title: A-ring modified betulinic acid derivatives as potent cancer preventive agents.
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.
authors.affiliation: 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.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hung
authors.affiliation: 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.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakagawa-Goto
authors.affiliation: Department of Complementary and Alternative Medicine, Clinical R&D Graduate School of Medicine Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
authors.forename: Harukuni
authors.initials: H
authors.lastname: Tokuda
authors.affiliation: Faculty of Agriculture, Kinki University, Nara 631-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Iida
authors.affiliation: Department of Complementary and Alternative Medicine, Clinical R&D Graduate School of Medicine Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA.
authors.forename: Ibrahim D
authors.initials: ID
authors.lastname: Bori
authors.affiliation: Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA. Electronic address: kdqian@unc.edu.
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.affiliation: 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: khlee@unc.edu.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000517:prevention & control*; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D016588:Anticarcinogenic Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid
keywords: Betulinic acid; Chemopreventive; EBV-EA; seco A-ring