Abstract
Background: Natural products (NPs) are evolutionarily chosen “privileged structures” that have a profound impact upon the anticancer drug discovery and development progress. However, the search for new drugs based on structure modification of NPs has often been hindered due to the tedious and complicated synthetic pathways. Fortunately, Mizoroki-Heck reaction and copper-catalyzed alkyne-azide cycloaddition (CuAAC) could provide perfect strategies for selective modification on NPs even in the presence of liable functionalities.
Objective: Here, we used oridonin, an ent-kaurane diterpenoid that showed a wide range of biological activities, as a parent molecule for the generation of analogues with anticancer activity.
Methods: Derivatives of oridonin were generated based on the structure-activity relationship study of oridonin and synthesized via Mizoroki-Heck reaction and CuAAC. The cytotoxicity of new oridonin derivatives were evaluated on both cancer cells and normal cells. Furthermore, the apoptotic effect and cell cycle arrest effect of the selected potent analogue were evaluated by flow cytometry and western blotting analysis.
Results: Two series of novel C-14 and C-17 modified derivatives of oridonin were obtained via Heck reaction and copper-catalyzed alkyne-azide cycloaddition (CuAAC), respectively. In vitro antiproliferative activities showed that the introduction of C-14 (2-triazole)acetoxyl- moiety could retain or enhance cytotoxicity, whereas the introduction of C-17 phenyl ring might exert negative effect. Further studies demonstrated that derivative 23 exhibited broad-spectrum antiproliferative activity, effectively overcame drug-resistance and showed weak cytotoxicity on non-cancer cells. Preliminary mechanistic studies indicated that 23 might cause G2/M phase arrest and induce apoptosis in PC-3 cells.
Conclusion: Mizoroki-Heck reaction and CuAAC are perfect strategies for structure modification of complex natural products. The introduction of C-14 (2-triazole)acetoxyl- moiety could retain or enhance the cytotoxicity of oridonin, the introduction of C-17 phenyl group might exert negative effect on its cytotoxicity.
Keywords: Natural products, oridonin, Mizoroki-Heck reaction, click chemistry, CuAAC, G2/M, apoptosis, cytotoxicity.
Graphical Abstract
[2]
Gottesman, M.M.; Fojo, T.; Bates, S.E. Multidrug resistance in cancer: Role of ATP–Dependent transporters. Nat. Rev. Cancer, 2002, 2, 48.
[3]
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod., 2012, 75(3), 311-335.
[4]
Sun, H-D.; Huang, S-X.; Han, Q-B. Diterpenoids from isodon species and their biological activities. Nat. Prod. Rep., 2006, 23(5), 673-698.
[5]
Aoyagi, Y.; Adachi, Y.; Ozawa, K.; Yokomizo, C.; Gui, M.Y.; Jin, Y.R.; Li, X.W.; Ohno, N.; Takeya, K. Synthesis of rabdokunmin c analogues and their inhibitory effect on NF-KB activation. Bioorg. Med. Chem., 2011, 19(7), 2450-2457.
[6]
Fujita, E.; Fujita, T.; Shibuya, M. Diterpenoid constituents of isodon trichocarpus and isodon japonicus (Terpenoids IV). Tetrahedron Lett., 1966, 7(27), 3153-3162.
[7]
Santagata, S.; Xu, Y.; Wijeratne, E.M.K.; Kontnik, R.; Rooney, C.; Perley, C.C.; Kwon, H.; Clardy, J.; Kesari, S.; Whitesell, L.; Lindquist, S.; Gunatilaka, A.A.L. Using the heat-shock response to discover anticancer compounds that target protein homeostasis. ACS Chem. Biol., 2012, 7(2), 340-349.
[8]
Wijeratne, E.M.K.; Bashyal, B.P.; Liu, M.X.; Rocha, D.D.; Gunaherath, G.M.K.B. U’Ren, J.M.; Gunatilaka, M.K.; Arnold, A.E.; Whitesell, L.; Gunatilaka, A.A.L. Geopyxins A-E, ent-kaurane diterpenoids from endolichenic fungal strains geopyxis aff. majalis and geopyxis sp. az0066: Structure-activity relationships of geopyxins and their analogues. J. Nat. Prod., 2012, 75(3), 361-369.
[9]
Wang, S.; Yang, H.; Yu, L.; Jin, J.; Qian, L.; Zhao, H.; Xu, Y.; Zhu, X. Oridonin attenuates Aβ1-42-induced neuroinflammation and inhibits NF-KB pathway. PLoS One, 2014, 9(8), 1-7.
[10]
Xu, S.; Pei, L.; Li, D.; Yao, H.; Cai, H.; Yao, H.; Wu, X.; Xu, J. Synthesis and antimycobacterial evaluation of natural oridonin and its enmein-type derivatives. Fitoterapia, 2015, 99(1), 300-306.
[11]
Ku, C-M.; Lin, J-Y. Anti-Inflammatory effects of 27 selected terpenoid compounds tested through modulating TH1/TH2 cytokine secretion profiles using murine primary splenocytes. Food Chem., 2013, 141(2), 1104-1113.
[12]
Li, Y.; Wang, Y.; Wang, S.; Gao, Y.; Zhang, X.; Lu, C. Oridonin Phosphate-induced autophagy effectively enhances cell apoptosis of human breast cancer cells. Med. Oncol., 2014, 32(1), 365.
[13]
Bu, H.Q.; Liu, D.L.; Wei, W.T.; Chen, L.; Huang, H.; Li, Y.; Cui, J.H. Oridonin induces apoptosis in SW1990 pancreatic cancer cells via p53- and caspase-dependent induction of p38 MAPK. Oncol. Rep., 2014, 31(2), 975-982.
[14]
Bao, R.; Shu, Y.; Wu, X.; Weng, H.; Ding, Q.; Cao, Y.; Li, M.; Mu, J.; Wu, W.; Ding, Q.; Tan, Z.; Liu, T.; Jiang, L.; Hu, Y.; Gu, J.; Liu, Y. Oridonin induces apoptosis and cell cycle arrest of gallbladder cancer cells via the mitochondrial pathway. BMC Cancer, 2014, 14(1), 217.
[15]
Zhou, G-B.; Kang, H.; Wang, L.; Gao, L.; Liu, P.; Xie, J.; Zhang, F-X.; Weng, X-Q.; Shen, Z-X.; Chen, J.; Gu, L-J.; Yan, M.; Zhang, D-E.; Chen, S-J.; Wang, Z-Y.; Chen, Z. Oridonin, a Diterpenoid extracted from medicinal herbs, targets aml1-eto fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood, 2007, 109(8), 3441LP-3450.
[16]
Li, X.; Li, X.; Wang, J.; Ye, Z.; Li, J-C. Oridonin up-regulates expression of P21 and induces autophagy and apoptosis in human prostate cancer cells. Int. J. Biol. Sci., 2012, 8(6), 901-912.
[17]
Shi, M.; Lu, X-J.; Zhang, J.; Diao, H.; Li, G.; Xu, L.; Wang, T.; Wei, J.; Meng, W.; Ma, J-L.; Yu, H.; Wang, Y-G. Oridonin, a novel lysine acetyltransferases inhibitor, inhibits proliferation and induces apoptosis in gastric cancer cells through p53- and caspase-3-mediated mechanisms. Oncotarget, 2016, 7(16), 22623-22631.
[18]
Li, C.; Wang, E.; Cheng, Y.; Bao, J. Oridonin: An active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics. Int. J. Biochem. Cell Biol., 2011, 43(5), 701-704.
[19]
Cui, Q.; Tashiro, S.; Onodera, S.; Ikejima, T. Augmentation of oridonin-induced apoptosis observed with reduced autophagy. J. Pharmacol. Sci., 2006, 101(3), 230-239.
[20]
Cui, Q.; Tashiro, S.; Onodera, S.; Minami, M.; Ikejima, T. Oridonin Induced autophagy in human cervical carcinoma HeLa cells through ras, JNK, and P38 regulation. J. Pharmacol. Sci., 2007, 105(4), 317-325.
[21]
Gao, X.; Li, J.; Wang, M.; Xu, S.; Liu, W.; Zang, L.; Li, Z.; Hua, H.; Xu, J.; Li, D. Novel enmein-type diterpenoid hybrids coupled with nitrogen mustards: Synthesis of promising candidates for anticancer therapeutics. Eur. J. Med. Chem., 2018, 146, 588-598.
[22]
Ding, Y.; Ding, C.; Ye, N.; Liu, Z.; Wold, E.A.; Chen, H.; Wild, C.; Shen, Q.; Zhou, J. Discovery and development of natural product oridonin-inspired anticancer agents. Eur. J. Med. Chem., 2016, 122, 102-117.
[23]
Li, D.; Xu, S.; Cai, H.; Pei, L.; Zhang, H.; Wang, L.; Yao, H.; Wu, X.; Jiang, J.; Sun, Y.; Xu, J. Enmein-type diterpenoid analogs from natural kaurene-type oridonin: Synthesis and their antitumor biological evaluation. Eur. J. Med. Chem., 2013, 64, 215-221.
[24]
Xu, J.; Yang, J.; Ran, Q.; Wang, L.; Liu, J.; Wang, Z.; Wu, X.; Hua, W.; Yuan, S.; Zhang, L.; Shen, M.; Ding, Y. Synthesis and biological evaluation of novel 1-O- and 14-O-Derivatives of oridonin as potential anticancer drug candidates. Bioorg. Med. Chem. Lett., 2008, 18(16), 4741-4744.
[25]
Xu, S.; Li, D.; Pei, L.; Yao, H.; Wang, C.; Cai, H.; Yao, H.; Wu, X.; Xu, J. Design, synthesis and antimycobacterial activity evaluation of natural oridonin derivatives. Bioorg. Med. Chem. Lett., 2014, 24(13), 2811-2814.
[26]
Zhang, Y.; Xu, S.; Wang, G.; Lin, Y.; Zhang, Y.; Pei, L.; Yao, H.; Hu, M.; Qiu, Y.; Huang, Z.; Xu, J. Novel anticancer oridonin derivatives possessing a Diazen-1-Ium-1,2-Diolate nitric oxide donor moiety: Design, synthesis, biological evaluation and nitric oxide release studies. Bioorg. Med. Chem. Lett., 2016, 26(12), 2795-2800.
[27]
Ke, Y.; Liang, J-J.; Hou, R-J.; Li, M-M.; Zhao, L-F.; Wang, W.; Liu, Y.; Xie, H.; Yang, R-H.; Hu, T-X.; Wang, J-Y.; Liu, H-M. Synthesis and biological evaluation of novel jiyuan oridonin a-1,2,3-triazole-azole derivatives as antiproliferative agents. Eur. J. Med. Chem., 2018, 157, 1249-1263.
[28]
Wang, M.; Li, H.; Xu, F.; Gao, X.; Li, J.; Xu, S.; Zhang, D.; Wu, X.; Xu, J.; Hua, H.; Li, D. Diterpenoid lead stevioside and its hydrolysis products steviol and isosteviol: Biological activity and structural modification. Eur. J. Med. Chem., 2018, 156, 885-906.
[29]
Xu, S.; Yao, H.; Pei, L.; Hu, M.; Li, D.; Qiu, Y.; Wang, G.; Wu, L.; Yao, H.; Zhu, Z.; Xu, J. Design, synthesis, and biological evaluation of NAD(P)H: Quinone Oxidoreductase (NQO1)-targeted oridonin prodrugs possessing indolequinone moiety for hypoxia-selective activation. Eur. J. Med. Chem., 2017, 132, 310-321.
[30]
Wang, C.; Yang, D.; Jiang, L.; Wang, S.; Wang, J.; Zhou, K.; Shi, X.; Chang, L.; Liu, Y.; Ke, Y.; Liu, H. Jesridonin in combination with paclitaxel demonstrates synergistic anti-tumor activity in human esophageal carcinoma cells. Bioorg. Med. Chem. Lett., 2017, 27(9), 2058-2062.
[31]
Ding, Y.; Li, D.; Ding, C.; Wang, P.; Liu, Z.; Wold, E.A.; Ye, N.; Chen, H.; White, M.A.; Shen, Q.; Zhou, J. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads. J. Med. Chem., 2018, 61(7), 2737-2752.
[32]
Ke, Y.; Wang, W.; Zhao, L-F.; Liang, J-J.; Liu, Y.; Zhang, X.; Feng, K.; Liu, H-M. Design, synthesis and biological mechanisms research on 1,2,3-triazole derivatives of jiyuan oridonin A. Bioorg. Med. Chem., 2018, 26(17), 4761-4773.
[33]
Ding, C.; Zhang, Y.; Chen, H.; Wild, C.; Wang, T.; White, M.A.; Shen, Q.; Zhou, J. Overcoming Synthetic Challenges of Oridonin A-Ring Structural Diversification: Regio- and stereoselective installation of azides and 1,2,3-triazoles at the c-1, c-2, or c-3 position. Org. Lett., 2013, 15(14), 3718-3721.
[34]
Xu, S.; Pei, L.; Wang, C.; Zhang, Y.K.; Li, D.; Yao, H.; Wu, X.; Chen, Z.S.; Sun, Y.; Xu, J. Novel hybrids of natural oridonin-bearing nitrogen mustards as potential anticancer drug candidates. ACS Med. Chem. Lett., 2014, 5(7), 797-802.
[35]
Ding, C.; Zhang, Y.; Chen, H.; Yang, Z.; Wild, C.; Ye, N.; Ester, C.D.; Xiong, A.; White, M.A.; Shen, Q.; Zhou, J. Oridonin ring a-based diverse constructions of enone functionality: Identification of novel dienone analogues effective for highly aggressive breast cancer by inducing apoptosis. J. Med. Chem., 2013, 56(21), 8814-8825.
[36]
Ding, C.; Zhang, Y.; Chen, H.; Yang, Z.; Wild, C.; Chu, L.; Liu, H.; Shen, Q.; Zhou, J. Novel nitrogen-enriched oridonin analogues with thiazole-fused a-ring: Protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility. J. Med. Chem., 2013, 56(12), 5048-5058.
[37]
Lin, Z.; Guo, Y.; Gao, Y.; Wang, S.; Wang, X.; Xie, Z.; Niu, H.; Chang, W.; Liu, L.; Yuan, H.; Lou, H. Ent-Kaurane diterpenoids from chinese liverworts and their antitumor activities through michael addition as detected in situ by a fluorescence probe. J. Med. Chem., 2015, 58(9), 3944-3956.
[38]
Xu, S.; Luo, S.; Yao, H.; Cai, H.; Miao, X.; Wu, F.; Yang, D.H.; Wu, X.; Xie, W.; Yao, H.; Chen, Z.S.; Xu, J. Probing the anticancer action of oridonin with fluorescent analogues: Visualizing subcellular localization to mitochondria. J. Med. Chem., 2016, 59(10), 5022-5034.
[39]
Wang, L.; Li, D.; Xu, S.; Cai, H.; Yao, H.; Zhang, Y.; Jiang, J.; Xu, J. The conversion of oridonin to spirolactone-type or enmein-type diterpenoid: Synthesis and biological evaluation of Ent-6,7-Seco-oridonin derivatives as novel potential anticancer agents. Eur. J. Med. Chem., 2012, 52, 242-250.
[40]
Li, D.; Cai, H.; Jiang, B.; Liu, G.; Wang, Y.; Wang, L.; Yao, H.; Wu, X.; Sun, Y.; Xu, J. Synthesis of spirolactone-type diterpenoid derivatives from kaurene-type oridonin with improved antiproliferative effects and their apoptosis-inducing activity in human hepatoma Bel-7402 Cells. Eur. J. Med. Chem., 2013, 59, 322-328.
[41]
Dounay, A.B.; Overman, L.E. The asymmetric intramolecular heck reaction in natural product total synthesis. Chem. Rev., 2003, 103(8), 2945-2963.
[42]
Mallepally, V.R.; Thota, N.; Payare, L.S.; Malhotra, P.; Ali, F.; Inshad, A.K.; Swapandeep, S.C.; Koul, S. Novel bisstyryl derivatives of bakuchiol: Targeting oral cavity pathogens. Eur. J. Med. Chem., 2010, 45(7), 3125-3134.
[43]
Liang, J.H.; Dong, L.J.; Wang, H.; An, K.; Li, X.L.; Yang, L.; Yao, G.W.; Xu, Y.C. Synthesis and antibacterial activities of 6-O-Methylerythromycin A 9-O-(3-aryl-2-propenyl) oxime ketolide, 2,3-enol ether, and alkylide analogues. Eur. J. Med. Chem., 2010, 45(9), 3627-3635.
[44]
Maiwald, F.; Benítez, D.; Charquero, D.; Dar, M.A.; Erdmann, H.; Preu, L.; Koch, O.; Hölscher, C.; Loaëc, N.; Meijer, L.; Comini, M.A.; Kunick, C. 9- and 11-Substituted 4-Azapaullones are potent and selective inhibitors of African trypanosoma. Eur. J. Med. Chem., 2014, 83, 274-283.
[45]
Xu, H.; Tang, H.; Feng, H.; Li, Y. design, synthesis and anticancer activity evaluation of novel C14 heterocycle substituted epi-triptolide. Eur. J. Med. Chem., 2014, 73, 46-55.
[46]
Hou, W.; Zhang, G.; Luo, Z.; Li, D.; Ruan, H.; Ruan, B.H.; Su, L.; Xu, H. Identification of a diverse synthetic abietane diterpenoid library and insight into the structure-activity relationships for antibacterial activity. Bioorg. Med. Chem. Lett., 2017, 27(24), 5382-5386.
[47]
Hou, W.; Luo, Z.; Zhang, G.; Cao, D.; Li, D.; Ruan, H.; Ruan, B.H.; Su, L.; Xu, H. Click chemistry-based synthesis and anticancer activity evaluation of novel C-14 1,2,3-Triazole dehydroabietic acid hybrids. Eur. J. Med. Chem., 2017, 138, 1042-1052.
[48]
Xu, H.; Liu, L.; Fan, X.; Zhang, G.; Li, Y.; Jiang, B. Identification of a diverse synthetic abietane diterpenoid library for anticancer activity. Bioorg. Med. Chem. Lett., 2017, 27(3), 505-510.
[49]
Hou, W.; Zhang, G.; Luo, Z.; Su, L.; Xu, H. Click chemistry-based synthesis and cytotoxic activity evaluation of 4α-triazole acetate podophyllotoxin derivatives. Chem. Biol. Drug Des., 2019, 93(4), 473-483.
[50]
Xu, H.; Fan, X.; Zhang, G.; Liu, X.; Li, Z.; Li, Y.; Jiang, B. LLDT-288, a novel triptolide analogue exhibits potent antitumor activity in vitro and in vivo. Biomed. Pharmacother., 2017, 93, 1004-1009.
[51]
Xu, H.; Tang, H.; Feng, H.; Li, Y. Divergent total synthesis of triptolide, triptonide, tripdiolide, 16-hydroxytriptolide, and their analogues. J. Org. Chem., 2014, 79(21), 10110-10122.
[52]
Xu, H.; Chen, Y.; Tang, H.; Feng, H.; Li, Y. Semisynthesis of triptolide analogues: Effect of B-Ring substituents on cytotoxic activities. Bioorg. Med. Chem. Lett., 2014, 24(24), 5671-5674.
[53]
Xu, H.; Tang, H.; Feng, H.; Li, Y. Design, synthesis and structure-activity relationships studies on the d ring of the natural product triptolide. ChemMedChem, 2014, 9(2)290295
[54]
How, W.; Zhou, Y.; Rui, J.; Bai, R.; Bhasin, A.K.K.; Ruan, B.H. Design and synthesis of novel tellurodibenzoic acid compounds as Kidney-Type Glutaminase (KGA) inhibitors. Bioorg. Med. Chem. Lett., 2019, •••
[http://dx.doi.org/10.1016/j.bmcl.2019.04.032]
[http://dx.doi.org/10.1016/j.bmcl.2019.04.032]
[56]
Chugh, R.; Sangwan, V.; Patil, S.P.; Dudeja, V.; Dawra, R.K.; Banerjee, S.; Schumacher, R.J.; Blazar, B.R.; Georg, G.I.; Vickers, S.M.; Saluja, A.K. A preclinical evaluation of minnelide as a therapeutic agent against pancreatic cancer. Sci. Transl. Med.,, 2012, 4(156), 156ra139-156ra139.
[57]
Tominaga, H.; Ishiyama, M.; Ohseto, F.; Sasamoto, K.; Hamamoto, T.; Suzuki, K.; Watanabe, M. A water-soluble tetrazolium salt useful for colorimetric cell viability assay. Anal. Commun., 1999, 36(2), 47-50.
[58]
Medical, C.; Accreditation, E.; Nursing, C.; Disclosures, A.; Continuing, A.C.S.; Education, P.; Disclosures, C.; Disclosures, A. Take free quizzes online at acsjournals.com/ce understanding,
recognizing, and managing toxicities of targeted anticancer
therapies. CA Cancer J. Clin.,, 2013, 63(4), 249-279.
[59]
Clarke, P.R.; Allan, L.A. Cell-cycle control in the face of damage – a matter of life or death. Trends Cell Biol., 2009, 19(3), 89-98.
[60]
Santamaría, D.; Barrière, C.; Cerqueira, A.; Hunt, S.; Tardy, C.; Newton, K.; Cáceres, J.F.; Dubus, P.; Malumbres, M.; Barbacid, M. Cdk1 is sufficient to drive the mammalian cell cycle. Nature, 2007, 448, 811.
[61]
Tadesse, S.; Caldon, E.C.; Tilley, W.; Wang, S. Cyclin-dependent kinase 2 inhibitors in cancer therapy: An update. J. Med. Chem., 2019, 62(9), 4233-4251.
[62]
Tutone, M.; Almerico, A.M. Recent advances on cdk inhibitors: An insight by means of in silico methods. Eur. J. Med. Chem., 2017, 142, 300-315.
[63]
Kalra, S.; Joshi, G.; Munshi, A.; Kumar, R. Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors. Eur. J. Med. Chem., 2017, 142, 424-458.
[65]
Evan, G.I.; Vousden, K.H. Proliferation, cell cycle and apoptosis in cancer. Nature, 2001, 411, 342-348.
[66]
Cui, Q.; Tashiro, S.; Onodera, S.; Minami, M.; Ikejima, T. Autophagy preceded apoptosis in oridonin-treated human breast cancer MCF-7 cells. Biol. Pharm. Bull., 2007, 30(5), 859-864.
[67]
Zhang, Y.; Wu, Y.; Wu, D.; Tashiro, S.; Onodera, S.; Ikejima, T. NF-Kb facilitates oridonin-induced apoptosis and autophagy in HT1080 cells through a P53-mediated pathway. Arch. Biochem. Biophys., 2009, 489(1), 25-33.
Related Journals
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Current Cancer Drug Targets
Current Cancer Therapy Reviews
Current Drug Safety
Current Drug Targets
Recent Patents on Anti-Cancer Drug Discovery
Letters in Drug Design & Discovery
Current Drug Discovery Technologies
Current Radiopharmaceuticals
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Clinical Drug Research - Anti-Cancer Agents
Advances in Organic Synthesis
Frontiers in Natural Product Chemistry
Recent Advances in Analytical Techniques
Frontiers in Drug Design and Discovery
NEOPLASIA and FERTILITY
Therapeutic Use of Plant Secondary Metabolites
Frontiers in Computational Chemistry
Frontiers in Bioactive Compounds
Article Metrics
69
6
1