Synthesis and Cytotoxicity Assessment of Novel 7-O- and 14-O-Derivatives of Glaucocalyxin A

Author(s): Hong-Chuan Liu, Li-Ming Qiao, Wei Zheng, Zhao-Bao Xiang, Hai-Sheng Chen, Shi-Chong Yu, Da-Zhi Zhang, Ting Wang, Yue-Fan Zhang, Yong-Sheng Jin*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 10 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Rabdosia japonica has been historically used in China as a popular folk medicine for the treatment of cancer, hepatitis, and gastricism. Glaucocalyxin A (GLA), an ent-kaurene diterpene isolated from Rabdosia japonica, is one of the main active ingredients showing potent inhibitory effects against several types of tumor cells. To the best of our knowledge, studies regarding the structural modification and Structure- Activity Relations (SAR) of this compound have not yet been reported.

Objective: The aim of this study was to discover more potent derivatives of GLA and investigate their SAR and cytotoxicity mechanisms.

Methods: Novel 7-O- and 14-O-derivatives of GLA were synthesized by condensation of acids or acyl chloride. The anti-tumor activities of these derivatives against various human cancer cell lines were evaluated in vitro by MTT assays. Apoptosis assays of compound 17 (7,14-diacylation product) were performed on A549 and HL-60 cells by flow cytometry and TUNNEL. The acute toxicity of this compound was tested on mice, at the dose of 300mg per kg body weight.

Results: Seventeen novel 7-O- and 14-O-derivatives of GLA (1-17) were synthesized. These compounds showed potent cytotoxicity against the tested cancer cell lines, and almost all of them were found to be more cytotoxic than GLA and oridonin. Of the synthesized derivatives, compound 17 presented the greatest cytotoxicity, with IC50 values of 0.26μM and 1.10μM in HL-60 and CCRF-CEM cells, respectively. Furthermore, this compound induced weak apoptosis of A549 cells but showed great potential in stimulating the apoptosis of HL- 60 cells. Acute toxicity assays indicated that compound 17 is relatively safer.

Conclusion: The results reported herein indicate that the synthesized GLA derivatives exhibited greater cytotoxicity against leukemia cells than against other types of tumors. In particular, 7,14-diacylation product of GLA was found to be an effective anti-tumor agent. However, the cytotoxicity mechanism of this product in A549 cells is expected to be different than that in other tumor cell lines. Further research is needed to confirm this hypothesis.

Keywords: Synthesis, glaucocalyxin A, cytotoxicity, Rabdosia japonica, apoptosis, SAR.

[1]
Yang, W.H.; Zhang, Z.; Sima, Y.H.; Zhang, J.; Wang, J.W. Glaucocalyxin A and B-induced cell death is related to GSH perturbation in human leukemia HL-60 cells. Anticancer Agents Med. Chem., 2013, 13(8), 1280-1290.
[http://dx.doi.org/10.2174/18715206113139990200] [PMID: 23796245]
[2]
Yang, W.; Zhang, J.; Gao, L.; Wang, J. Preliminary investigation on glaucocalyxin A-induced cytotoxicity in K562 cells. Zhongguo Shiyan Fangjixue Zazhi, 2011, 17(19), 181-184.
[3]
Xiang, Z.B.; Shen, X.; Tang, Y.; Yao, G.; Li, X.H. Cytotoxic activity of diterpenoids from Rabdosia japonica var. glaucocalyx. Asian J. Chem., 2011, 23(8), 3761-3762.
[4]
Ding, L.; Wang, H.; Liu, G.; Yang, D. A new ent-kaurane diterpenoid from Isodon excisoides (Sun ex C. H. Hu) C. Y. Wu et H. W. Li. J. Chem. Res., 2004, 10, 697-698.
[http://dx.doi.org/10.3184/0308234043431898]
[5]
Huang, J-J.; Wang, X-Z.; Jiang, X-G.; Gu, Z-L.; Guo, C-Y. Effect of Glaucocalyxin A on HeLa cells and its molecular mechanism. Zhongguo Yaolixue Tongbao, 2012, 28(3), 421-424.
[6]
Wang, H.; Ding, L.; Liu, G-A.; Yang, D-J.; Sun, K. Studies on antitumor activities of diterpenoids from Isodon excisoides. Xibei Shifan Daxue Xuebao. Ziran Kexue Ban, 2005, 41(6), 54-57.
[7]
Liu, H-C.; Xiang, Z-B.; Wang, Q.; Li, B-Y.; Jin, Y-S.; Chen, H-S. Monomeric and dimeric ent-kauranoid-type diterpenoids from rabdosia japonica and their cytotoxicity and anti-HBV activities. Fitoterapia, 2017, 118, 94-100.
[http://dx.doi.org/10.1016/j.fitote.2017.03.006] [PMID: 28300699]
[8]
Xiang, Z-B.; Jin, Y-S. Diterpenoids from isodon japonica var. glaucocalyx: A review.J. Chongqing Tech. Bus Univ. (Nat. Sci. Ed.), 2020, 37, 1-16 .http://kns.cnki.net/kcms/detail/50.1155.N.20200102.1112.002.html
[9]
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.
[http://dx.doi.org/10.1016/j.bmcl.2014.04.119] [PMID: 24835198]
[10]
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.
[http://dx.doi.org/10.1016/j.bmcl.2008.06.097] [PMID: 18644718]
[11]
Wang, L.; Ran, Q.; Li, D.; Yao, H.; Zhang, Y.; Yuan, S.; Zhang, L.; Shen, M.; Xu, J. Synthesis and anti-tumor activity of 14-Oderivatives of natural oridonin. Chin. J. Nat. Med., 2011, 9(3), 0194-0198.
[12]
Aoyagi, Y.; Nishioka, Y.; Tobe, F.; Hasuda, T.; Takeya, K.; Gui, M.Y.; Jin, Y.R.; Li, X.W. Synthesis of 1-O-monoacyl or 12-Omonoacyl, 1-,12-O-diacyl-, and 11,12-dehydrated excisanin A 7,14-acetonides and their cytotoxic activity. Bioorg. Med. Chem., 2006, 14(17), 5802-5811.
[http://dx.doi.org/10.1016/j.bmc.2006.05.058] [PMID: 16828562]
[13]
Liang, H-J.; Zhang, Y-X.; Hai, G-F.; Bai, S-P.; Yuan, Y-L.; Ye, DD.; Zhou, N-Q. Isolation, structural elucidation, and cytotoxicity of three new ent-kaurane diterpenoids from Isodon japonica var. glaucocalyx. Planta Med., 2012, 78(6), 589-596.
[http://dx.doi.org/10.1055/s-0031-1298265] [PMID: 22322394]
[14]
Wang, Y.Y.; He, Y.; Yang, L.F.; Peng, S.H.; He, X.L.; Wang, J.H.; Lv, F.; Hao, Y.; Liu, M.Y.; Yi, Z.; Qiu, W.W. Synthesis of novel diterpenoid analogs with in-vivo antitumor activity. Eur. J. Med. Chem., 2016, 120, 13-25.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.071] [PMID: 27187855]
[15]
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.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00408] [PMID: 27089099]
[16]
Huang, H.; Weng, H.; Dong, B.; Zhao, P.; Zhou, H.; Qu, L. Oridonin triggers chaperon-mediated proteasomal degradation of BCR-ABL in leukemia. Sci. Rep., 2017, 7, 41525.
[http://dx.doi.org/10.1038/srep41525] [PMID: 28128329]
[17]
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), 3441-3450.
[http://dx.doi.org/10.1182/blood-2006-06-032250] [PMID: 17197433]
[18]
Li, D.; Han, T.; Liao, J.; Hu, X.; Xu, S.; Tian, K.; Gu, X.; Cheng, K.; Li, Z.; Hua, H.; Xu, J. Oridonin, a promising ent-Kaurane diterpenoid lead compound. Int. J. Mol. Sci., 2016, 17(9), E1395.
[http://dx.doi.org/10.3390/ijms17091395] [PMID: 27563888]
[19]
Wu, J.; Ding, Y.; Chen, C.H.; Zhou, Z.; Ding, C.; Chen, H.; Zhou, J.; Chen, C. A new oridonin analog suppresses triple-negative breast cancer cells and tumor growth via the induction of death receptor 5. Cancer Lett., 2016, 380(2), 393-402.
[http://dx.doi.org/10.1016/j.canlet.2016.06.024] [PMID: 27387452]
[20]
Wu, Q.X.; Yuan, S.X.; Ren, C.M.; Yu, Y.; Sun, W.J.; He, B.C.; Wu, K. Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells. Oncol. Rep., 2016, 35(6), 3341-3348.
[http://dx.doi.org/10.3892/or.2016.4735] [PMID: 27108927]
[21]
Zhang, W.; Huang, Q.; Hua, Z-C. Oridonin: A promising anticancer drug from China. Front. Biol., 2010, 5(6), 540-545.
[http://dx.doi.org/10.1007/s11515-010-0610-8]
[22]
Liu, Z.; Ouyang, L.; Peng, H.; Zhang, W.Z. Oridonin: Targeting programmed cell death pathways as an anti-tumour agent. Cell Prolif., 2012, 45(6), 499-507.
[http://dx.doi.org/10.1111/j.1365-2184.2012.00849.x] [PMID: 23106297]
[23]
Yang, S.J.; Liu, M.C.; Xiang, H.M.; Zhao, Q.; Xue, W.; Yang, S. Synthesis and in vitro antitumor evaluation of betulin acid ester derivatives as novel apoptosis inducers. Eur. J. Med. Chem., 2015, 102, 249-255.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.004] [PMID: 26280921]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 10
Year: 2020
Published on: 01 March, 2020
Page: [1241 - 1249]
Pages: 9
DOI: 10.2174/1871520620666200302114550
Price: $65

Article Metrics

PDF: 33
HTML: 1