Cytotoxic Activities and Anti-Tumor-Promoting Effects of Microbial Transformation Products of Prenylated Chalcones from Angelica keiskei

• Published in: Chemistry & biodiversity Vol. 9; no. 2; pp. 318 - 330
• Main Authors: Akihisa, Toshihiro, Motoi, Toshihiro, Seki, Akihito, Kikuchi, Takashi, Fukatsu, Makoto, Tokuda, Harukuni, Suzuki, Nobutaka, Kimura, Yumiko
• Format: Journal Article
• Language: English
• Published: Zürich WILEY-VCH Verlag 01-02-2012; WILEY‐VCH Verlag
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Angelica - chemistry; Angelica keiskei; Animals; Anti-tumor-promoting activity; Antigens, Viral - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Aspergillus - drug effects; Aspergillus - growth & development; Aspergillus saitoi; Carcinogenicity Tests; Carcinogens - toxicity; Cell Transformation, Neoplastic - drug effects; Chalcones; Chalcones - chemistry; Chalcones - pharmacology; Cytotoxic activity; Humans; Metabolites; Mice; Molecular Structure; Prenylation; Skin Neoplasms - chemically induced; Skin Neoplasms - prevention & control; Tetradecanoylphorbol Acetate - pharmacology; Tumor Cells, Cultured
• ISSN: 1612-1872; 1612-1880
• DOI: 10.1002/cbdv.201100255

Three prenylated chalcones, 4‐hydroxyderricin (1), xanthoangelol (2), and xanthoangelol F (3), isolated from Angelica keiskei, were transformed by the fungus Aspergillus saitoi. These chalcones were converted to flavanones (i.e., 4, 8, and 12), and prenyl‐chain‐hydrated (i.e., 5, 7, 9–11, and 13) and ring‐B‐hydroxylated (i.e., 6) chalcones. The structures of three new metabolites, 7, 9, and 13, were established as 2″,3″‐dihydro‐4,3″‐dihydroxyderricin, 6″,7″‐dihydro‐7″‐hydroxyxanthoangelol, and 6″,7″‐dihydro‐7″‐hydroxyxanthoangelol F, respectively. Upon evaluation of cytotoxic activities of compounds 1–13, the metabolite 7 exhibited potent cytotoxicity against HL60 cells, and this cell death was revealed to be mostly due to apoptosis. In addition, compounds 1–4, 7–10, 12, and 13 were examined for their inhibitory effects on the induction of EpsteinBarr virus early antigen (EBV‐EA) by 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) in Raji cells. All compounds tested showed inhibitory effects against EBV‐EA activation with potencies higher than that of β‐carotene. Furthermore, the metabolite 13 exhibited inhibitory effect on skin tumor promotion in an in vivo two‐stage mouse skin carcinogenesis test based on 7,12‐dimethylbenz[a]anthracene (DMBA) as initiator, and with TPA as promoter.