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Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization

Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkalo...

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Autores principales: Zhang, Yu, Goto, Masuo, Oda, Akifumi, Hsu, Pei-Ling, Guo, Ling-Li, Fu, Yan-Hui, Morris-Natschke, Susan L., Hamel, Ernest, Lee, Kuo-Hsiung, Hao, Xiao-Jiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480704/
https://www.ncbi.nlm.nih.gov/pubmed/30935100
http://dx.doi.org/10.3390/molecules24071256
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author Zhang, Yu
Goto, Masuo
Oda, Akifumi
Hsu, Pei-Ling
Guo, Ling-Li
Fu, Yan-Hui
Morris-Natschke, Susan L.
Hamel, Ernest
Lee, Kuo-Hsiung
Hao, Xiao-Jiang
author_facet Zhang, Yu
Goto, Masuo
Oda, Akifumi
Hsu, Pei-Ling
Guo, Ling-Li
Fu, Yan-Hui
Morris-Natschke, Susan L.
Hamel, Ernest
Lee, Kuo-Hsiung
Hao, Xiao-Jiang
author_sort Zhang, Yu
collection PubMed
description Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1–14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC(50) values ranging from 0.5–0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site.
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spelling pubmed-64807042019-04-30 Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization Zhang, Yu Goto, Masuo Oda, Akifumi Hsu, Pei-Ling Guo, Ling-Li Fu, Yan-Hui Morris-Natschke, Susan L. Hamel, Ernest Lee, Kuo-Hsiung Hao, Xiao-Jiang Molecules Article Monoterpenoid indole alkaloids are structurally diverse natural products found in plants of the family Apocynaceae. Among them, vincristine and its derivatives are well known for their anticancer activity. Bousigonia mekongensis, a species in this family, contains various monoterpenoid indole alkaloids. In the current study, fourteen known aspidosperma-type monoterpenoid indole alkaloids (1–14) were isolated and identified from a methanol extract of the twigs and leaves of B. mekongensis for the first time. Among them, compounds 3, 6, 9, and 13 exhibited similar antiproliferative activity spectra against A549, KB, and multidrug-resistant (MDR) KB subline KB-VIN cells with IC(50) values ranging from 0.5–0.9 μM. The above alkaloids efficiently induced cell cycle arrest at the G2/M phase by inhibiting tubulin polymerization as well as mitotic bipolar spindle formation. Computer modeling studies indicated that compound 7 likely forms a hydrogen bond (H-bond) with α- or β-tubulin at the colchicine site. Evaluation of the antiproliferative effects and SAR analysis suggested that a 14,15-double bond or 3α-acetonyl group is critical for enhanced antiproliferative activity. Mechanism of action studies demonstrated for the first time that compounds 3, 4, 6, 7, and 13 efficiently induce cell cycle arrest at G2/M by inhibiting tubulin polymerization by binding to the colchicine site. MDPI 2019-03-31 /pmc/articles/PMC6480704/ /pubmed/30935100 http://dx.doi.org/10.3390/molecules24071256 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Yu
Goto, Masuo
Oda, Akifumi
Hsu, Pei-Ling
Guo, Ling-Li
Fu, Yan-Hui
Morris-Natschke, Susan L.
Hamel, Ernest
Lee, Kuo-Hsiung
Hao, Xiao-Jiang
Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
title Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
title_full Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
title_fullStr Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
title_full_unstemmed Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
title_short Antiproliferative Aspidosperma-Type Monoterpenoid Indole Alkaloids from Bousigonia mekongensis Inhibit Tubulin Polymerization
title_sort antiproliferative aspidosperma-type monoterpenoid indole alkaloids from bousigonia mekongensis inhibit tubulin polymerization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480704/
https://www.ncbi.nlm.nih.gov/pubmed/30935100
http://dx.doi.org/10.3390/molecules24071256
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