Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities

Natural phenolic products from herbal medicines and dietary plants constitute the main source of lead compounds for the development of the new drug. 4,4-Dimethylcurcumin (<b>DMCU</b>) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and l...

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Autores principales:	Der-Yen Lee, Hui-Yi Lin, Manickavasakam Ramasamy, Sheng-Chu Kuo, Pei-Chih Lee, Min-Tsang Hsieh
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cellular uptake 4,4-dimethylcurcumin LC-MS spectroscopy lung cancer water solubility Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/ca82165300ea4a049a17af6cc97b4170
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spelling	oai:doaj.org-article:ca82165300ea4a049a17af6cc97b41702021-11-25T18:29:28ZSynthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities10.3390/molecules262270501420-3049https://doaj.org/article/ca82165300ea4a049a17af6cc97b41702021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/7050https://doaj.org/toc/1420-3049Natural phenolic products from herbal medicines and dietary plants constitute the main source of lead compounds for the development of the new drug. 4,4-Dimethylcurcumin (<b>DMCU</b>) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and liver cancers. However, further development of <b>DMCU</b> is limited by unfavorable compound properties such as very low aqueous solubility and moderate stability. To increase its solubility, we installed either or both of the ethylene-carbonate-linked L-valine side chains to <b>DMCU</b> phenolic groups and produced targeted <b>1</b>-<b>trifluoroacetic acid</b> (<b>1-TFA</b>) and <b>2</b>-<b>trifluoroacetic acid</b> (<b>2-TFA</b>) derivatives. The terminus L-valine of ethylene-carbonate-linked side chain is known to be a L-type amino acid transporter 1 (LAT1) recognition element and therefore, these two derivatives were expected to readily enter into LAT1-expressing cancer cells. In practice, <b>1-TFA</b> or <b>2-TFA</b> were synthesized from <b>DMCU</b> in four steps with 34–48% overall yield. Based on the corresponding LC-MS analysis, water solubility of <b>DMCU</b>, <b>1-TFA</b>, and <b>2-TFA</b> at room temperature (25 ± 1 °C) were 0.018, 249.7, and 375.8 mg/mL, respectively, indicating >10,000-fold higher solubility of <b>1-TFA</b> and <b>2-TFA</b> than <b>DMCU</b>. Importantly, anti-proliferative assay demonstrated that <b>2-TFA</b> is a potent anti-cancer agent against LAT1-expressing lung cancer cells NCI-H460, NCI-H358, and A549 cells due to its high intracellular uptake compared to <b>DMCU</b> and <b>1-TFA</b>. In this study, we logically designed and synthesized the targeted compounds, established the LC-MS analytical methods for evaluations of drug solubility and intracellular uptake levels, and showed improved solubility and anti-cancer activities of <b>2-TFA</b>. Our results provide a strategical direction for the future development of curcuminoid-like phenolic compounds.Der-Yen LeeHui-Yi LinManickavasakam RamasamySheng-Chu KuoPei-Chih LeeMin-Tsang HsiehMDPI AGarticlecellular uptake4,4-dimethylcurcuminLC-MS spectroscopylung cancerwater solubilityOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 7050, p 7050 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cellular uptake 4,4-dimethylcurcumin LC-MS spectroscopy lung cancer water solubility Organic chemistry QD241-441
spellingShingle	cellular uptake 4,4-dimethylcurcumin LC-MS spectroscopy lung cancer water solubility Organic chemistry QD241-441 Der-Yen Lee Hui-Yi Lin Manickavasakam Ramasamy Sheng-Chu Kuo Pei-Chih Lee Min-Tsang Hsieh Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities
description	Natural phenolic products from herbal medicines and dietary plants constitute the main source of lead compounds for the development of the new drug. 4,4-Dimethylcurcumin (<b>DMCU</b>) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and liver cancers. However, further development of <b>DMCU</b> is limited by unfavorable compound properties such as very low aqueous solubility and moderate stability. To increase its solubility, we installed either or both of the ethylene-carbonate-linked L-valine side chains to <b>DMCU</b> phenolic groups and produced targeted <b>1</b>-<b>trifluoroacetic acid</b> (<b>1-TFA</b>) and <b>2</b>-<b>trifluoroacetic acid</b> (<b>2-TFA</b>) derivatives. The terminus L-valine of ethylene-carbonate-linked side chain is known to be a L-type amino acid transporter 1 (LAT1) recognition element and therefore, these two derivatives were expected to readily enter into LAT1-expressing cancer cells. In practice, <b>1-TFA</b> or <b>2-TFA</b> were synthesized from <b>DMCU</b> in four steps with 34–48% overall yield. Based on the corresponding LC-MS analysis, water solubility of <b>DMCU</b>, <b>1-TFA</b>, and <b>2-TFA</b> at room temperature (25 ± 1 °C) were 0.018, 249.7, and 375.8 mg/mL, respectively, indicating >10,000-fold higher solubility of <b>1-TFA</b> and <b>2-TFA</b> than <b>DMCU</b>. Importantly, anti-proliferative assay demonstrated that <b>2-TFA</b> is a potent anti-cancer agent against LAT1-expressing lung cancer cells NCI-H460, NCI-H358, and A549 cells due to its high intracellular uptake compared to <b>DMCU</b> and <b>1-TFA</b>. In this study, we logically designed and synthesized the targeted compounds, established the LC-MS analytical methods for evaluations of drug solubility and intracellular uptake levels, and showed improved solubility and anti-cancer activities of <b>2-TFA</b>. Our results provide a strategical direction for the future development of curcuminoid-like phenolic compounds.
format	article
author	Der-Yen Lee Hui-Yi Lin Manickavasakam Ramasamy Sheng-Chu Kuo Pei-Chih Lee Min-Tsang Hsieh
author_facet	Der-Yen Lee Hui-Yi Lin Manickavasakam Ramasamy Sheng-Chu Kuo Pei-Chih Lee Min-Tsang Hsieh
author_sort	Der-Yen Lee
title	Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities
title_short	Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities
title_full	Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities
title_fullStr	Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities
title_full_unstemmed	Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities
title_sort	synthesis and characterization of the ethylene-carbonate-linked l-valine derivatives of 4,4-dimethylcurcumin with potential anticancer activities
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ca82165300ea4a049a17af6cc97b4170
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Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities

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