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: | , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/ca82165300ea4a049a17af6cc97b4170 |
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| Sumario: | 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. |
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