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

Abstract

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 (DMCU) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and liver cancers. However, further development of DMCU 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 DMCU phenolic groups and produced targeted 1-trifluoroacetic acid (1-TFA) and 2-trifluoroacetic acid (2-TFA) 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, 1-TFA or 2-TFA were synthesized from DMCU in four steps with 34–48% overall yield. Based on the corresponding LC-MS analysis, water solubility of DMCU, 1-TFA, and 2-TFA at room temperature (25 ± 1 °C) were 0.018, 249.7, and 375.8 mg/mL, respectively, indicating >10,000-fold higher solubility of 1-TFA and 2-TFA than DMCU. Importantly, anti-proliferative assay demonstrated that 2-TFA 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 DMCU and 1-TFA. 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 2-TFA. Our results provide a strategical direction for the future development of curcuminoid-like phenolic compounds.

The Effects of a Curcumin Derivative and Osimertinib on Fatty Acyl Metabolism and Mitochondrial Functions in HCC827 Cells and Tumors

“…Previously, we developed a series of curcumin derivatives and evaluated their anticancer potential. Among these derivatives, bis(hydroxymethyl) alkanoate curcuminoid derivatives exhibited in vitro antiproliferative and in vivo antitumor activities [26][27][28][29]. In our investigations, we identified 35d, a propargyl modified bis(hydroxymethyl) alkanoate curcuminoid, as particularly effective in inhibiting the proliferation of HCC827 cells.…”

Antiproliferative Activity of Aminobenzylnaphthols Deriving from the Betti Reaction

“…For example, boroxazolidones were reported to have modest antitumor properties; however, the L-valine derivatives showed strong cytotoxic effects [31]. Along the same lines, L-valine modified dimethyl-curcumin showed a great increase in anti-proliferative activity compared to the original drug, thus distinguishing itself as a potent anticancer agent [32].…”

4,4‐Diallyl curcumin bis(2,2‐hydroxymethyl)propanoate ameliorates nonalcoholic steatohepatitis in methionine‐choline‐deficient diet and Western diet mouse models

“…To address these limitations, using a structural modification strategy, we synthesized a series of bis(hydroxymethyl) alkanoate curcuminoid derivatives as effective anticancer agents against breast, colon, prostate, and lung cancers. These derivatives display superior stability, solubility, potency, and pharmacokinetic profiles compared to their parent curcuminoids (Hsieh et al, 2017;Lee et al, 2020Lee et al, , 2021. Among these derivatives (Figure 1), compound 9a, induced ER stress, mitochondrial stress, and expression of the proteins heme oxygenase 1 that exhibited both anti-inflammatory and antioxidant consequences in MDA-MB-231 cells (Chang et al, 2018).…”