Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity
Received 16 May 2019
Accepted for publication 8 September 2019
Published 23 October 2019 Volume 2019:13 Pages 3683—3692
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Dragan Hrncic
Peer reviewer comments 4
Editor who approved publication: Professor Jianbo Sun
Cheng-Ting Zi,1,2,* Liu Yang,2,* Qing-Hua Kong,2 Hong-Mei Li,2 Xing-Zhi Yang,2 Zhong-Tao Ding,3 Zi-Hua Jiang,4 Jiang-Miao Hu,2 Jun Zhou2
1Key Laboratory of Pu-Er Tea Science, Ministry of Education, College of Science, Yunnan Agricultural University, Kunming, 650201, People’s Republic of China; 2State 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; 3Key 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; 4Department of Chemistry, Lakehead University, Thunder Bay ON P7B 5E1, Canada
*These authors contributed equally to this work
Correspondence: Zi-Hua Jiang
Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay ON P7B 5EI, Canada
Tel +1 807 766 7171
Fax +1 807 346 7775
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, No. 132, Lanhei Road, Kunming 650201, People’s Republic of China
Tel +86 871 6522 3264
Fax +86 871 6522 3261
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.
Keywords: podophyllotoxin, glucoside, synthesis, cytotoxicity, physicochemical properties
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