Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer

Jing Liu; Qi He; Jiaoli Ding; Zhipeng Zhang; Weixin Zhou; Saisai Xie

doi:doi:10.11648/j.bmb.20180304.11

| Peer-Reviewed

Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer

Jing Liu, Qi He, Jiaoli Ding, Zhipeng Zhang, Weixin Zhou, Saisai Xie

Published in Biochemistry and Molecular Biology (Volume 3, Issue 4)

Received: 16 November 2018 Accepted: 6 December 2018 Published: 18 December 2018

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

Abstract

Aim: Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, showed many biological activities related to the treatment of cancer. However, the comparatively weak activity hinders its further application in clinical. Therefore, the aim of the present study was design and synthesis of a series of novel osthole derivatives by introducing different secondary amine groups at 7-O position of coumarin ring to improve its anticancer activity. Method: After the demethylation of osthole, the target derivatives 4a-l were successfully synthesized through two steps in high yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR. The antiproliferative activity of these compounds was evaluated against four selected cancer cell lines (SGC7901, MCF-7, HCT116 and HepG2) using MTT method, and the most potent compound was selected for Hoechst 333258 staining assay to further investigate its possible mechanism on cancer cells. Results: Twelve osthole derivatives were synthesized and their structures were identified. Biological studies showed that most of them showed moderate to good growth inhibition against all the tested cancer cells. Especially, compound 4l displayed the most potent activity with IC₅₀ values of 37.57 μM, 25.12 μM, 46.54 μM and 18.39 μM against SCG7901, HCT116, MCF-7 and HepG2, respectively, which was more potent than those of its parent compound osthole and the anticancer agent 5-Fu. The Hoechst 33258 staining assay revealed that compound 4l could induce cell apoptosis in HepG2 cells. Conclusion: The modification of osthole to improve its activity is feasible, and compound 4l can be considered as a potential agent for the treatment of cancer.

Published in	Biochemistry and Molecular Biology (Volume 3, Issue 4)
DOI	10.11648/j.bmb.20180304.11
Page(s)	56-62
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Osthole, Anticancer Activity, Synthesis, Apoptosis, Coumarin

References

[1]	Kim S. K. (2015), Handbook of Anticancer Drugs from Marine Origin, Springer international polishing, Switzerland.
[2]	Salas-Vega S., Mossialos E (2017). Overestimating the Benefit of Cancer Drugs-Reply. JAMA oncol. 3: 1738-39.
[3]	Wang, W., Zhang, Y., Yao, G., et al. (2018), Synthesis of new sarsasapogenin derivatives with antiproliferative and apoptotic effects in MCF-7 cells, Steroids, 131: 23-31.
[4]	Ramos, P., Bentires-Alj, M (2015). Mechanism-based cancer therapy: resistance to therapy, therapy for resistance, Oncogene, 34: 3617-3626.
[5]	Ozben T. (2006), Mechanisms and strategies to overcome multiple drug resistance in cancer, FEBS Lett. 580: 2903-2909.
[6]	Cragg G. M., Newman D. J. (2013), Natural products: a continuing source of novel drug leads, Biochim. Biophys. Acta. 1830: 3670-3695.
[7]	Kumar, M. S., Adki, K. M (2018), Marine natural products for multi-targeted cancer treatment: A future insight, Biomed. Pharmacother, 105: 233-245.
[8]	Wang, Y., Zhong, J., Bai, J., et al. (2018), The Application of Natural Products in Cancer Therapy by Targeting Apoptosis Pathways, Curr. Drug Metab. 19: 739-749.
[9]	Newman, D. J., Cragg, G. M., Snader, K. M. (2003), Natural products as sources of new drugs over the period 1981-2002, J. Nat. Prod. 66: 1022-1037.
[10]	Yuan, R., Hou, Y., Sun, W., Yu, J., Liu, X., et al. (2017), Natural products to prevent drug resistance in cancer chemotherapy: a review, Ann N Y Acad. Sci., 1401: 19-27.
[11]	Zimecki M., Artym J., Cisowski W., et. al (2009), Immunomodulatory and anti-inflammatory activity of selected osthole derivatives, Z. Naturforsch. C 64 (5–6) 361–368.
[12]	Chao X., Zhou X., Zheng G., et. al (2014), Osthole induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Pharmaceutical biology, 52 (5): 544-550.
[13]	Zhang Z. R., Leung W. N., Cheung H. Y. (2015), Osthole: a review on its bioactivities, pharmacological properties, and potential as alternative medicine. Evidence-Based Complementary and Alternative Medicine, 2015.
[14]	You L., An R., Wang X., Li Y. (2010), Discovery of novel osthole derivatives as potential anti-breast cancer treatment, Bioorg. Med. Chem. Lett. 20: 7426-7428.
[15]	You L., Feng S., An R., Wang X. (2009), Osthole: a promising lead compound for drug discovery from a traditional Chinese medicine (TCM), Nat. Prod. Commun. 4: 297-302.
[16]	Putnam K. P., Bombick D. W., Doolittle D. J. (2002), Evaluation of eight in vitro assays for assessing the cytotoxicity of cigarette smoke condensate, Toxicol. In Vitro 16: 599-607.
[17]	Kaise, A., Ohta, K., Shirata, C., Endo, Y. (2017), Design and synthesis of p-carborane-containing sulfamates as multitarget anti-breast cancer agents, Bioorg. Med. Chem. 25: 6417-6426.
[18]	Duan Y. C., Ma Y. C., Zhang E., et. al. (2013), Design and synthesis of novel 1,2,3-triazole-dithiocarbamate hybrids as potential anticancer agents, Eur. J. Med. Chem. 62: 11-19.
[19]	Ahmed, M. F., Magdy, N. (2017), Design and Synthesis of 4-substituted Quinazolines as Potent EGFR Inhibitors with Anti-breast Cancer Activity, Anticancer Agents Med. Chem., 17: 832-838.
[20]	Bunz F. (2001), Cell death and cancer therapy, Curr. Opin. Pharmacol., 1: 337-341.
[21]	Guo, C., Yang, R. J., Jang, K., Zhou, X. L., Liu, Y. Z. (2017), Protective Effects of Pretreatment with Quercetin Against Lipopolysaccharide-Induced Apoptosis and the Inhibition of Osteoblast Differentiation via the MAPK and Wnt/beta-Catenin Pathways in MC3T3-E1 Cells, Cell Physiol Biochem, 43: 1547-1561.
[22]	Krajarng A., Nilwarankoon S., Suksamrarn S., Watanapokasin R. (2012), Antiproliferative effect of alpha-mangostin on canine osteosarcoma cells, Res. Vet. Sci. 93: 788-794.
[23]	Huang X. C., Wang M., Wang H. S., et. al (2014), Synthesis and antitumor activities of novel dipeptide derivatives derived from dehydroabietic acid, Bioorg. Med. Chem. Lett. 24: 1511-1518.
[24]	Wu J. J., Ma T., Wang Z. M., Xu W. J., et. al (2017). Polycyclic xanthones via pH-switched biotransformation of α-mangostin catalysed by horseradish peroxidase exhibited cytotoxicity against hepatoblastoma cells in vitro. Journal of Functional Foods, 28: 205-214.
[25]	Zhang, B., Huang, R., Hua, J. et al. (2016), Antitumor lignanamides from the aerial parts of Corydalis saxicola, Phytomedicine, 23: 1599-1609.
[26]	Liu M. C., Yang S. J., Jin L. H., et. al (2012), Synthesis and cytotoxicity of novel ursolic acid derivatives containing an acyl piperazine moiety, Eur. J. Med. Chem., 58: 128-135.
[27]	Tian, L., Wang, X., Li, X., et al. (2016), In vitro antitumor activity of Latcripin-15 regulator of chromosome condensation 1 domain protein, Oncol. Lett., 12: 3153-3160.
[28]	Rubino S., Portanova P., Albanese A. (2007), Mono- and polynuclear complexes of Pt (II) with polypyridyl ligands. Synthesis, spectroscopic and structural characterization and cytotoxic activity, J. Inorg. Biochem. 101: 1473-1482.

Cite This Article

Plain Text BibTeX RIS

APA Style

Jing Liu, Qi He, Jiaoli Ding, Zhipeng Zhang, Weixin Zhou, et al. (2018). Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer. Biochemistry and Molecular Biology, 3(4), 56-62. https://doi.org/10.11648/j.bmb.20180304.11

Copy | Download

ACS Style

Jing Liu; Qi He; Jiaoli Ding; Zhipeng Zhang; Weixin Zhou, et al. Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer. Biochem. Mol. Biol. 2018, 3(4), 56-62. doi: 10.11648/j.bmb.20180304.11

Copy | Download

AMA Style

Jing Liu, Qi He, Jiaoli Ding, Zhipeng Zhang, Weixin Zhou, et al. Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer. Biochem Mol Biol. 2018;3(4):56-62. doi: 10.11648/j.bmb.20180304.11

Copy | Download

@article{10.11648/j.bmb.20180304.11,
  author = {Jing Liu and Qi He and Jiaoli Ding and Zhipeng Zhang and Weixin Zhou and Saisai Xie},
  title = {Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer},
  journal = {Biochemistry and Molecular Biology},
  volume = {3},
  number = {4},
  pages = {56-62},
  doi = {10.11648/j.bmb.20180304.11},
  url = {https://doi.org/10.11648/j.bmb.20180304.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bmb.20180304.11},
  abstract = {Aim: Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, showed many biological activities related to the treatment of cancer. However, the comparatively weak activity hinders its further application in clinical. Therefore, the aim of the present study was design and synthesis of a series of novel osthole derivatives by introducing different secondary amine groups at 7-O position of coumarin ring to improve its anticancer activity. Method: After the demethylation of osthole, the target derivatives 4a-l were successfully synthesized through two steps in high yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR. The antiproliferative activity of these compounds was evaluated against four selected cancer cell lines (SGC7901, MCF-7, HCT116 and HepG2) using MTT method, and the most potent compound was selected for Hoechst 333258 staining assay to further investigate its possible mechanism on cancer cells. Results: Twelve osthole derivatives were synthesized and their structures were identified. Biological studies showed that most of them showed moderate to good growth inhibition against all the tested cancer cells. Especially, compound 4l displayed the most potent activity with IC50 values of 37.57 μM, 25.12 μM, 46.54 μM and 18.39 μM against SCG7901, HCT116, MCF-7 and HepG2, respectively, which was more potent than those of its parent compound osthole and the anticancer agent 5-Fu. The Hoechst 33258 staining assay revealed that compound 4l could induce cell apoptosis in HepG2 cells. Conclusion: The modification of osthole to improve its activity is feasible, and compound 4l can be considered as a potential agent for the treatment of cancer.},
 year = {2018}
}

Copy | Download

TY  - JOUR
T1  - Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer
AU  - Jing Liu
AU  - Qi He
AU  - Jiaoli Ding
AU  - Zhipeng Zhang
AU  - Weixin Zhou
AU  - Saisai Xie
Y1  - 2018/12/18
PY  - 2018
N1  - https://doi.org/10.11648/j.bmb.20180304.11
DO  - 10.11648/j.bmb.20180304.11
T2  - Biochemistry and Molecular Biology
JF  - Biochemistry and Molecular Biology
JO  - Biochemistry and Molecular Biology
SP  - 56
EP  - 62
PB  - Science Publishing Group
SN  - 2575-5048
UR  - https://doi.org/10.11648/j.bmb.20180304.11
AB  - Aim: Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, showed many biological activities related to the treatment of cancer. However, the comparatively weak activity hinders its further application in clinical. Therefore, the aim of the present study was design and synthesis of a series of novel osthole derivatives by introducing different secondary amine groups at 7-O position of coumarin ring to improve its anticancer activity. Method: After the demethylation of osthole, the target derivatives 4a-l were successfully synthesized through two steps in high yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR. The antiproliferative activity of these compounds was evaluated against four selected cancer cell lines (SGC7901, MCF-7, HCT116 and HepG2) using MTT method, and the most potent compound was selected for Hoechst 333258 staining assay to further investigate its possible mechanism on cancer cells. Results: Twelve osthole derivatives were synthesized and their structures were identified. Biological studies showed that most of them showed moderate to good growth inhibition against all the tested cancer cells. Especially, compound 4l displayed the most potent activity with IC50 values of 37.57 μM, 25.12 μM, 46.54 μM and 18.39 μM against SCG7901, HCT116, MCF-7 and HepG2, respectively, which was more potent than those of its parent compound osthole and the anticancer agent 5-Fu. The Hoechst 33258 staining assay revealed that compound 4l could induce cell apoptosis in HepG2 cells. Conclusion: The modification of osthole to improve its activity is feasible, and compound 4l can be considered as a potential agent for the treatment of cancer.
VL  - 3
IS  - 4
ER  -

Copy | Download

Author Information

Jing Liu

School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
Qi He

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
Jiaoli Ding

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
Zhipeng Zhang

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
Weixin Zhou

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
Saisai Xie

National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

Jing Liu, Qi He, Jiaoli Ding, Zhipeng Zhang, Weixin Zhou, et al. (2018). Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer. Biochemistry and Molecular Biology, 3(4), 56-62. https://doi.org/10.11648/j.bmb.20180304.11

Copy | Download

ACS Style

Jing Liu; Qi He; Jiaoli Ding; Zhipeng Zhang; Weixin Zhou, et al. Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer. Biochem. Mol. Biol. 2018, 3(4), 56-62. doi: 10.11648/j.bmb.20180304.11

Copy | Download

AMA Style

Jing Liu, Qi He, Jiaoli Ding, Zhipeng Zhang, Weixin Zhou, et al. Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer. Biochem Mol Biol. 2018;3(4):56-62. doi: 10.11648/j.bmb.20180304.11

Copy | Download

@article{10.11648/j.bmb.20180304.11,
  author = {Jing Liu and Qi He and Jiaoli Ding and Zhipeng Zhang and Weixin Zhou and Saisai Xie},
  title = {Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer},
  journal = {Biochemistry and Molecular Biology},
  volume = {3},
  number = {4},
  pages = {56-62},
  doi = {10.11648/j.bmb.20180304.11},
  url = {https://doi.org/10.11648/j.bmb.20180304.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.bmb.20180304.11},
  abstract = {Aim: Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, showed many biological activities related to the treatment of cancer. However, the comparatively weak activity hinders its further application in clinical. Therefore, the aim of the present study was design and synthesis of a series of novel osthole derivatives by introducing different secondary amine groups at 7-O position of coumarin ring to improve its anticancer activity. Method: After the demethylation of osthole, the target derivatives 4a-l were successfully synthesized through two steps in high yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR. The antiproliferative activity of these compounds was evaluated against four selected cancer cell lines (SGC7901, MCF-7, HCT116 and HepG2) using MTT method, and the most potent compound was selected for Hoechst 333258 staining assay to further investigate its possible mechanism on cancer cells. Results: Twelve osthole derivatives were synthesized and their structures were identified. Biological studies showed that most of them showed moderate to good growth inhibition against all the tested cancer cells. Especially, compound 4l displayed the most potent activity with IC50 values of 37.57 μM, 25.12 μM, 46.54 μM and 18.39 μM against SCG7901, HCT116, MCF-7 and HepG2, respectively, which was more potent than those of its parent compound osthole and the anticancer agent 5-Fu. The Hoechst 33258 staining assay revealed that compound 4l could induce cell apoptosis in HepG2 cells. Conclusion: The modification of osthole to improve its activity is feasible, and compound 4l can be considered as a potential agent for the treatment of cancer.},
 year = {2018}
}

Copy | Download

TY  - JOUR
T1  - Design, Synthesis and Biological Evaluation of Novel Osthole Derivatives as Potential Agents for the Treatment of Cancer
AU  - Jing Liu
AU  - Qi He
AU  - Jiaoli Ding
AU  - Zhipeng Zhang
AU  - Weixin Zhou
AU  - Saisai Xie
Y1  - 2018/12/18
PY  - 2018
N1  - https://doi.org/10.11648/j.bmb.20180304.11
DO  - 10.11648/j.bmb.20180304.11
T2  - Biochemistry and Molecular Biology
JF  - Biochemistry and Molecular Biology
JO  - Biochemistry and Molecular Biology
SP  - 56
EP  - 62
PB  - Science Publishing Group
SN  - 2575-5048
UR  - https://doi.org/10.11648/j.bmb.20180304.11
AB  - Aim: Osthole, an ingredient of Traditional Chinese Medicine (TCM) from natural product Cnidium monnieri (L.) Cusson, showed many biological activities related to the treatment of cancer. However, the comparatively weak activity hinders its further application in clinical. Therefore, the aim of the present study was design and synthesis of a series of novel osthole derivatives by introducing different secondary amine groups at 7-O position of coumarin ring to improve its anticancer activity. Method: After the demethylation of osthole, the target derivatives 4a-l were successfully synthesized through two steps in high yield. The structures of the synthesized compounds were confirmed by 1H and 13C NMR. The antiproliferative activity of these compounds was evaluated against four selected cancer cell lines (SGC7901, MCF-7, HCT116 and HepG2) using MTT method, and the most potent compound was selected for Hoechst 333258 staining assay to further investigate its possible mechanism on cancer cells. Results: Twelve osthole derivatives were synthesized and their structures were identified. Biological studies showed that most of them showed moderate to good growth inhibition against all the tested cancer cells. Especially, compound 4l displayed the most potent activity with IC50 values of 37.57 μM, 25.12 μM, 46.54 μM and 18.39 μM against SCG7901, HCT116, MCF-7 and HepG2, respectively, which was more potent than those of its parent compound osthole and the anticancer agent 5-Fu. The Hoechst 33258 staining assay revealed that compound 4l could induce cell apoptosis in HepG2 cells. Conclusion: The modification of osthole to improve its activity is feasible, and compound 4l can be considered as a potential agent for the treatment of cancer.
VL  - 3
IS  - 4
ER  -

Copy | Download