Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity

Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and β′-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioacti...

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Autores principales:	Chen-Yin Chen, Jin-Cherng Lien, Chien-Yu Chen, Chin-Chuan Hung, Hui-Chang Lin
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	curcumin curcuminoids <i>Alnus</i> diarylheptanoids α,β-unsaturated β-diketone anticancer activity Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/b245757ba61b4da18941a44ec3666bab
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spelling	oai:doaj.org-article:b245757ba61b4da18941a44ec3666bab2021-11-25T17:54:00ZDesign, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity10.3390/ijms2222121711422-00671661-6596https://doaj.org/article/b245757ba61b4da18941a44ec3666bab2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12171https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and β′-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioactivities, including antioxidant, anti-inflammatory, anti-proliferation and anticancer activity. A series of novel curcuminoid derivatives (a total of 55 new compounds) and three reference compounds were synthesized with good yields using three-step organic synthesis. The anti-proliferative activities of curcumin derivatives were examined for six human cancer cell lines: HeLaS3, KBvin, MCF-7, HepG2, NCI-H460 and NCI-H460/MX20. Compared to the IC<sub>50</sub> values of all the synthesized derivatives, most α,β-unsaturated ketones displayed potent anti-proliferative effects against all six human cancer cell lines, whereas β′-hydroxy-α,β-unsaturated ketones and α,β-unsaturated β-diketones presented moderate anti-proliferative effects. Two potent curcuminoid derivatives were found among all the novel derivatives and reference compounds: (<i>E</i>)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound <b>3</b>) and (1<i>E</i>,4<i>E</i>)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound <b>MD12a</b>). These were selected for further analysis after the evaluation of their anti-proliferative effects against all human cancer cell lines. The results of apoptosis assays revealed that the number of dead cells was increased in early apoptosis and late apoptosis, while cell proliferation was also decreased after applying various concentrations of (<i>E</i>)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound <b>3</b>) and (1<i>E</i>,4<i>E</i>)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound <b>MD12a</b>) to MCF-7 and HpeG2 cancer cells. Analysis of the gene expression arrays showed that three genes (GADD45B, SESN2 and BBC3) were correlated with the p53 pathway. From the quantitative PCR analysis, it was seen that (1<i>E</i>,4<i>E</i>)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound <b>MD12a</b>) effectively induced the up-regulated expression of GADD45B, leading to the suppression of MCF-7 cancer cell formation and cell death. Molecular docking analysis was used to predict and sketch the interactions of the GADD45B-α,β-unsaturated ketone complex for help in drug design.Chen-Yin ChenJin-Cherng LienChien-Yu ChenChin-Chuan HungHui-Chang LinMDPI AGarticlecurcumincurcuminoids<i>Alnus</i>diarylheptanoidsα,β-unsaturated β-diketoneanticancer activityBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12171, p 12171 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	curcumin curcuminoids <i>Alnus</i> diarylheptanoids α,β-unsaturated β-diketone anticancer activity Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	curcumin curcuminoids <i>Alnus</i> diarylheptanoids α,β-unsaturated β-diketone anticancer activity Biology (General) QH301-705.5 Chemistry QD1-999 Chen-Yin Chen Jin-Cherng Lien Chien-Yu Chen Chin-Chuan Hung Hui-Chang Lin Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
description	Curcumin and curcuminoids have been discussed frequently due to their promising functional groups (such as scaffolds of α,β-unsaturated β-diketone, α,β-unsaturated ketone and β′-hydroxy-α,β-unsaturated ketone connected with aromatic rings on both sides) that play an important role in various bioactivities, including antioxidant, anti-inflammatory, anti-proliferation and anticancer activity. A series of novel curcuminoid derivatives (a total of 55 new compounds) and three reference compounds were synthesized with good yields using three-step organic synthesis. The anti-proliferative activities of curcumin derivatives were examined for six human cancer cell lines: HeLaS3, KBvin, MCF-7, HepG2, NCI-H460 and NCI-H460/MX20. Compared to the IC<sub>50</sub> values of all the synthesized derivatives, most α,β-unsaturated ketones displayed potent anti-proliferative effects against all six human cancer cell lines, whereas β′-hydroxy-α,β-unsaturated ketones and α,β-unsaturated β-diketones presented moderate anti-proliferative effects. Two potent curcuminoid derivatives were found among all the novel derivatives and reference compounds: (<i>E</i>)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound <b>3</b>) and (1<i>E</i>,4<i>E</i>)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound <b>MD12a</b>). These were selected for further analysis after the evaluation of their anti-proliferative effects against all human cancer cell lines. The results of apoptosis assays revealed that the number of dead cells was increased in early apoptosis and late apoptosis, while cell proliferation was also decreased after applying various concentrations of (<i>E</i>)-5-hydroxy-7-phenyl-1-(3,4,5-trimethoxyphenyl)hept-1-en-3-one (compound <b>3</b>) and (1<i>E</i>,4<i>E</i>)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound <b>MD12a</b>) to MCF-7 and HpeG2 cancer cells. Analysis of the gene expression arrays showed that three genes (GADD45B, SESN2 and BBC3) were correlated with the p53 pathway. From the quantitative PCR analysis, it was seen that (1<i>E</i>,4<i>E</i>)-1,7-bis(3,4,5-trimethoxyphenyl)hepta-1,4-dien-3-one (compound <b>MD12a</b>) effectively induced the up-regulated expression of GADD45B, leading to the suppression of MCF-7 cancer cell formation and cell death. Molecular docking analysis was used to predict and sketch the interactions of the GADD45B-α,β-unsaturated ketone complex for help in drug design.
format	article
author	Chen-Yin Chen Jin-Cherng Lien Chien-Yu Chen Chin-Chuan Hung Hui-Chang Lin
author_facet	Chen-Yin Chen Jin-Cherng Lien Chien-Yu Chen Chin-Chuan Hung Hui-Chang Lin
author_sort	Chen-Yin Chen
title	Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
title_short	Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
title_full	Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
title_fullStr	Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
title_full_unstemmed	Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity
title_sort	design, synthesis and evaluation of novel derivatives of curcuminoids with cytotoxicity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b245757ba61b4da18941a44ec3666bab
work_keys_str_mv	AT chenyinchen designsynthesisandevaluationofnovelderivativesofcurcuminoidswithcytotoxicity AT jinchernglien designsynthesisandevaluationofnovelderivativesofcurcuminoidswithcytotoxicity AT chienyuchen designsynthesisandevaluationofnovelderivativesofcurcuminoidswithcytotoxicity AT chinchuanhung designsynthesisandevaluationofnovelderivativesofcurcuminoidswithcytotoxicity AT huichanglin designsynthesisandevaluationofnovelderivativesofcurcuminoidswithcytotoxicity
_version_	1718411881074393088

Design, Synthesis and Evaluation of Novel Derivatives of Curcuminoids with Cytotoxicity

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