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Cytotoxic and Melanogenesis‐Inhibitory Activities of Limonoids from the Leaves of Azadirachta indica (Neem)
Author(s) -
Takagi Mio,
Tachi Yosuke,
Zhang Jie,
Shinozaki Takuro,
Ishii Kenta,
Kikuchi Takashi,
Ukiya Motohiko,
Banno Norihiro,
Tokuda Harukuni,
Akihisa Toshihiro
Publication year - 2014
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.201300348
Subject(s) - azadirachta , meliaceae , chemistry , traditional medicine , azadirachtin , cytotoxic t cell , botany , biology , biochemistry , in vitro , pesticide , medicine , agronomy
Seventeen limonoids (tetranortriterpenoids), 1 – 17 , including three new compounds, i.e. , 17‐defurano‐17‐(2,5‐dihydro‐2‐oxofuran‐3‐yl)‐28‐deoxonimbolide ( 14 ), 17‐defurano‐17‐(2 ξ ‐2,5‐dihydro‐2‐hydroxy‐5‐oxofuran‐3‐yl)‐28‐deoxonimbolide ( 15 ), and 17‐defurano‐17‐(5 ξ ‐2,5‐dihydro‐5‐hydroxy‐2‐oxofuran‐3‐yl)‐2′,3′‐dehydrosalannol ( 17 ), were isolated from an EtOH extract of the leaf of neem ( Azadirachta indica ). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with literature. Upon evaluation of the cytotoxic activities of these compounds against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK‐BR‐3) cancer cell lines, seven compounds, i.e. , 1 – 3, 12, 13, 15 , and 16 , exhibited potent cytotoxicities with IC 50 values in the range of 0.1–9.9 μ M against one or more cell lines. Among these compounds, cytotoxicity of nimonol ( 1 ; IC 50 2.8 μ M ) against HL60 cells was demonstrated to be mainly due to the induction of apoptosis by flow cytometry. Western blot analysis suggested that compound 1 induced apoptosis via both the mitochondrial and death receptor‐mediated pathways in HL60 cells. In addition, when compounds 1 – 17 were evaluated for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α ‐melanocyte‐stimulating hormone ( α ‐MSH), seven compounds, 1, 2, 4 – 6, 15 , and 16 , exhibited inhibitory activities with 31–94% reduction of melanin content at 10 μ M concentration with no or low toxicity to the cells (82–112% of cell viability at 10 μ M ). All 17 compounds were further 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.