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.
Highlights
Plant-derived phenolic compounds such as stilbenoids, lignans, flavonoids and curcuminoids constitute major sources of natural therapeutic agents and have been shown to have wide applications in chemoprevention and degenerative diseases [1,2,3]
2-trifluoroacetic acid (2-trifluoroacetic acid (TFA))-treated group was higher than that in DMCU-treated and 1-trifluoroacetic acid (1-TFA)-treated groups at 30 and 60 min after treatment (Figure 4D). These results indicated that 2-TFA were absorbed, accumulated in the NCI-H460 cancer cells and the intracellular 2-TFA were subsequently converted to DMCU and 1-TFA and treatment of 2-TFA exhibited stronger anti-cancer effects than DMCU and 1-TFA
Additional works on the changes of L-valine into other branched-chain amino acids (BCAAs) have been scheduled for enhancement of cellular uptake in lung cancer cells
Summary
Plant-derived phenolic compounds such as stilbenoids, lignans, flavonoids and curcuminoids constitute major sources of natural therapeutic agents and have been shown to have wide applications in chemoprevention and degenerative diseases [1,2,3]. These natural products endowed with metabolically unstable functional groups often exhibit moderateto-high in vitro potency but unobvious in vivo efficacy [4]. The previous structure–activity relationship (SAR) analysis on curcuminoid derivatives showed that disconnection of the highly conjugated enol system exerted positive effects on the stability and pharmaceutical activities [7]. DMCU exhibited improved anticancer activity against the MCF-7 breast cancer, HCT-116 colon cancer, A549 lung cancer and HepG2 liver cancer cell lines than curcumin [8], conceivably due to the greater reactive oxygen species producing activity and free radical scavenging activity compared to curcumin [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
