Physicochemical Characterization and Toxicity of Decursin and Their Derivatives from Angelica gigas

被引:15
作者
Mahat, Bimit [1 ]
Chae, Jung-woo [1 ]
Baek, In-hwan [4 ]
Song, Gyu-yong [1 ]
Song, Jin-sook [2 ]
Cho, Seong-kwon [3 ]
Kwon, Kwang-il [1 ]
机构
[1] Chungnam Natl Univ, Coll Pharm, Taejon 305764, South Korea
[2] Korea Res Inst Chem Technol, Div Bioorgan Sci, Drug Discovery Platform Technol Team, Taejon 305600, South Korea
[3] Samnam Pharmaceut, Geumsan 312802, South Korea
[4] Yuhan Res Inst, Gyeonggi Do 446902, South Korea
关键词
Institute of Cancer Research mice; diketone decursin; Angelica gigas; physicochemical; toxicology; CAPILLARY-ELECTROPHORESIS; DRUG DISCOVERY; PK(A) DETERMINATION; LOG-P; SOLUBILITY; CONSTANTS; ASSAY; RATS; CARCINOGENS; VALIDATION;
D O I
10.1248/bpb.b12-00046
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The present study provided a physicochemical and toxicological characterization of compounds in A. gigas NAKAI (decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin). Diketone decursin (173.16 mu g/mL) and epoxide decursin (122.12 mu g/mL) exhibited >100 mu g/mL kinetic solubility after applying nephelometry, suggesting a highly soluble compound. The Student's t-test revealed significant differences in the pK(a) ranges of the compounds by automatic titration from capillary electrophoresis (p<0.05). Diketone decursin, epoxide decursin and oxim decursin might be formulated into an oral dosage form (log P: 0-3) by an automatic titration analysis. A parallel artificial membrane permeability assay demonstrated permeability coefficients of <10x10(-6) cm/s for all of the compounds, suggesting poor permeability. Ether decursin exhibited a toxic effect after being applied to mouse (NIH 3T3, EC50: 57.9 mu M) and human (HT-29, EC50: 36.1 mu M; Hep-G2, EC50: 4.92 mu M) cells. Additionally, epoxide and oxim decursin were toxic through acute oral toxicity (four and three deaths of Institute of Cancer Research (ICR) mice) and mutation toxicity testing by applying Salmonella typhimurium cells with and without S9. Although diketone decursin exhibited less permeability, it is potentially valuable pharmacological compound that should be investigated.
引用
收藏
页码:1084 / 1090
页数:7
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