2. Academic Validation
  3. Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions

Toward synthesis of third-generation spin-labeled podophyllotoxin derivatives using isocyanide multicomponent reactions

  • Eur J Med Chem. 2014 Mar 21:75:282-8. doi: 10.1016/j.ejmech.2014.01.038.
Liang Kou 1,  Mei-Juan Wang 1,  Li-Ting Wang 2,  Xiao-Bo Zhao 1,  Xiang Nan 1,  Liu Yang 3,  Ying-Qian Liu 4,  Susan L Morris-Natschke 2,  Kuo-Hsiung Lee 5
Affiliations

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, USA.
  • 3 Environmental and Municipal Engineering School, Lanzhou Jiaotong University, Lanzhou 730000, PR China.
  • 4 School of Pharmacy, Lanzhou University, Lanzhou 730000, PR China; Xinjiang Production & Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, 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, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@email.unc.edu.
PMID: 24553146 DOI: 10.1016/j.ejmech.2014.01.038
Abstract

Spin-labeled podophyllotoxins have elicited widespread interest due to their far superior antitumor activity compared to podophyllotoxin. To extend our prior studies in this Research Area, we synthesized a new generation of spin-labeled podophyllotoxin analogs via isocyanide multicomponent reactions and evaluated their cytotoxicity against four human Cancer cell lines (A-549, DU-145, KB and KBvin). Most of the compounds exhibited potent cytotoxic activity against all four cell lines, notably against the drug resistant KBvin Cancer cell line. Among the new analogs, compounds 12e (IC50: 0.60-0.75 μM) and 12h (IC50: 1.12-2.03 μM) showed superior potency to etoposide (IC50: 2.03 to >20 μM), a clinically available Anticancer drug. With a concise efficient synthesis and potent cytotoxic profiles, compounds 12e and 12h merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.

Keywords

C-4 position; Cytotoxic activity; Isocyanide multicomponent reactions; Podophyllotoxin; Spin labeled.

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