A-ring modified betulinic acid derivatives as potent cancer preventive agents

  • Bioorg Med Chem Lett. 2014 Feb 1;24(3):1005-8. doi: 10.1016/j.bmcl.2013.12.041.
Hsin-Yi Hung  1 ,  Kyoko Nakagawa-Goto  2 ,  Harukuni Tokuda  3 ,  Akira Iida  4 ,  Nobutaka Suzuki  3 ,  Ibrahim D Bori  5 ,  Keduo Qian  6 ,  Kuo-Hsiung Lee  7
Affiliations
  • 1. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 401, Taiwan.
  • 2. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA; Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
  • 3. Department of Complementary and Alternative Medicine, Clinical R&D Graduate School of Medicine Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
  • 4. Faculty of Agriculture, Kinki University, Nara 631-8505, Japan.
  • 5. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
  • 6. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. Electronic address: [email protected].
  • 7. Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 401, Taiwan. Electronic address: [email protected].
PMID: 24411124 DOI: 10.1016/j.bmcl.2013.12.041
Abstract

Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

Keywords
Betulinic acid; Chemopreventive; EBV-EA; seco A-ring.