Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities

Six new limonoids, 7-benzoyl-17-epinimbocinol (5), 3-acetyl-7- tigloylnimbidinin (8), 1-isovaleroyl-1-detigloylsalanninolide (15), 2,3-dihydro-3α-methoxynimbolide (16), deacetyl-20,21-epoxy-20,22-dihydro- 21-deoxyisonimbinolide (26), and deacetyl-20,21,22,23-tetrahydro-20,22- dihydroxy-21,23-dimetho...

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Main Authors: Aranya Manosroi, Worapong Kitdamrongtham, Kenta Ishii, Takuro Shinozaki, Yosuke Tachi, Mio Takagi, Kodai Ebina, Jie Zhang, Jiradej Manosroi, Rima Akihisa, Toshihiro Akihisa
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Published: 2018
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spelling th-cmuir.6653943832-532842018-09-04T09:48:11Z Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities Aranya Manosroi Worapong Kitdamrongtham Kenta Ishii Takuro Shinozaki Yosuke Tachi Mio Takagi Kodai Ebina Jie Zhang Jiradej Manosroi Rima Akihisa Toshihiro Akihisa Biochemistry, Genetics and Molecular Biology Chemical Engineering Chemistry Six new limonoids, 7-benzoyl-17-epinimbocinol (5), 3-acetyl-7- tigloylnimbidinin (8), 1-isovaleroyl-1-detigloylsalanninolide (15), 2,3-dihydro-3α-methoxynimbolide (16), deacetyl-20,21-epoxy-20,22-dihydro- 21-deoxyisonimbinolide (26), and deacetyl-20,21,22,23-tetrahydro-20,22- dihydroxy-21,23-dimethoxynimbin (27), along with 28 known limonoids, 1-4, 6, 7, 9-14, 17-25, and 28-34, and two known flavonoids, 35 and 36, have been isolated from the extracts of bark, leaves, roots, and seeds of Azadirachta indica A. Juss. var. siamensis Valeton (Siamese neem tree; Meliaceae). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. All of these compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. Eleven compounds, 1, 2, 4-7, 13, 16, 17, 29, and 30, exhibited potent cytotoxicities against one or more cell lines with IC<inf>50</inf> values in the range of 0.1-9.3 μM. Compound 16 induced apoptotic cell death in AZ521 cells upon evaluation of the apoptosis-inducing activity by flow cytometric analysis. Western blot analysis on AZ521 cells revealed that compound 16 activated caspases-3, -8, and -9, while increasing the ratio of Bax/Bcl-2. This suggested that 16 induced apoptosis via both mitochondrial and death receptor pathways in AZ521. In addition, upon evaluation of all compounds against the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), 20 limonoids, i.e., 1-3, 6, 9-11, 18, 19, 21-29, 32, and 34, and two flavonoids, 35 and 36, exhibited melanogenesis-inhibitory activities, with no, or almost no, toxicities to the cells at lower and/or higher concentrations, which were more potent than the reference arbutin, a known melanogenesis inhibitor. Western blot analysis showed that nimbin (18) reduced the protein levels of microphtalmia-associated transcription factor (MITF), tyrosinase, tyrosine-related protein 1 (TRP-1), and TRP-2 mostly in a concentration-dependent manner, indicating that 18 inhibits melanogenesis on a α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich. 2018-09-04T09:46:21Z 2018-09-04T09:46:21Z 2014-01-01 Journal 16121880 16121872 2-s2.0-84898728866 10.1002/cbdv.201300406 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84898728866&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/53284
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Biochemistry, Genetics and Molecular Biology
Chemical Engineering
Chemistry
spellingShingle Biochemistry, Genetics and Molecular Biology
Chemical Engineering
Chemistry
Aranya Manosroi
Worapong Kitdamrongtham
Kenta Ishii
Takuro Shinozaki
Yosuke Tachi
Mio Takagi
Kodai Ebina
Jie Zhang
Jiradej Manosroi
Rima Akihisa
Toshihiro Akihisa
Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
description Six new limonoids, 7-benzoyl-17-epinimbocinol (5), 3-acetyl-7- tigloylnimbidinin (8), 1-isovaleroyl-1-detigloylsalanninolide (15), 2,3-dihydro-3α-methoxynimbolide (16), deacetyl-20,21-epoxy-20,22-dihydro- 21-deoxyisonimbinolide (26), and deacetyl-20,21,22,23-tetrahydro-20,22- dihydroxy-21,23-dimethoxynimbin (27), along with 28 known limonoids, 1-4, 6, 7, 9-14, 17-25, and 28-34, and two known flavonoids, 35 and 36, have been isolated from the extracts of bark, leaves, roots, and seeds of Azadirachta indica A. Juss. var. siamensis Valeton (Siamese neem tree; Meliaceae). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. All of these compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. Eleven compounds, 1, 2, 4-7, 13, 16, 17, 29, and 30, exhibited potent cytotoxicities against one or more cell lines with IC<inf>50</inf> values in the range of 0.1-9.3 μM. Compound 16 induced apoptotic cell death in AZ521 cells upon evaluation of the apoptosis-inducing activity by flow cytometric analysis. Western blot analysis on AZ521 cells revealed that compound 16 activated caspases-3, -8, and -9, while increasing the ratio of Bax/Bcl-2. This suggested that 16 induced apoptosis via both mitochondrial and death receptor pathways in AZ521. In addition, upon evaluation of all compounds against the melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), 20 limonoids, i.e., 1-3, 6, 9-11, 18, 19, 21-29, 32, and 34, and two flavonoids, 35 and 36, exhibited melanogenesis-inhibitory activities, with no, or almost no, toxicities to the cells at lower and/or higher concentrations, which were more potent than the reference arbutin, a known melanogenesis inhibitor. Western blot analysis showed that nimbin (18) reduced the protein levels of microphtalmia-associated transcription factor (MITF), tyrosinase, tyrosine-related protein 1 (TRP-1), and TRP-2 mostly in a concentration-dependent manner, indicating that 18 inhibits melanogenesis on a α-MSH-stimulated B16 melanoma cells by, at least in part, inhibiting the expression of MITF, followed by decreasing the expression of tyrosinase, TRP-1, and TRP-2. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.
format Journal
author Aranya Manosroi
Worapong Kitdamrongtham
Kenta Ishii
Takuro Shinozaki
Yosuke Tachi
Mio Takagi
Kodai Ebina
Jie Zhang
Jiradej Manosroi
Rima Akihisa
Toshihiro Akihisa
author_facet Aranya Manosroi
Worapong Kitdamrongtham
Kenta Ishii
Takuro Shinozaki
Yosuke Tachi
Mio Takagi
Kodai Ebina
Jie Zhang
Jiradej Manosroi
Rima Akihisa
Toshihiro Akihisa
author_sort Aranya Manosroi
title Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
title_short Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
title_full Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
title_fullStr Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
title_full_unstemmed Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
title_sort limonoids from azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities
publishDate 2018
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84898728866&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/53284
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