Design, synthesis and potent cytotoxic activity of novel podophyllotoxin derivatives

Bioorg Med Chem. 2013 Apr 15;21(8):2363-2369. doi: 10.1016/j.bmc.2013.01.069.

Wen-Qun Li ¹, Xu-Li Wang ¹, Keduo Qian ², Ying-Qian Liu ³, Chih-Ya Wang ², Liu Yang ⁴, Jin Tian ¹, Susan L Morris-Natschke ², Xing-Wen Zhou ¹, Kuo-Hsiung Lee ⁵

Affiliations

1 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China.
2 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States.
3 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: khlee@email.unc.edu.
4 Environmental and Municipal Engineering School, Lanzhou Jiaotong University, Lanzhou 730000, PR China.
5 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: yqliu@lzu.edu.cn.

PMID: 23490151 DOI: 10.1016/j.bmc.2013.01.069

Abstract

Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 μM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 μM, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

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