Design, synthesis and cytotoxic activity of novel sulfonylurea derivatives of podophyllotoxin
- Bioorg Med Chem. 2014 Jan 1;22(1):204-10. doi: 10.1016/j.bmc.2013.11.035.
- 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: [email protected].
- 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: [email protected].
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.