Limonoids from the fruits of Melia azedarach and their cytotoxic activities

• Published in: Phytochemistry (Oxford) 2013-05, Vol.89, p.59-70
• Main Authors: Akihisa, Toshihiro, Pan, Xin, Nakamura, Yasuhiro, Kikuchi, Takashi, Takahashi, Nami, Matsumoto, Masahiro, Ogihara, Eri, Fukatsu, Makoto, Koike, Kazuo, Tokuda, Harukuni
• Format: Article
• Language: English
• Subjects: antigens; Antigens, Viral - metabolism; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; apoptosis; Apoptosis - drug effects; Cell Line, Tumor; Cytotoxic activities; cytotoxicity; death; Epstein–Barr virus early antigen (EBV-EA); flow cytometry; Fruit - chemistry; Fruits; Herpesvirus 4, Human - immunology; Humans; Inhibitory Concentration 50; Limonins - isolation & purification; Limonins - pharmacology; Limonins - toxicity; Limonoids; Lymphocytes - cytology; Lymphocytes - drug effects; Melia azedarach; Melia azedarach - chemistry; Meliaceae; spectroscopy; viruses; Western blotting
• ISSN: 0031-9422; 1873-3700
• DOI: 10.1016/j.phytochem.2013.01.015

Limonoids, meliarachin C and 3-O-deacetyl-4′-demethyl-28-oxosalannin, were isolated from fruits of Melia azedarach. They induced caspase-dependent apoptotic cell death in HL60 human leukemia cells. [Display omitted] ► Thirty-one limonoids and a triterpenoid were isolated from Melia azedarach fruits. ► Fourteen were previously unrecorded in the literature. ► Meliarachin C and a salannin derivative induced apoptotic cell death in HL60 cells. ► Meliarachin C and a salannin derivative exhibited selective toxicity in leukemia cells. Thirty-one limonoids and one tirucallane-type triterpenoid were isolated from the fruits of Melia azedarach (Meliaceae). The structures of 14 of these isolated compounds were elucidated on the basis of spectroscopic analyses and comparison with literature. All of these compounds were evaluated for their cytotoxic activities against HL60, A549, AZ521, and SK-BR-3 human cancer cell lines. Meliarachin C (IC50 0.65μM) and 3-O-deacetyl-4′-demethyl-28-oxosalannin (IC50 2.8μM) exhibited potent cytotoxic activity against HL60 cells, and this was demonstrated mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that both compounds induced apoptosis via both the mitochondrial and death receptor-mediated pathways. In addition, 25 compounds were evaluated for their inhibitory effects against the Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells.