The Synthesis and Evaluation of Arctigenin Amino Acid Ester Derivatives

Abstract

The use of arctigenin (ARG), a traditional medicine with many pharmacological activities, has been restricted due to its poor solubility in water. Five amino acid derivatives of ARG have been synthesized using glycine, o-alanine, valine, leucine, and isoleucine, which have t-butyloxy carbonyl (BOC) as a protective group. In this study, we examined the effects of removing these protective groups. The results showed that the amino acid derivatives have better solubility and nitrite-clearing ability than ARG. Among the compounds tested, the amino acid derivatives without protective group were the best. Based on these results, ARG and its two amino acid derivatives without protective group (ARG8, ARG10) were selected to evaluate their anti-tumor activity in vivo at a dosage of 40 mg/kg. The results indicated that ARG8 and ARG10 both exhibit more anti-tumor activity than ARG in H 22 tumor-bearing mice. The tumor inhibition rates of ARG8 and ARG10 were 69.27 and 43.58%, which was much higher than ARG. Furthermore, the mice treated with these compounds exhibited less damage to the liver, kidney and immune organs compared with the positive group. Furthermore, ARG8 and ARG10 improved the serum cytokine levels significantly compared to ARG. In brief, this study provides a method to improve the water solubility of drugs, and we also provide a reference basis for new drug development.

Oleanolic Acid-amino Acids Derivatives: Design, Synthesis, and Hepatoprotective Evaluation In Vitro and In Vivo

“…After introducing different amino acids in the 3-hydroxyl of OA using the ester condensation reaction, the ClogP of the derivatives reduced to a certain degree, which of glycine, alanine, and lysine conjugates was most significant. It was also in line with the theory of drug design and our previous reports, as well as others [ 22 , 23 , 24 , 25 ]. More importantly, most of the derivatives had some alkalinity with different cell inhibitory activities.…”

“…Amino acids are the most basic material composed of proteins in organisms and related to life activities. When amino acids or peptides were introduced into the structure of the active ingredients from traditional Chinese medicine, it could improve the hydrophilicity, increase the bioactivity, and mitigate the adverse reaction significantly [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. In our previous study, different polarity amino acids or dipeptides were introduced into 3-hydroxyl o Oleanolic acid-ligustrazine derivative (TOA) and Betulinic acid-ligustrazine derivative (TBA), the anticancer lead compound [ 28 , 29 , 30 ].…”

Experimental study of the anti-tumour activity and pharmacokinetics of arctigenin and its valine ester derivative

“…Previous studies in our laboratory have shown that ARG-V has better solubility and nitrite removal activity than ARG 28 . On this basis, their pharmacological activities and their impact on immune function were compared in H 22 tumour-bearing mice.…”

“…Our team has studied the nitrate scavenging activity of ARG and ARG-V using diazo coupling spectrophotometric method 28 .…”

Application of Amino Acids in the Structural Modification of Natural Products: A Review

“…Cai et al ( 2016 ) synthesized a series of ARG amino acid derivatives, all of which have better solubility and nitrite elimination ability than those of ARG. This compound and its two amino acid derivatives without a Boc protection group ( 22 , 23 ) were selected for in vivo antitumor activity evaluation.…”