Anticancer Properties and Mechanism of Action of Oblongifolin C, Guttiferone K and Related Polyprenylated Acylphloroglucinols

doi:10.1007/s13659-021-00320-1

摘要/Abstract

摘要： Polyprenylated acylphloroglucinols represent an important class of natural products found in many plants. Among them, the two related products oblongifolin C (Ob-C) and guttiferone K (Gt-K) isolated from Garcinia species (notably from edible fruits), have attracted attention due to their marked anticancer properties. The two compounds only differ by the nature of the C-6 side chain, prenyl (Gt-K) or geranyl (Ob-C) on the phloroglucinol core. Their origin, method of extraction and biological properties are presented here, with a focus on the targets and pathways implicated in their anticancer activities. Both compounds markedly reduce cancer cell proliferation in vitro, as well as tumor growth and metastasis in vivo. They are both potent inducer of tumor cell apoptosis, and regulation of autophagy flux is a hallmark of their mode of action. The distinct mechanism leading to autophagosome accumulation in cells and the implicated molecular targets are discussed. The specific role of the chaperone protein HSPA8, known to interact with Ob-C, is addressed. Molecular models of Gt-K and Ob-C bound to HSPA8 provide a structural basis to their common HSPA8-binding recognition capacity. The review shed light on the mechanism of action of these compounds, to encourage their studies and potential development.

关键词: Anticancer, Autophagy, HSPA8, Natural products, Polyprenylated acylphloroglucinols

Abstract: Polyprenylated acylphloroglucinols represent an important class of natural products found in many plants. Among them, the two related products oblongifolin C (Ob-C) and guttiferone K (Gt-K) isolated from Garcinia species (notably from edible fruits), have attracted attention due to their marked anticancer properties. The two compounds only differ by the nature of the C-6 side chain, prenyl (Gt-K) or geranyl (Ob-C) on the phloroglucinol core. Their origin, method of extraction and biological properties are presented here, with a focus on the targets and pathways implicated in their anticancer activities. Both compounds markedly reduce cancer cell proliferation in vitro, as well as tumor growth and metastasis in vivo. They are both potent inducer of tumor cell apoptosis, and regulation of autophagy flux is a hallmark of their mode of action. The distinct mechanism leading to autophagosome accumulation in cells and the implicated molecular targets are discussed. The specific role of the chaperone protein HSPA8, known to interact with Ob-C, is addressed. Molecular models of Gt-K and Ob-C bound to HSPA8 provide a structural basis to their common HSPA8-binding recognition capacity. The review shed light on the mechanism of action of these compounds, to encourage their studies and potential development.

Key words: Anticancer, Autophagy, HSPA8, Natural products, Polyprenylated acylphloroglucinols

Christian Bailly, Gérard Vergoten. Anticancer Properties and Mechanism of Action of Oblongifolin C, Guttiferone K and Related Polyprenylated Acylphloroglucinols[J]. 应用天然产物, 2021, 11(6): 629-641.

Christian Bailly, Gérard Vergoten. Anticancer Properties and Mechanism of Action of Oblongifolin C, Guttiferone K and Related Polyprenylated Acylphloroglucinols[J]. Natural Products and Bioprospecting, 2021, 11(6): 629-641.

参考文献

1. R. Ciochina, R.B. Grossman, Polycyclic polyprenylated acylphloroglucinols. Chem. Rev. 106, 3963–3986 (2006)
2. J.A. Richard, R.H. Pouwer, D.Y. Chen, The chemistry of the polycyclic polyprenylated acylphloroglucinols. Angew Chem. Int. Ed. Engl. 51, 4536–4561 (2012)
3. X.W. Yang, R.B. Grossman, G. Xu, Research Progress of Polycyclic Polyprenylated Acylphloroglucinols. Chem. Rev. 118, 3508–3558 (2018)
4. http://www.chem.uky.edu/research/grossman/PPAPs
5. T.W. Cao, X. Liu, Zhou HM. Yan-SongYe, D.W. Liu, W.Y. Xiong, G. Xu, Anti-adipogenicadamantane type polycyclic polyprenylated acylphloroglucinols from Hypericum subsessile. Fitoterapia 147, e104755 (2020)
6. C. Coste, N. Gérard, C.P. Dinh, A. Bruguière, C. Rouger, S.T. Leong, K. Awang, P. Richomme, S. Derbré, B. Charreau, Targeting MHC regulation using polycyclic polyprenylated acylphloroglucinols isolated from Garcinia bancana. Biomolecules 10, 1266 (2020)
7. Y. Fromentin, K. Cottet, M. Kritsanida, S. Michel, N. GaboriaudKolar, M.C. Lallemand, Symphonia globulifera, a widespread source of complex metabolites with potent biological activities. Planta Med. 81, 95–107 (2015)
8. J. Ma, Y.D. Zang, J.J. Zhang, C.J. Li, Y. Li, Y.L. Su, A.G. Wang, D.M. Zhang, Nine prenylated acylphloroglucinols with potential anti-depressive and hepatoprotective activities from Hypericum scabrum. Bioorg. Chem. 107, e104529 (2020)
9. T.H. Chen, M.J. Tsai, Y.S. Fu, C.F. Weng, The exploration of natural compounds for anti-diabetes from distinctive species Garcinia linii with comprehensive review of the Garcinia family. Biomolecules 9, 641 (2019)
10. S.X. Huang, C. Feng, Y. Zhou, G. Xu, Q.B. Han, C.F. Qiao, D.C. Chang, K.Q. Luo, H.X. Xu, Bioassay-guided isolation of xanthones and polycyclic prenylated acylphloroglucinols from Garcinia oblongifolia. J. Nat. Prod. 72, 130–135 (2009)
11. D.L. Li, F.W. Xing, Ethnobotanical study on medicinal plants used by local Hoklos people on Hainan Island. China. J. Ethnopharmacol. 194, 358–368 (2016)
12. T.D. Popoola, O. Awodele, F. Babawale, O. Oguns, O. Onabanjo, I. Ibanga, H. Godwin, T. Oyeniyi, A.A. Fatokun, O. Akinloye, Antioxidative, antimitotic, and DNA-damaging activities of Garcinia kola stem bark, Uvaria chamae root, and Olax subscorpioidea root used in the ethnotherapy of cancers. J. Basic Clin. Physiol. Pharmacol. 31, 73 (2019)
13. P. Li, H. AnandhiSenthilkumar, S.B. Wu, B. Liu, Z.Y. Guo, J.E. Fata, E.J. Kennelly, C.L. Long, Comparative UPLC-QTOFMS-based metabolomics and bioactivities analyses of Garcinia oblongifolia. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 1011, 179–195 (2016)
14. Y. Liu, Y. Chen, L. Lin, H. Li, Gambogic acid as a candidate for cancer therapy: a review. Int. J. Nanomed. 15, 10385–10399 (2020)
15. I. See, GCL. Ee, VYM. Jong, SS. Teh, CLC. Acuña, SH. Mah, Cytotoxic activity of phytochemicals from Garcinia mangostana L. and G. benthamiana (Planch. & Triana) Pipoly against breast cancer cells. Nat Prod Res (2020) https://doi.org/10.1080/14786419.2020.1836629. Online ahead of print
16. A.M. Recalde-Gil, L. Klein-Júnior, J. Salton, S. Bordignon, V. Cechinel-Filho, C. Matté, A. Henriques, Aromatase (CYP19) inhibition by biflavonoids obtained from the branches of Garcinia gardneriana (Clusiaceae). Z Naturforsch C J. Biosci. 74, 279–282 (2019)
17. H.N. Murthy, D. Dalawai, Y.H. Dewir, A. Ibrahim, Phytochemicals and biological activities of Garcinia morella (Gaertn) Desr: A review. Molecules 25, e5690 (2020)
18. K. Cottet, A. Neudörffer, M. Kritsanida, S. Michel, M.C. Lallemand, M. Largeron, Polycyclic polyprenylated xanthones from symphonia globulifera: isolation and biomimetic electrosynthesis. J. Nat. Prod. 78, 2136–2140 (2015)
19. B.K. Nganou, I. Simo Konga, A.G. Fankam, G.T.M. Bitchagno, G. Sonfack, P. Nayim, I. Celik, S. Koyutürk, V. Kuete, P. Tane, Guttiferone BL with antibacterial activity from the fruits of Allanblackia gabonensis. Nat. Prod. Res. 33, 2638–2646 (2019)
20. W. Hamed, S. Brajeul, F. Mahuteau-Betzer, O. Thoison, S. Mons, B. Delpech, V.H. Nguyen, T. Sévenet, C. Marazano, Oblongifolins A-D, polyprenylated benzoylphloroglucinol derivatives from Garcinia oblongifolia. J. Nat. Prod. 69, 774–777 (2006)
21. C. Feng, S.X. Huang, X.M. Gao, H.X. Xu, K.Q. Luo, Characterization of proapoptotic compounds from the bark of Garcinia oblongifolia. J. Nat. Prod. 77, 1111–1116 (2014)
22. H. Zhang, L. Tao, W.W. Fu, S. Liang, Y.F. Yang, Q.H. Yuan, D.J. Yang, A.P. Lu, H.X. Xu, Prenylated benzoylphloroglucinols and xanthones from the leaves of Garcinia oblongifolia with antienteroviral activity. J. Nat. Prod. 77, 1037–1046 (2014)
23. G. Xu, C. Feng, Y. Zhou, Q.B. Han, C.F. Qiao, S.X. Huang, D.C. Chang, Q.S. Zhao, K.Q. Luo, H.X. Xu, Bioassay and ultraperformance liquid chromatography/mass spectrometry guided isolation of apoptosis-inducing benzophenones and xanthone from the pericarp of Garcinia yunnanensis Hu. J. Agric. Food Chem. 56, 11144–11150 (2008)
24. C. Ito, T. Matsui, E. Noda, N. Ruangrungsi, M. Itoigawa, Biphenyl derivatives from Garcinia schomburgkiana and the cytotoxicity of the isolated compounds. Nat. Prod. Commun. 8, 1265– 1267 (2013)
25. R.B. Williams, J. Hoch, T.E. Glass, R. Evans, J.S. Miller, J.H. Wisse, D.G. Kingston, A novel cytotoxic guttiferone analogue from Garcinia macrophylla from the Suriname rainforest. Planta Med. 69, 864–866 (2003)
26. S. Baggett, P. Protiva, E.P. Mazzola, H. Yang, E.T. Ressler, M.J. Basile, I.B. Weinstein, E.J. Kennelly, Bioactive benzophenones from Garcinia xanthochymus fruits. J. Nat. Prod. 68, 354–360 (2005)
27. D. Roux, H.A. Hadi, S. Thoret, D. Guénard, O. Thoison, M. Païs, T. Sévenet, Structure-activity relationship of polyisoprenyl benzophenones from Garcinia pyrifera on the tubulin/microtubule system. J. Nat. Prod. 63, 1070–1076 (2000)
28. K. Herath, H. Jayasuriya, J.G. Ondeyka, Z. Guan, R.P. Borris, E. Stijfhoorn, D. Stevenson, J. Wang, N. Sharma, K. Macnaul, J.G. Menke, A. Ali, M.J. Schulman, S.B. Singh, Guttiferone I, a new prenylated benzophenone from Garcinia humilis as a liver X receptor ligand. J. Nat. Prod. 68, 617–619 (2005)
29. L.H. Nguyen, G. Venkatraman, K.Y. Sim, L.J. Harrison, Xanthones and benzophenones from Garcinia griffithii and Garcinia mangostana. Phytochemistry 66, 1718–1723 (2005)
30. S. Ngouela, B.N. Lenta, D.T. Noungoue, J. Ngoupayo, F.F. Boyom, E. Tsamo, J. Gut, P.J. Rosenthal, J.D. Connolly, Antiplasmodial and antioxidant activities of constituents of the seed shells of Symphonia globulifera Linn f. Phytochemistry 67, 302–306 (2006)
31. A.G. Azebaze, B.M. Ouahouo, J.C. Vardamides, A. Valentin, V. Kuete, L. Acebey, V.P. Beng, A.E. Nkengfack, M. Meyer, Antimicrobial and antileishmanial xanthones from the stem bark of Allanblackia gabonensis (Guttiferae). Nat. Prod. Res. 22, 333–341 (2008)
32. J. Kolodziejczyk, M. Masullo, B. Olas, S. Piacente, B. Wachowicz, Effects of garcinol and guttiferone K isolated from Garcinia cambogia on oxidative/nitrative modifications in blood platelets and plasma. Platelets 20, 487–492 (2009)
33. H. Li, X.X. Meng, L. Zhang, B.J. Zhang, X.Y. Liu, W.W. Fu, H.S. Tan, Y.Z. Lao, H.X. Xu, Oblongifolin C and guttiferone K extracted from Garcinia yunnanensis fruit synergistically induce apoptosis in human colorectal cancer cells in vitro. Acta Pharmacol. Sin. 38, 252–263 (2017)
34. S. Cao, P.J. Brodie, J.S. Miller, F. Ratovoson, C. Birkinshaw, S. Randrianasolo, E. Rakotobe, V.E. Rasamison, D.G. Kingston, Guttiferones K and L, antiproliferative compounds of Rheedia calcicola from the Madagascar rain forest. J. Nat. Prod. 70, 686– 688 (2007)
35. G.R. Almanza, R. Quispe, P. Mollinedo, G. Rodrigo, O. Fukushima, R. Villagomez, B. Akesson, O. Sterner, Antioxidant and antimutagenic polyisoprenylated benzophenones and xanthones from Rheedia acuminata. Nat. Prod. Commun. 6, 1269–1274 (2011)
36. A.L. Piccinelli, C. Lotti, L. Campone, O. Cuesta-Rubio, M. Campo Fernandez, L. Rastrelli, Cuban and Brazilian red propolis: botanical origin and comparative analysis by high-performance liquid chromatography-photodiode array detection/electrospray ionization tandem mass spectrometry. J. Agric. Food Chem. 59, 6484–6491 (2011)
37. D. Fasolo, A.M. Bergold, G. von Poser, H.F. Teixeira, Determination of benzophenones in lipophilic extract of Brazilian red propolis, nanotechnology-based product and porcine skin and mucosa: analytical and bioanalytical assays. J. Pharm. Biomed. Anal. 124, 57–66 (2016)
38. G.V. Ccana-Ccapatinta, J.A.A. Mejía, M.H. Tanimoto, M. Groppo, J.C.A.S. Carvalho, J.K. Bastos, Dalbergia ecastaphyllum (L.) Taub and Symphonia globulifera L.f.: the botanical sources of isoflavonoids and benzophenones in Brazilian red propolis. Molecules 25, e2060 (2020)
39. W.W. Fu, H.S. Tan, Xu HX [research progress of chemistry and anti-cancer activities of natural products from Chinese Garcinia plants]. Yao Xue Xue Bao 49, 166–174 (2014)
40. L. Wang, R. Wu, W. Fu, Y. Lao, C. Zheng, H. Tan, H. Xu, Synthesis and biological evaluation of Oblongifolin C derivatives as c-Met inhibitors. Bioorg. Med. Chem. 24, 4120–4128 (2016)
41. N. Biber, K. Möws, B. Plietker, The total synthesis of hyperpapuanone, hyperibone L, epi-clusianone and oblongifolin A. Nat. Chem. 3, 938–942 (2011)
42. F. Horeischi, N. Biber, B. Plietker, The total syntheses of guttiferone A and 6-epi-guttiferone A. J. Am. Chem. Soc. 136, 4026–4030 (2014)
43. N.A. McGrath, J.R. Binner, G. Markopoulos, M. Brichacek, J.T. Njardarson, An efficient oxidative dearomatization-radical cyclization approach to symmetrically substituted bicyclic guttiferone natural products. Chem. Commun. (Camb). 47, 209–211 (2011)
44. K.S. Dias, J.P. Januário, D’ Dego JL, Dias AL, dos Santos MH, Camps I, Coelho LF, Viegas C Jr., Semisynthesis and antimicrobial activity of novel guttiferone-A derivatives. Bioorg. Med. Chem. 20, 2713–2720 (2012)
45. L. Wang, W. Fu, Y. Shen, H. Tan, H. Xu, Molecularly imprinted polymers for selective extraction of Oblongifolin C from Garcinia yunnanensis Hu. Molecules 22, 508 (2017)
46. Z. Karimi Baker, S. Sardari, Molecularly imprinted polymer (MIP) applications in natural product studies based on medicinal plant and secondary metabolite analysis. Iran Biomed. J. 25, 68–77 (2021)
47. J. Li, R. Gao, D. Zhao, X. Huang, Y. Chen, F. Gan, H. Liu, G. Yang, Separation and preparation of xanthochymol and guttiferone E by high performance liquid chromatography and high speed counter-current chromatography combined with silver nitrate coordination reaction. J. Chromatogr. A 1511, 143–148 (2017)
48. H. Zhang, D. Zheng, H.H. Li, H. Wang, H.S. Tan, H.X. Xu, Diagnostic filtering to screen polycyclic polyprenylated acylphloroglucinols from Garcinia oblongifolia by ultrahigh performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry. Anal. Chim. Acta. 912, 85–96 (2016)
49. F.J. Naldoni, A.L. Claudino, J.W. Cruz Jr., J.K. Chavasco, Faria e Silva PM, Veloso MP, Dos Santos MH., Antimicrobial activity of benzophenones and extracts from the fruits of Garcinia brasiliensis. J. Med. Food 12, 403–407 (2009)
50. L. Monzote, O. Cuesta-Rubio, A. Matheeussen, T. Van Assche, L. Maes, P. Cos, Antimicrobial evaluation of the polyisoprenylated benzophenones nemorosone and guttiferone A. Phytother. Res. 25, 458–462 (2011)
51. R. Ribeiro de Carvalho, N. Chaves Silva, M. Cusinato, K.S. Tranches Dias, M.H. Dos Santos, C. Viegas Junior, É. Gonçalves Silva, A.L. Tranches Dias, Promising synergistic activity of fluconazole with bioactive Guttiferone-A and derivatives against non-albicans Candida species. J. Mycol. Med. 28, 645–650 (2018)
52. Y. Fromentin, N. Gaboriaud-Kolar, B.N. Lenta, J.D. Wansi, D. Buisson, E. Mouray, P. Grellier, P.M. Loiseau, M.C. Lallemand, S. Michel, Synthesis of novel guttiferone A derivatives: in-vitro evaluation toward Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani. Eur. J. Med. Chem. 65, 284–294 (2013)
53. R. Duval, K. Cottet, M. Blaud, A. Merckx, S. Houzé, P. Grellier, M.C. Lallemand, S. Michel, A photoalkylative fluorogenic probe of guttiferone A for Live cell imaging and proteome labeling in plasmodium falciparum. Molecules 25, 5139 (2020)
54. Q. Zhang, J. Sun, Y. Fu, W. He, Y. Li, H. Tan, H. Xu, X. Jiang, Guttiferone K exerts the anti-inflammatory effect on mycobacterium tuberculosis-(H37Ra-) infected macrophages by targeting the TLR/IRAK-1 Mediated Akt and NF-kappaB pathway. Mediators Inflamm. 2020, 8528901 (2020)
55. C. Feng, L.Y. Zhou, T. Yu, G. Xu, H.L. Tian, J.J. Xu, H.X. Xu, K.Q. Luo, A new anticancer compound, oblongifolin C, inhibits tumor growth and promotes apoptosis in HeLa cells through Bax activation. Int. J. Cancer 131, 1445–1454 (2012)
56. A. Zhang, W. He, H. Shi, X. Huang, G. Ji, Natural compound oblongifolin C inhibits autophagic flux, and induces apoptosis and mitochondrial dysfunction in human cholangiocarcinoma QBC939 cells. Mol. Med. Rep. 14, 3179–3183 (2016)
57. W. Xu, M. Cheng, Y. Lao, X. Wang, J. Wu, L. Zhou, Y. Zhang, H. Xu, N. Xu, DNA damage and ER stress contribute to oblongifolin C-induced cell killing in Bax/Bak-deficient cells. Biochem. Biophys. Res. Commun. 457, 300–306 (2015)
58. Y. Li, Z. Xi, X. Chen, S. Cai, C. Liang, Z. Wang, Y. Li, H. Tan, Y. Lao, H. Xu, Natural compound Oblongifolin C confers gemcitabine resistance in pancreatic cancer by downregulating Src/MAPK/ERK pathways. Cell Death Dis. 9, 538 (2018)
59. W.L. Kan, C. Yin, H.X. Xu, G. Xu, K.K. To, C.H. Cho, J.A. Rudd, G. Lin, Antitumor effects of novel compound, guttiferone K, on colon cancer by p21Waf1/Cip1-mediated G(0) /G(1) cell cycle arrest and apoptosis. Int. J. Cancer 132, 707–716 (2013)
60. Y. Lao, G. Wan, Z. Liu, X. Wang, P. Ruan, W. Xu, D. Xu, W. Xie, Y. Zhang, H. Xu, N. Xu, The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation. Autophagy 10, 736–749 (2014)
61. Z. Huang, T. Wang, W. Xia, Q. Li, X. Chen, X. Liu, P. Wei, W. Xu, M. Lv, Oblongifolin C reverses GEM resistance via suppressing autophagy flux in bladder cancer cells. Exp. Ther. Med. 20, 1431–1440 (2020)
62. M. Wu, Y. Lao, N. Xu, X. Wang, H. Tan, W. Fu, Z. Lin, H. Xu, Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death. Phytomedicine 22, 902–910 (2015)
63. Y. Wang, M.L. Tsai, L.Y. Chiou, C.T. Ho, M.H. Pan, Antitumor activity of Garcinol in human prostate cancer cells and xenograft mice. J. Agric. Food Chem. 63, 9047–9052 (2015)
64. F. Pietrocola, S. Lachkar, D.P. Enot, M. Niso-Santano, J.M. Bravo-San Pedro, V. Sica, V. Izzo, M.C. Maiuri, F. Madeo, G. Mariño, G. Kroemer, Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015)
65. S.I. Son, D. Su, T.T. Ho, H. Lin, Garcinol Is an HDAC11 Inhibitor. ACS Chem. Biol. 15, 2866–2871 (2020)
66. S. Di Micco, M. Masullo, A.F. Bandak, J.M. Berger, R. Riccio, S. Piacente, G. Bifulco, Garcinol and related polyisoprenylated benzophenones as topoisomerase ii inhibitors: biochemical and molecular modeling studies. J. Nat. Prod. 82, 2768–2779 (2019)
67. M.K. Mazumder, R. Paul, B.C. Phukan, A. Dutta, J. Chakrabarty, P. Bhattacharya, A. Borah, Garcinol, an effective monoamine oxidase-B inhibitor for the treatment of Parkinson’s disease. Med. Hypotheses. 117, 54–58 (2018)
68. Y. Kang, Y. Sun, T. Li, Z. Ren, Garcinol protects against cerebral ischemia-reperfusion injury in vivo and in vitro by inhibiting inflammation and oxidative stress. Mol. Cell Probes. 54, e101672 (2020)
69. A.K. Behera, M.M. Swamy, N. Natesh, T.K. Kundu, Garcinol and its role in chronic diseases. Adv. Exp. Med. Biol. 928, 435–452 (2016)
70. R. Schobert, B. Biersack, Chemical and biological aspects of garcinol and isogarcinol: recent developments. Chem. Biodivers. 16, e1900366 (2019)
71. V. Aggarwal, H.S. Tuli, J. Kaur, D. Aggarwal, G. Parashar, N. Chaturvedi Parashar, S. Kulkarni, G. Kaur, K. Sak, M. Kumar, K.S. Ahn, Garcinol exhibits anti-neoplastic effects by targeting diverse oncogenic factors in tumor cells. Biomedicines. 8, 103 (2020)
72. X. Wang, Y. Lao, N. Xu, Z. Xi, M. Wu, H. Wang, X. Li, H. Tan, M. Sun, H. Xu, Oblongifolin C inhibits metastasis by upregulating keratin 18 and tubulins. Sci. Rep. 5, 10293 (2015)
73. A.M. Fortier, E. Asselin, M. Cadrin, Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin1 up-regulation. J. Biol. Chem. 288, 11555–11571 (2013)
74. H. Zhang, D. Zheng, Z.J. Ding, Y.Z. Lao, H.S. Tan, H.X. Xu, UPLC-PDA-QTOFMS-guided isolation of prenylated xanthones and benzoylphloroglucinols from the leaves of Garcinia oblongifolia and their migration-inhibitory activity. Sci. Rep. 6, 35789 (2016)
75. K. Shen, Z. Xi, J. Xie, H. Wang, C. Xie, C.S. Lee, P. Fahey, Q. Dong, H. Xu, Guttiferone K suppresses cell motility and metastasis of hepatocellular carcinoma by restoring aberrantly reduced profilin 1. Oncotarget 7, 56650–56663 (2016)
76. M. Chen, Y. Dai, S. Liu, Y. Fan, Z. Ding, D. Li, TFEB biology and agonists at a glance. Cells 10, 333 (2021)
77. J. Xu, X.Q. Zhang, Z. Zhang, Transcription factor EB agonists from natural products for treating human diseases with impaired autophagy-lysosome pathway. Chin. Med. 15, 123 (2020)
78. M. Wu, Y.Z. Lao, H.S. Tan, G. Lu, Y. Ren, Z.Q. Zheng, J. Yi, W.W. Fu, H.M. Shen, H.X. Xu, Oblongifolin C suppresses lysosomal function independently of TFEB nuclear translocation. Acta Pharmacol. Sin. 40, 929–937 (2019)
79. A.S. Dossou, A. Basu, The emerging roles of mTORC1 in macromanaging autophagy. Cancers (Basel). 11, 1422 (2019)
80. P. Protiva, M.E. Hopkins, S. Baggett, H. Yang, M. Lipkin, P.R. Holt, E.J. Kennelly, W.I. Bernard, Growth inhibition of colon cancer cells by polyisoprenylated benzophenones is associated with induction of the endoplasmic reticulum response. Int. J. Cancer 123, 687–694 (2008)
81. C.Y. Yang, C. Chen, C.Y. Lin, Y.H. Chen, C.Y. Lin, C.W. Chi, Y.J. Chen, S.C. Liu, T.K. Chang, C.H. Tang, Y.W. Lai, H.J. Tsai, J.J. Chen, S.W. Wang, Garcimultiflorone K inhibits angiogenesis through Akt/eNOS- and mTOR-dependent pathways in human endothelial progenitor cells. Phytomedicine 64, e152911 (2019)
82. Z. Tang, L. Lu, X. Zhou, J. Shen, W. Song, Y. Tang, Z. Xia, A new cytotoxic polycyclic polyprenylated acylphloroglucinol from Garcinia nujiangensis screened by the LC-PDA and LC-MS. Nat. Prod. Res. 34, 2448–2455 (2020)
83. J. Yu, W. Wang, W. Yao, Z. Yang, P. Gao, M. Liu, H. Wang, S. Chen, D. Wang, W. Wang, G. Sun, Gambogic acid affects ESCC progression through regulation of PI3K/AKT/mTOR signal pathway. J. Cancer 11, 5568–5577 (2020)
84. X. Li, X. Tang, J. Su, G. Xu, L. Zhao, Q. Qi, Involvement of E-cadherin/AMPK/mTOR axis in LKB1-induced sensitivity of non-small cell lung cancer to gambogic acid. Biochem. Pharmacol. 169, e113635 (2019)
85. G. Luo, S. Jiang, X. Zhang, Y. Ling, H. Luo, Y. Zhang, Gambogic acid affects ribosomal occurrence in glioma cells by downregulating the phosphoinositide kinase-3/protein kinase b/mammalian target of rapamycin signaling pathway. J. Nanosci. Nanotechnol. 20, 3361–3372 (2020)
86. L. Han, D. Xu, Z. Xi, M. Wu, W.N. Nik Nabil, J. Zhang, H. Sui, W. Fu, H. Zhou, Y. Lao, G. Xu, C. Guo, H. Xu, The natural compound oblongifolin C exhibits anticancer activity by inhibiting HSPA8 and cathepsin B in vitro. Front Pharmacol. 11, e564833 (2020)
87. K.M. Flaherty, C. DeLuca-Flaherty, D.B. McKay, Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature 346, 623–628 (1990)
88. C. Bailly, G. Vergoten, Interaction of fumigaclavine C with High Mobility Group Box 1 protein (HMGB1) and its DNA complex: a computational approach. Comput Biol Chem. 89, e107409 (2020)
89. C. Bailly, G. Vergoten, N-glycosylation and ubiquitinylation of PD-L1 do not restrict interaction with BMS-202: a molecular modeling study. Comput. Biol. Chem. 88, e107362 (2020)
90. F. Stricher, C. Macri, M. Ruff, S. Muller, HSPA8/HSC70 chaperone protein: structure, function, and chemical targeting. Autophagy 9, 1937–1954 (2013)
91. S.R. Bonam, M. Ruff, S. Muller, HSPA8/HSC70 in immune disorders: a molecular rheostat that adjusts chaperone-mediated autophagy substrates. Cells 8, 849 (2019)
92. S.R. Bonam, F. Wang, S. Muller, Autophagy: a new concept in autoimmunity regulation and a novel therapeutic option. J Autoimmun. 94, 16–32 (2018)
93. F. Wang, I. Tasset, A.M. Cuervo, S. Muller, In vivo remodeling of altered autophagy-lysosomal pathway by a phosphopeptide in lupus. Cells 9, 2328 (2020)
94. C. Rouger, S. Pagie, S. Derbré, A.M. Le Ray, P. Richomme, B. Charreau, Prenylated Polyphenols from Clusiaceae and Calophyllaceae with Immunomodulatory Activity on Endothelial Cells. PLoS One 11, e0167361 (2016)
95. Y. Lu, S. Cai, H. Tan, W. Fu, H. Zhang, H. Xu, Inhibitory effect of oblongifolin C on allergic inflammation through the suppression of mast cell activation. Mol. Cell Biochem. 406, 263–271 (2015)
96. H. Sui, H. Tan, J. Fu, Q. Song, R. Jia, L. Han, Y. Lv, H. Zhang, D. Zheng, L. Dong, S. Wang, Q. Li, H. Xu, The active fraction of Garcinia yunnanensis suppresses the progression of colorectal carcinoma by interfering with tumorassociated macrophage-associated M2 macrophage polarization in vivo and in vitro. FASEB J. 34, 7387–7403 (2020)
97. Y. Phang, X. Wang, Y. Lu, W. Fu, C. Zheng, H. Xu, Bicyclic polyprenylated acylphloroglucinols and their derivatives: structural modification, structure-activity relationship, biological activity and mechanism of action. Eur. J. Med. Chem. 205, e112646 (2020)
98. C. Blanchard, D. Pouchain, P. Vanderkam, M.C. Perault-Pochat, R. Boussageon, H. Vaillant-Roussel, Efficacy of phloroglucinol for treatment of abdominal pain: a systematic review of literature and meta-analysis of randomised controlled trials versus placebo. Eur. J. Clin. Pharmacol. 74(5), 541–548 (2018)
99. K.E. Keramaris, K. Konstantopoulos, L.H. Margaritis, A.D. Velentzas, I.S. Papassideri, D.J. Stravopodis, Exploitation of drosophila choriogenesis process as a model cellular system for assessment of compound toxicity: the phloroglucinol paradigm. Sci. Rep. 10, 242 (2020)
100. K. Broadley, L. Larsen, P.M. Herst, R.A. Smith, M.V. Berridge, M.J. McConnell, The novel phloroglucinol PMT7 kills glycolytic cancer cells by blocking autophagy and sensitizing to nutrient stress. J. Cell Biochem. 112, 1869–1879 (2011)
101. Q. You, J. Xu, Z. Zhu, Z. Hu, Q. Cai, Phloretin flavonoid exhibits selective antiproliferative activity in doxorubicin-resistant gastric cancer cells by inducing autophagy, inhibiting cell migration and invasion, cell cycle arrest and targeting ERK1/2 MAP pathway. J. BUON. 25, 308–313 (2020)
102. P. Zhu, C. Lv, C. Fang, X. Peng, H. Sheng, P. Xiao, N. Kumar Ojha, Y. Yan, M. Liao, J. Zhou, Heat shock protein member 8 is an attachment factor for infectious bronchitis virus. Front Microbiol. 11, 1630 (2020)
103. Y.S. Su, P.Y. Hsieh, J.S. Li, Y.H. Pao, C.J. Chen, L.H. Hwang, The heat shock protein 70 family of chaperones regulates all phases of the enterovirus A71 life cycle. Front Microbiol. 11, 1656 (2020)
104. M. Wang, Q. Dong, H. Wang, Y. He, Y. Chen, H. Zhang, R. Wu, X. Chen, B. Zhou, J. He, H.F. Kung, C. Huang, Y. Wei, J.D. Huang, H. Xu, M.L. He, Oblongifolin M, an active compound isolated from a Chinese medical herb Garcinia oblongifolia, potently inhibits enterovirus 71 reproduction through downregulation of ERp57. Oncotarget 7, 8797–8808 (2016)
105. Y. Okamoto, Y. Nagasawa, Y. Obara, K. Ishii, D. Takagi, K. Ono, Molecular identification of HSPA8 as an accessory protein of a hyperpolarization-activated chloride channel from rat pulmonary vein cardiomyocytes. J. Biol. Chem. 294, 16049–16061 (2019)
106. N. Zou, L. Ao, J.C. Cleveland Jr., X. Yang, X. Su, G.Y. Cai, A. Banerjee, D.A. Fullerton, X. Meng, Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion. Am. J. Physiol. Heart Circ. Physiol. 294, H2805–H2813 (2008)

[1]	Hesham R. El-Seedi, Mohamed S. Refaey, Nizar Elias, Mohamed F. El-Mallah, Faisal M. K. Albaqami, Ismail Dergaa, Ming Du, Mohamed F. Salem, Haroon Elrasheid Tahir, Maria Dagliaa, Nermeen Yosri, Hongcheng Zhang, Awg H. El-Seedi, Zhiming Guo, Shaden A. M. Khalifa. Marine natural products as a source of novel anticancer drugs: an updated review (2019-2023)[J]. 应用天然产物, 2025, 15(2): 13-13.
[2]	María I. Osella, Mario O. Salazar, Carlos M. Solís, Ricardo L. E. Furlan. New semisynthetic α-glucosidase inhibitor from a doubly-chemically engineered extract[J]. 应用天然产物, 2025, 15(1): 4-4.
[3]	Ahmed H. Elbanna, Xinhui Kou, Dilip V. Prajapati, Surasree Rakshit, Rebecca A. Butcher. Discovery of a parallel family of euglenatide analogs in Euglena gracilis[J]. 应用天然产物, 2025, 15(1): 10-10.
[4]	Song-Yu Hou, Bing-Chao Yan, Han-Dong Sun, Pema-Tenzin Puno. Recent advances in the application of [2+2] cycloaddition in the chemical synthesis of cyclobutane-containing natural products[J]. 应用天然产物, 2024, 14(5): 37-37.
[5]	Felaine Anne Sumang, Alan Ward, Jeff Errington, Yousef Dashti. Hibiscus acid and hydroxycitric acid dimethyl esters from Hibiscus flowers induce production of dithiolopyrrolone antibiotics by Streptomyces Strain MBN2-2[J]. 应用天然产物, 2024, 14(5): 40-40.
[6]	Antonio Evidente. Advances on anticancer fungal metabolites: sources, chemical and biological activities in the last decade (2012-2023)[J]. 应用天然产物, 2024, 14(4): 31-31.
[7]	Chunsong Hu. Marine natural products and human immunity: novel biomedical resources for anti-infection of SARS-CoV-2 and related cardiovascular disease[J]. 应用天然产物, 2024, 14(2): 2-2.
[8]	Shohreh Ariaeenejad, Javad Gharechahi, Mehdi Foroozandeh Shahraki, Fereshteh Fallah Atanaki, Jian-Lin Han, Xue-Zhi Ding, Falk Hildebrand, Mohammad Bahram, Kaveh Kavousi, Ghasem Hosseini Salekdeh. Precision enzyme discovery through targeted mining of metagenomic data[J]. 应用天然产物, 2024, 14(1): 7-7.
[9]	Daniel W. Armstrong, Alain Berthod. Occurrence of D-amino acids in natural products[J]. 应用天然产物, 2023, 13(6): 47-47.
[10]	Dalila Carbone, Carmela Gallo, Genoveffa Nuzzo, Giusi Barra, Mario Dell'Isola, Mario Affuso, Olimpia Follero, Federica Albiani, Clementina Sansone, Emiliano Manzo, Giuliana d'Ippolito, Angelo Fontana. Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway[J]. 应用天然产物, 2023, 13(5): 34-34.
[11]	Phanankosi Moyo, Luke Invernizzi, Sephora M. Mianda, Wiehan Rudolph, Warren A. Andayi, Mingxun Wang, Neil R. Crouch, Vinesh J. Maharaj. Leveraging off higher plant phylogenetic insights for antiplasmodial drug discovery[J]. 应用天然产物, 2023, 13(5): 35-35.
[12]	Phanankosi Moyo, Luke Invernizzi, Sephora M. Mianda, Wiehan Rudolph, Andrew W. Andayi, Mingxun Wang, Neil R. Crouch, Vinesh J. Maharaj. Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery[J]. 应用天然产物, 2023, 13(5): 37-37.
[13]	Ya-Li Hu, Xing-Ren Li, Gang Xu. Carascynol A, a hybrid of caryophyllane-type terpenoid and a C₆ unit degraded by polyprenylated acylphloroglucinols from Hypericum ascyron[J]. 应用天然产物, 2022, 12(6): 38-38.
[14]	Ji-Kai Liu. Natural products in cosmetics[J]. 应用天然产物, 2022, 12(6): 40-40.
[15]	Si-Yuan Luo, Jun-Yu Zhu, Ming-Feng Zou, Sheng Yin, Gui-Hua Tang. Mulberry Diels–Alder-type adducts: isolation, structure, bioactivity, and synthesis[J]. 应用天然产物, 2022, 12(5): 31-31.