Zhi-Jun Zhang1, Jing Tian1, Li-Ting Wang2, Mei-Juan Wang1, Xiang Nan1, Liu Yang3, Ying-Qian Liu4, Susan L Morris-Natschke2, Kuo-Hsiung Lee5. 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. Environmental and Municipal Engineering School, Lanzhou Jiaotong University, Lanzhou 730000, PR China. 4. School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China. Electronic address: yqliu@lzu.edu.cn. 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: khlee@email.unc.edu.
Abstract
Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC₅₀: 1.41-1.76 μM) and 14e (IC₅₀: 1.72-2.01 μM) showed superior cytotoxic activity compared with etoposide (IC₅₀: 2.03 to >20 μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4'-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin's 4β position can significantly improve cytotoxic activity.
Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro n class="Disease">cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC₅₀: 1.41-1.76 μM) and 14e (IC₅₀: 1.72-2.01 μM) showed superior cytotoxic activity compared with etoposide (IC₅₀: 2.03 to >20 μM), a clinically available anticancer drug. Significantly, most of the compounds exhibited comparable cytotoxicity against the drug-resistant tumor cell line KBvin, while etoposide lost activity completely. Preliminary structure-activity relationship (SAR) correlations indicated that the 4'-O-methyl functionality in podophyllotoxin analogues may be essential to maintain cytotoxic activity, while an arylsulfonylurea side chain at podophyllotoxin's 4β position can significantly improve cytotoxic activity.
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