2): 97-109.
[29] Schroeder H C, Merz H, Steffen R, et al. Differential in vitro anti-HIV activity of natural lignans. Z. Naturforsch., C: Biosci., 1990, 45, (11-12): 1215-1221.
[30] Hayashi K, Narutaki K, Nagaoka Y, et al. Therapeutic effect of arctiin and arctigenin in immunocompetent and immunocompromised mice infected with influenza A virus. Biol. Pharm. Bull., 2010, 33, (7): 1199-1205.
[31] Chen J, Li W, Jin E, et al. The antiviral activity of arctigenin in traditional Chinese medicine on porcine circovirus type 2. Res. Vet. Sci., 2016, 106: 159-164.
[32] Shen Y e, Liu L, Chen W h, et al. Evaluation on the antiviral activity of arctigenin against spring viraemia of carp virus. Aquaculture, 2018, 483: 252-262.
[33] Xu X, Li Q, Pang L, et al. Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway. Biochem. Biophys. Res. Commun., 2013, 441, (2): 321-326.
[34] Chang C Z, Wu S C, Chang C M, et al. Arctigenin, a potent ingredient of Arctium lappa L., induces endothelial nitric oxide synthase and attenuates subarachnoid hemorrhage-induced vasospasm through PI3K/Akt pathway in a rat model. BioMed Res. Int., 2015: 490209/490201-490209/490211.
[35] Swarup V, Ghosh J, Mishra M K, et al. Novel strategy for treatment of Japanese encephalitis using arctigenin, a plant lignan. J. Antimicrob. Chemother., 2008, 61, (3): 679-688.
[36] Wu R M, Sun Y Y, Zhou T T, et al. Arctigenin enhances swimming endurance of sedentary rats partially by regulation of antioxidant pathways. Acta Pharmacol. Sin., 2014, 35, (10): 1274-1284.
[37] Borbely S, Jocsak G, Moldovan K, et al. Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors. Neurochem. Int., 2016, 97: 83-90.
[38] Zhu Z, Yan J, Jiang W, et al. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance. J. Neurosci., 2013, 33, (32): 13138-13149.
[39] Song J, Li N, Xia Y, et al. Arctigenin treatment protects against brain damage through an anti-inflammatory and anti-apoptotic mechanism after needle insertion. Front. Pharmacol., 2016, 7: 182/181-182/116.
[40] Fan T, Jiang W L, Zhu J, et al. Arctigenin protects focal cerebral ischemia-reperfusion rats through inhibiting neuroinflammation. Biol. Pharm. Bull., 2012, 35, (11): 2004-2009.
[41] Jeong Y H, Park J S, Kim D H, et al. Arctigenin increases hemeoxygenase-1 gene expression by modulating PI3K/AKT signaling pathway in rat primary astrocytes. Biomol. Ther., 2014, 22, (6): 497-502.
[42] Li A, Wang J, Wu M, et al. The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1 phase cell cycle arrest: Persistent p27Kip1 induction by interfering with PI3K/Akt/FOXO3a signaling pathway. Eur. J. Pharmacol., 2015, 747: 71-87.
[43] Wang G X, Han J, Feng T T, et al. Bioassay-guided isolation and identification of active compounds from Fructus Arctii against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus). Parasitol. Res., 2009, 106, (1): 247-255.
[44] Tu X, Huang A, Hu Y, et al. Arctigenin: An emerging candidate against infections of Gyrodactylus. Aquaculture, 2018, 495: 983-991.
[45] Dias M M, Zuza O, Riani L R, et al. In vitro schistosomicidal and antiviral activities of Arctium lappa L. (Asteraceae) against Schistosoma mansoni and Herpes simplex virus-1. Biomed. Pharmacother., 2017, 94: 489-498.
[46] Jang Y P, Kim S R, Kim Y C. Neuroprotective dibenzylbutyrolactone lignans of Torreya nucifera. Planta Med., 2001, 67, (5): 470-472.
[47] Zhao Z, Yin Y, Wu H, et al. Arctigenin, a Potential Anti-Arrhythmic Agent, Inhibits Aconitine-Induced Arrhythmia by Regulating Multi-Ion Channels. Cell. Physiol. Biochem., 2013, 32, (5): 1342-1353.
[48] Wang L, Zhao F, Liu K. Advances in studies on pharmacological effects of arctiin and arctigenin. Zhongcaoyao, 2008, 39, (3): 467-470.
[49] Wu X, Tong B, Yang Y, et al. Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17 differentiation. Oncotarget, 2016, 7, (51): 83893-83906.
[50] Gu Y, Sun X X, Ye J M, et al. Arctigenin alleviates ER stress via activating AMPK. Acta Pharmacol. Sin., 2012, 33, (7): 941-952.
[51] Ogungbe I V, Crouch R A, Demeritte T. (-) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β. J. Chem. Inf. Model., 2014, 54, (11): 3051-3055.
[52] Park H, Song K H, Jung P M, et al. Inhibitory Effect of Arctigenin from Fructus Arctii Extract on Melanin Synthesis via Repression of Tyrosinase Expression. Evid. Based Complement. Alternat. Med., 2013, 2013: 965312.
[53] Ishihara K, Yamagishi N, Saito Y, et al. Arctigenin from Fructus Arctii is a novel suppressor of heat shock response in mammalian cells. Cell Stress Chaperones, 2006, 11, (2): 154-161.
[54] Zhang N, Wen Q, Ren L, et al. Neuroprotective effect of arctigenin via upregulation of P-CREB in mouse primary neurons and human SH-SY5Y neuroblastoma cells. Int. J. Mol. Sci., 2013, 14, (9): 18657-18669.
[55] Gao Y, Kang T, Zhang X. Study on the calcium antagonist action of arctigenin. Zhongcaoyao, 2000, 31, (10): 758-762.
[56] Huang S L, Yu R T, Gong J, et al. Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice. Diabetologia, 2012, 55, (5): 1469-1481.
[57] Gu Y, Qi C, Sun X, et al. Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism. Biochem. Pharmacol., 2012, 84, (4): 468-476.
[58] Wang P, Wang B, Chung S, et al. Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells. RSC Adv., 2014, 4, (66): 35242-35250.
[59] Wang P, Phan T, Gordon D, et al. Arctigenin in combination with quercetin synergistically enhances the antiproliferative effect in prostate cancer cells. Mol. Nutr. Food Res., 2015, 59, (2): 250-261.
[60] Cai E, Guo S, Yang L, et al. Synthesis and antitumour activity of arctigenin amino acid ester derivatives against H22 hepatocellular carcinoma. Nat. Prod. Res., 2018, 32, (4): 406-411.
[61] Cai E B, Yang L M, Jia C X, et al. The synthesis and evaluation of arctigenin amino acid ester derivatives. Chem. Pharm. Bull., 2016, 64, (10): 1466-1473.
[62] Li D, Xie K, Wolff R, et al. Pancreatic cancer. Lancet, 2004, 363, (9414): 1049-1057.
[63] Shore S, Vimalachandran D, Raraty M G T, et al. Cancer in the elderly: pancreatic cancer. Surg. Oncol., 2004, 13, (4): 201-210.
[64] Chung H W, Bang S M, Park S W, et al. A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer. Int. J. Radiat. Oncol., Biol., Phys., 2004, 60, (5): 1494-1501.
[65] Ahne W, Bjorklund H V, Essbauer S, et al. Spring viremia of carp (SVC). Dis. Aquat. Organ., 2002, 52, (3): 261-272.
[66] Koutna M, Vesely T, Psikal I, et al. Identification of spring viraemia of carp virus (SVCV) by combined RT-PCR and nested PCR. Dis. Aquat. Org., 2003, 55, (3): 229-235.
[67] Mizushima N, Komatsu M. Autophagy: Renovation of Cells and Tissues. Cell (Cambridge, MA, U. S.), 2011, 147, (4): 728-741.
[68] Chen W C, Hu Y, Liu L, et al. Synthesis and in vitro activities evaluation of arctigenin derivatives against spring viraemia of carp virus. Fish Shellfish Immunol., 2018, 82: 17-26.
[69] Hu Y, Liu L, Liu G-L, et al. Synthesis and anthelmintic activity of arctigenin derivatives against Dactylogyrus intermedius in goldfish. Bioorg. Med. Chem. Lett., 2017, 27, (15): 3310-3316.
[70] Dixon P, Paley R, Oidtmann B, et al. Epidemiological characteristics of infectious hematopoietic necrosis virus (IHNV): a review. Vet. Res., 2016, 47, (1): 63.
[71] Ahmadivand S, Soltani M, Mardani K, et al. Infectious hematopoietic necrosis virus (IHNV) outbreak in farmed rainbow trout in Iran: Viral isolation, pathological findings, molecular confirmation, and genetic analysis. Virus Res., 2017, 229: 17-23.
[72] Hu Y, Li B, Shen Y, et al. Synthesis of arctigenin derivatives against infectious hematopoietic necrosis virus. Eur. J. Med. Chem., 2019, 163: 183-194.
[73] Luder C G, Bohne W, Soldati D. Toxoplasmosis: a persisting challenge. Trends Parasitol., 2001, 17, (10): 460-463.
[74] Mui E J, Jacobus D, Milhous W K, et al. Triazine inhibits Toxoplasma gondii tachyzoites in vitro and in vivo. Antimicrob. Agents Chemother., 2005, 49, (8): 3463-3467.
[75] Zhang H B, Shen Q K, Wang H, et al. Synthesis and evaluation of novel arctigenin derivatives as potential anti-Toxoplasma gondii agents. Eur. J. Med. Chem., 2018, 158: 414-427.
[76] Winder W W. Energy-sensing and signaling by AMP-activated protein kinase in skeletal muscle. J. Appl. Physiol., 2001, 91, (3): 1017-1028.
[77] Hardie D G, Carling D, Carlson M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu. Rev. Biochem., 1998, 67: 821-855.
[78] Towler M C, Hardie D G. AMP-activated protein kinase in metabolic control and insulin signaling. Circ. Res., 2007, 100, (3): 328-341.
[79] Winder W W, Hardie D G. AMP-activated protein kinase, a metabolic master switch: possible roles in type 2 diabetes. Am. J. Physiol., 1999, 277, (1): E1-E10.
[80] Luo Z, Saha A K, Xiang X, et al. AMPK, the metabolic syndrome and cancer. Trends Pharmacol. Sci., 2005, 26, (2): 69-76.
[81] Lim C T, Kola B, Korbonits M. AMPK as a mediator of hormonal signalling. J. Mol. Endocrinol., 2010, 44, (2): 87-97.
[82] Musi N, Fujii N, Hirshman M F, et al. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes, 2001, 50, (5): 921-927.
[83] Moller D E. New drug targets for type 2 diabetes and the metabolic syndrome. Nature (London, U. K.), 2001, 414, (6865): 821-827.
[84] Viollet B, Lantier L, Devin-Leclerc J, et al. Targeting the AMPK pathway for the treatment of Type 2 diabetes. Front. Biosci., Landmark Ed., 2009, 14, (9): 3380-3400.
[85] Zhang B B, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab., 2009, 9, (5): 407-416.
[86] Zhou G, Sebhat I K, Zhang B B. AMPK activators - potential therapeutics for metabolic and other diseases. Acta Physiol., 2009, 196, (1): 175-190.
[87] Shen S, Zhuang J, Chen Y, et al. Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK. Bioorg. Med. Chem., 2013, 21, (13): 3882-3893.
[88] Sambasiva Rao P, Kurumurthy C, Veeraswamy B, et al. Synthesis of novel 5-(3-alkylquinolin-2-yl)-3-aryl isoxazole derivatives and their cytotoxic activity. Bioorg. Med. Chem. Lett., 2014, 24, (5): 1349-1351.
[89] Zheng X J, Li C S, Cui M Y, et al. Synthesis, biological evaluation of benzothiazole derivatives bearing a 1,3,4-oxadiazole moiety as potential anti-oxidant and anti-inflammatory agents. Bioorg. Med. Chem. Lett., 2020, 30, (13): 127237.
[90] 张海滨. 牛蒡子苷元衍生物的合成及抗弓形虫研究. 硕士, 延边大学, 2018.
[91] Zheng X Y, Mao C Y, Qiao H, et al. Plumbagin suppresses chronic periodontitis in rats via down-regulation of TNF-α, IL-1β and IL-6 expression. Acta Pharmacol. Sin., 2017, 38, (8): 1150-1160.
[92] Lee S B, Lee W S, Shin J S, et al. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int. Immunopharmacol., 2017, 49: 21-29.
[93] 卞明. 甘草次酸、补骨脂酚和柠檬苦素衍生物的设计合成及其抗炎活性研究[D]. 延边大学, 2021.