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Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity.
Drug Des Devel Ther 2019; 13:3683-3692DD

Abstract

Background

Widespread concern of the side effects and the broad-spectrum anticancer property of podophyllotoxin as an antitumor agent highlight the need for the development of new podophyllotoxin derivatives. Although some per-butyrylated glucosides of podophyllotoxin and 4β-triazolyl-podophyllotoxin glycosides show good anticancer activity, the per-acetylated/free of podophyllotoxin glucosides and their per-acetylated are not well studied.

Methods

A few glucoside derivatives of PPT were synthesized and evaluated for their in vitro cytotoxic activities against five human cancer cell lines, HL-60 (leukemia), SMMC-7721 (hepatoma), A-549 (lung cancer), MCF-7 (breast cancer), and SW480 (colon cancer), as well as the normal human pulmonary epithelial cell line (BEAS-2B). In addition, we investigated the structure-activity relationship and the physicochemical property-anticancer activity relationship of these compounds.

Results

Compound 6b shows the highest cytotoxic potency against all five cancer cell lines tested, with IC50 values ranging from 3.27±0.21 to 11.37±0.52 μM. We have also found that 6b displays higher selectivity than the etoposide except in the case of HL-60 cell line. The active compounds possess similar physicochemical properties: MSA > 900, %PSA < 20, ClogP > 2, MW > 700 Da, and RB > 10.

Conclusion

We synthesized several glucoside derivatives of PPT and tested their cytotoxicity. Among them, compound 6b showed the highest cytotoxicity. Further studies including selectivity of active compounds have shown that the selectivity indexes of 6b are much greater than the etoposide except in the case of HL-60 cell line. The active compounds possessed similar physicochemical properties. This study indicates that active glucoside analogs of podophyllotoxin have potential as lead compounds for developing novel anticancer agents.

Authors+Show Affiliations

Key Laboratory of Pu-Er Tea Science, Ministry of Education, College of Science, Yunnan Agricultural University, Kunming, 650201, People's Republic of China. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.Key Laboratory of Medicinal Chemistry for Nature Resource, Ministry of Education, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China.Department of Chemistry, Lakehead University, Thunder Bay ON P7B 5E1, Canada.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31695335

Citation

Zi, Cheng-Ting, et al. "Glucoside Derivatives of Podophyllotoxin: Synthesis, Physicochemical Properties, and Cytotoxicity." Drug Design, Development and Therapy, vol. 13, 2019, pp. 3683-3692.
Zi CT, Yang L, Kong QH, et al. Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity. Drug Des Devel Ther. 2019;13:3683-3692.
Zi, C. T., Yang, L., Kong, Q. H., Li, H. M., Yang, X. Z., Ding, Z. T., ... Zhou, J. (2019). Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity. Drug Design, Development and Therapy, 13, pp. 3683-3692. doi:10.2147/DDDT.S215895.
Zi CT, et al. Glucoside Derivatives of Podophyllotoxin: Synthesis, Physicochemical Properties, and Cytotoxicity. Drug Des Devel Ther. 2019;13:3683-3692. PubMed PMID: 31695335.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity. AU - Zi,Cheng-Ting, AU - Yang,Liu, AU - Kong,Qing-Hua, AU - Li,Hong-Mei, AU - Yang,Xing-Zhi, AU - Ding,Zhong-Tao, AU - Jiang,Zi-Hua, AU - Hu,Jiang-Miao, AU - Zhou,Jun, Y1 - 2019/10/23/ PY - 2019/05/16/received PY - 2019/09/08/accepted PY - 2019/11/8/entrez PY - 2019/11/7/pubmed PY - 2019/11/7/medline KW - cytotoxicity KW - glucoside KW - physicochemical properties KW - podophyllotoxin KW - synthesis SP - 3683 EP - 3692 JF - Drug design, development and therapy JO - Drug Des Devel Ther VL - 13 N2 - Background: Widespread concern of the side effects and the broad-spectrum anticancer property of podophyllotoxin as an antitumor agent highlight the need for the development of new podophyllotoxin derivatives. Although some per-butyrylated glucosides of podophyllotoxin and 4β-triazolyl-podophyllotoxin glycosides show good anticancer activity, the per-acetylated/free of podophyllotoxin glucosides and their per-acetylated are not well studied. Methods: A few glucoside derivatives of PPT were synthesized and evaluated for their in vitro cytotoxic activities against five human cancer cell lines, HL-60 (leukemia), SMMC-7721 (hepatoma), A-549 (lung cancer), MCF-7 (breast cancer), and SW480 (colon cancer), as well as the normal human pulmonary epithelial cell line (BEAS-2B). In addition, we investigated the structure-activity relationship and the physicochemical property-anticancer activity relationship of these compounds. Results: Compound 6b shows the highest cytotoxic potency against all five cancer cell lines tested, with IC50 values ranging from 3.27±0.21 to 11.37±0.52 μM. We have also found that 6b displays higher selectivity than the etoposide except in the case of HL-60 cell line. The active compounds possess similar physicochemical properties: MSA > 900, %PSA < 20, ClogP > 2, MW > 700 Da, and RB > 10. Conclusion: We synthesized several glucoside derivatives of PPT and tested their cytotoxicity. Among them, compound 6b showed the highest cytotoxicity. Further studies including selectivity of active compounds have shown that the selectivity indexes of 6b are much greater than the etoposide except in the case of HL-60 cell line. The active compounds possessed similar physicochemical properties. This study indicates that active glucoside analogs of podophyllotoxin have potential as lead compounds for developing novel anticancer agents. SN - 1177-8881 UR - https://www.unboundmedicine.com/medline/citation/31695335/Glucoside_Derivatives_Of_Podophyllotoxin:_Synthesis,_Physicochemical_Properties,_And_Cytotoxicity L2 - https://dx.doi.org/10.2147/DDDT.S215895 DB - PRIME DP - Unbound Medicine ER -